Pingsheng Wu

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.

Evidence for a causal relationship between respiratory syncytial virus infection and asthma

Respiratory syncytial virus (RSV) infects all children early in life, is the most common cause of infant lower respiratory tract infections, and causes disease exacerbations in children with asthma. Episodes of lower respiratory tract infection in early life are associated with asthma development. Whether RSV infection early in life directly causes asthma or simply identifies infants who are genetically predisposed to develop subsequent wheezing is debatable. Recent studies suggest that these two explanations are not mutually exclusive, and are likely both important in asthma development. An open-label study of RSV immunoprophylaxis administered to preterm infants reduced recurrent wheezing by 50%. Clinical trials of infant RSV prevention, delay or severity reduction on the outcome of childhood asthma would confirm the causal relationship between RSV infection and asthma, and offer a primary prevention strategy.

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.

Maternal antidepressant use and adverse outcomes: a cohort study of 228,876 pregnancies

OBJECTIVE The purpose of this study was to describe antidepressant medication use patterns during pregnancy and pregnancy outcomes. STUDY DESIGN We evaluated a cohort of 228,876 singleton pregnancies that were covered by Tennessee Medicaid, 1995-2007. RESULTS Of 23,280 pregnant women with antidepressant prescriptions before pregnancy, 75% of them filled none in the second or third trimesters of pregnancy, and 10.7% of them used antidepressants throughout pregnancy. Filling 1, 2, and ≥3 antidepressant prescriptions during the second trimester was associated with shortened gestational age by 1.7 (95% confidence interval [CI], 1.2-2.3), 3.7 (95% CI, 2.8-4.6), and 4.9 (95% CI, 3.9-5.8) days, when controlled for measured confounders. Third-trimester selective serotonin reuptake inhibitor use was associated with infant convulsions; adjusted odds ratios were 1.4 (95% CI, 0.7-2.8); 2.8 (95% CI, 1.9-5.5); and 4.9 (95% CI, 2.6-9.5) for filling 1, 2, and ≥3 prescriptions, respectively. CONCLUSION Most women discontinue antidepressant medications before or during the first trimester of pregnancy. Second-trimester antidepressant use is associated with preterm birth, and third-trimester selective serotonin reuptake inhibitor use is associated with infant convulsions.

The Effect of Resistance Exercise to Augment Long-term Benefits of Intradialytic Oral Nutritional Supplementation in Chronic Hemodialysis Patients

BACKGROUND Resistance exercise combined with intradialytic oral nutrition (IDON) supplementation improves net protein balance in the acute setting in chronic hemodialysis patients. We hypothesized that combination of long-term resistance exercise and IDON would improve markers of muscle mass and strength further compared with IDON alone. METHODS Thirty-two participants (21 male; mean age, 43 ± 13 years) on chronic hemodialysis were randomly assigned to IDON plus resistance exercise (NS + EX), or IDON (NS) alone for 6 months. IDON consisted of a lactose-free formula consisting of protein, carbohydrate, and fat. Three sets of 12 repetitions of leg-press were completed before each dialysis session in the NS + EX arm. Primary outcome measurement was lean body mass. Muscle strength and other nutritional parameters were measured as secondary outcomes. RESULTS Of 32 participants, 22 completed the 6-month intervention. There were no statistically significant differences between the study interventions with respect to changes in lean body mass and body weight, when comparing NS + EX to NS. There were also no statistically significant differences in any of the secondary outcomes measured in the study. Body weight (80.3 ± 16.6 kg, 81.1 ± 17.5 kg, and 80.9 ± 18.2 kg at baseline, month 3, and month 6, respectively; P = .02) and 1-repetition maximum (468 ± 148 lb, 535 ± 144 lb, and 552 ± