Sherian Xu Li

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

Incidence of Dravet Syndrome in a US Population.

OBJECTIVE: De novo mutations of the gene sodium channel 1α (SCN1A) are the major cause of Dravet syndrome, an infantile epileptic encephalopathy. US incidence of DS has been estimated at 1 in 40 000, but no US epidemiologic studies have been performed since the advent of genetic testing. METHODS: In a retrospective, population-based cohort of all infants born at Kaiser Permanente Northern California during 2007–2010, we electronically identified patients who received ≥2 seizure diagnoses before age 12 months and who were also prescribed anticonvulsants at 24 months. A child neurologist reviewed records to identify infants who met 4 of 5 criteria for clinical Dravet syndrome: normal development before seizure onset; ≥2 seizures before age 12 months; myoclonic, hemiclonic, or generalized tonic-clonic seizures; ≥2 seizures lasting >10 minutes; and refractory seizures after age 2 years. SCN1A gene sequencing was performed as part of routine clinical care. RESULTS: Eight infants met the study criteria for clinical Dravet syndrome, yielding an incidence of 1 per 15 700. Six of these infants (incidence of 1 per 20 900) had a de novo SCN1A missense mutation that is likely to be pathogenic. One infant had an inherited SCN1A variant that is unlikely to be pathogenic. All 8 experienced febrile seizures, and 6 had prolonged seizures lasting >10 minutes by age 1 year. CONCLUSIONS: Dravet syndrome due to an SCN1A mutation is twice as common in the United States as previously thought. Genetic testing should be considered in children with ≥2 prolonged febrile seizures by 1 year of age.

Persistent recurring wheezing in the fifth year of life after laboratory-confirmed, medically attended respiratory syncytial virus infection in infancy

BackgroundRespiratory syncytial virus (RSV) infection in infancy is associated with subsequent recurrent wheezing.MethodsA retrospective cohort study examined children born at ≥32 weeks gestation between 1996–2004. All children were enrolled in an integrated health care delivery system in Northern California and were followed through the fifth year of life. The primary endpoint was recurrent wheezing in the fifth year of life and its association with laboratory-confirmed, medically-attended RSV infection during the first year, prematurity, and supplemental oxygen during birth hospitalization. Other outcomes measured were recurrent wheezing quantified through outpatient visits, inpatient hospital stays, and asthma prescriptions.ResultsThe study sample included 72,602 children. The rate of recurrent wheezing in the second year was 5.6% and fell to 4.7% by the fifth year. Recurrent wheezing rates varied by risk status: the rate was 12.5% among infants with RSV hospitalization, 8% among infants 32–33 weeks gestation, and 18% in infants with bronchopulmonary dysplasia. In multivariate analyses, increasing severity of respiratory syncytial virus infection was significantly associated with recurrent wheezing in year 5; compared with children without RSV infection in infancy, children who only had an outpatient RSV encounter had an adjusted odds ratio of 1.38 (95% CI,1.03–1.85), while children with a prolonged RSV hospitalization had an adjusted odds ratio of 2.59 (95% CI, 1.49–4.50).ConclusionsLaboratory-confirmed, medically attended RSV infection, prematurity, and neonatal exposure to supplemental oxygen have independent associations with development of recurrent wheezing in the fifth year of life.

Relative Importance and Additive Effects of Maternal and Infant Risk Factors on Childhood Asthma.

Background Environmental exposures that occur in utero and during early life may contribute to the development of childhood asthma through alteration of the human microbiome. The objectives of this study were to estimate the cumulative effect and relative importance of environmental exposures on the risk of childhood asthma. Methods We conducted a population-based birth cohort study of mother-child dyads who were born between 1995 and 2003 and were continuously enrolled in the PRIMA (Prevention of RSV: Impact on Morbidity and Asthma) cohort. The individual and cumulative impact of maternal urinary tract infections (UTI) during pregnancy, maternal colonization with group B streptococcus (GBS), mode of delivery, infant antibiotic use, and older siblings at home, on the risk of childhood asthma were estimated using logistic regression. Dose-response effect on childhood asthma risk was assessed for continuous risk factors: number of maternal UTIs during pregnancy, courses of infant antibiotics, and number of older siblings at home. We further assessed and compared the relative importance of these exposures on the asthma risk. In a subgroup of children for whom maternal antibiotic use during pregnancy information was available, the effect of maternal antibiotic use on the risk of childhood asthma was estimated. Results Among 136,098 singleton birth infants, 13.29% developed asthma. In both univariate and adjusted analyses, maternal UTI during pregnancy (odds ratio [OR] 1.2, 95% confidence interval [CI] 1.18, 1.25; adjusted OR [AOR] 1.04, 95%CI 1.02, 1.07 for every additional UTI) and infant antibiotic use (OR 1.21, 95%CI 1.20, 1.22; AOR 1.16, 95%CI 1.15, 1.17 for every additional course) were associated with an increased risk of childhood asthma, while having older siblings at home (OR 0.92, 95%CI 0.91, 0.93; AOR 0.85, 95%CI 0.84, 0.87 for each additional sibling) was associated with a decreased risk of childhood asthma, in a dose-dependent manner. Compared with vaginal delivery, C-section delivery increased odds of childhood asthma by 34% (OR 1.34, 95%CI 1.29, 1.39) in the univariate analysis and 11% after adjusting for other environmental exposures and covariates (AOR 1.11, 95%CI 1.06, 1.15). Maternal GBS was associated with a significant increased risk of childhood asthma in the univariate analysis (OR 1.27, 95%CI 1.19, 1.35), but not in the adjusted analysis (AOR 1.03, 95%CI 0.96, 1.10). In the subgroup analysis of children whose maternal antibiotic use information was available, maternal antibiotic use was associated with an increased risk of childhood asthma in a similar dose-dependent manner in the univariate and adjusted analyses (OR 1.13, 95%CI 1.12, 1.15; AOR 1.06, 95%CI 1.05, 1.08 for every additional course). Compared with infants with the lowest number of exposures (no UTI during pregnancy, vaginal delivery, at least five older siblings at home, no antibiotics during infancy), infants with the highest number of exposures (at least three UTIs during pregnancy, C-section delivery, no older siblings, eight or more courses of antibiotics during infancy) had a 7.77 fold increased odds of developing asthma (AOR: 7.77, 95%CI: 6.25, 9.65). Lastly, infant antibiotic use had the greatest impact on asthma risk compared with maternal UTI during pregnancy, mode of delivery and having older siblings at home. Conclusion Early-life exposures, maternal UTI during pregnancy (maternal antibiotic use), mode of delivery, infant antibiotic use, and having older siblings at home, are associated with an increased risk of childhood asthma in a cumulative manner, and for those continuous variables, a dose-dependent relationship. Compared with in utero exposures, exposures occurring during infancy have a greater impact on the risk of developing childhood asthma.

Frequency, duration and predictors of bronchiolitis episodes of care among infants ≥32 weeks gestation in a large integrated healthcare system: a retrospective cohort study.

BackgroundBronchiolitis is common in the first two years of life and is the most frequent cause of hospitalization in this age group. No previous studies have used an episode-of-care analysis to describe the frequency, duration, and predictors of bronchiolitis episodes of care during the first two years.MethodsWe conducted a retrospective cohort study of 123,264 infants ≥32 weeks gestation born at 6 Northern California Kaiser Permanente hospitals between 1996 and 2002. We used electronic medical records to concatenate hospital, emergency department and outpatient health care encounters for bronchiolitis into discrete episodes of care. We used descriptive statistics to report frequency and duration of bronchiolitis episodes and used logistic regression to assess the effect of gestational age and other clinical and demographic predictors on the outcome of bronchiolitis episodes.ResultsAmong all infants, the rate of bronchiolitis episodes was 162 per 1000 children during the first 2 years of life; approximately 40% required >1 day of medical attention with a mean duration of 7.0 ± 5.9 days. Prematurity was associated with increased risk of bronchiolitis episodes and longer duration. Bronchiolitis episodes rates per 1000 infants were 246 for 32–33 weeks gestational age, 204 for 34–36 weeks, and 148–178 for >36 weeks. Male gender, African-American and Hispanic race/ethnicity, and parental history of asthma were associated with an increased risk of having a bronchiolitis episode and/or longer duration.ConclusionsBronchiolitis episodes of care are frequent during the first two years of life and the duration ranges from 1 to 27 days. Prematurity was associated with more frequent and longer duration of bronchiolitis episodes of care, which may reflect illness severity and/or perceived vulnerability.

Respiratory syncytial virus immunoprophylaxis in high-risk infants and development of childhood asthma.

Background: Respiratory syncytial virus (RSV) lower respiratory tract infection is implicated in asthma development. RSV immunoprophylaxis during infancy is efficacious in preventing RSV‐related hospitalizations and has been associated with decreased wheezing in the first years of life. Objective: We investigated whether greater adherence to immunoprophylaxis in infants at high risk for severe RSV would be associated with decreased childhood asthma. Methods: We conducted a retrospective cohort investigation including children born from 1996‐2003 who were enrolled in Kaiser Permanente Northern California or Tennessee Medicaid and eligible to receive RSV immunoprophylaxis. Asthma was defined at 4.5 to 6 years of age by using asthma‐specific health care visits and medication fills. We classified children into immunoprophylaxis eligibility groups and calculated adherence (percentage receipt of recommended doses). We used a set of statistical strategies (multivariable logistic regression and propensity score [PS]–adjusted and PS‐matched analyses) to overcome confounding by medical complexity because infants with higher adherence (≥70%) have higher prevalence of chronic lung disease, lower birth weight, and longer nursery stays. Results: By using multivariable logistic regression and PS‐adjusted models in the combined group, higher adherence to RSV immunoprophylaxis was not associated with decreased asthma. However, in PS‐matched analysis, treated children with 70% or greater adherence had decreased odds of asthma compared with those with 20% or less adherence (odds ratio, 0.62; 95% CI, 0.50‐0.78). Conclusions: This investigation of RSV immunoprophylaxis in high‐risk children primarily found nonsignificant associations on prevention of asthma in specific preterm groups. Our findings highlight the need for larger studies and prospective cohorts and provide estimates of potential preventive effect sizes in high‐risk children.

Adherence to Immunoprophylaxis Regimens for Respiratory Syncytial Virus Infection in Insured and Medicaid Populations

BACKGROUND Immunoprophylaxis is the only pharmaceutical intervention for mitigating respiratory syncytial virus (RSV) infection. Patient level data on adherence to American Academy of Pediatrics (AAP) immunoprophylaxis recommendations are limited. This study characterizes adherence to AAP guidelines in privately insured and Medicaid populations. METHODS We performed a retrospective birth cohort study of 211 174 privately insured children in Northern California; and 458 837 publicly insured children in Tennessee born between January 1, 1996 and December 31, 2008. Adherence to the AAP guideline was defined for eligible infants as the number of doses of RSV immunoprophylaxis administered over the number recommended for 4 mutually exclusive eligibility groups: chronic lung disease, prematurity <29 weeks, prematurity <32 weeks, and other eligibility. RESULTS We identified 3456 California (Kaiser Permanente Northern California [KPNC]) and 12 251 Tennessee (Tennessee Medicaid [TennCare]) infants meeting AAP eligibility criteria. Immunoprophylaxis administration increased over the study period, from 15% for all eligible groups in 1998 to 54% in 2007. Adherence was highest among babies with chronic lung disease (KPNC 67% and TennCare 55%). Nonadherence (0% adherence) was greatest among infants of African American mothers (adjusted odds ratio [AOR] = 1.32; 95% confidence interval [CI] = .98-1.78); those with mothers with less than a high school education (AOR = 1.58; CI = 1.09-2.30) in KPNC; and in infants of Hispanic mothers in TennCare (AOR = 1.65; CI = 1.24-2.20). In KPNC, 0.11% of ineligible term infants and 5% of ineligible premature infants received immunoprophylaxis; the corresponding proportions in TennCare were 1% and 11%. CONCLUSIONS Overall adherence with AAP guidelines has increased over time. Considerable overuse and underuse of immunoprophylaxis are evident with identifiable risk groups to target for improvement.

Utilization of Health Services Among Adults With Recurrent Clostridium difficile Infection: A 12-Year Population-Based Study.

BACKGROUND Considerable efforts have been dedicated to developing strategies to prevent and treat recurrent Clostridium difficile infection (rCDI); however, evidence of the impact of rCDI on patient healthcare utilization and outcomes is limited. OBJECTIVE To compare healthcare utilization and 1-year mortality among adults who had rCDI, nonrecurrent CDI, or no CDI. METHODS We performed a nested case-control study among adult Kaiser Foundation Health Plan members from September 1, 2001, through December 31, 2013. We identified CDI through the presence of a positive laboratory test result and divided patients into 3 groups: patients with rCDI, defined as CDI in the 14-57 days after initial CDI; patients with nonrecurrent CDI; and patients who never had CDI. We conducted 3 matched comparisons: (1) rCDI vs no CDI; (2) rCDI vs nonrecurrent CDI; (3) nonrecurrent CDI vs no CDI. We followed patients for 1 year and compared healthcare utilization between groups, after matching patients on age, sex, and comorbidity. RESULTS We found that patients with rCDI consistently have substantially higher levels of healthcare utilization in various settings and greater 1-year mortality risk than both patients who had nonrecurrent CDI and patients who never had CDI. CONCLUSIONS Patients who develop an initial CDI are generally characterized by excess underlying, severe illness and utilization. However, patients with rCDI experience even greater adverse consequences of their disease than patients who do not experience rCDI. Our results further support the need for continued emphasis on identifying and using novel approaches to prevent and treat rCDI. Infect Control Hosp Epidemiol. 2016;1-8.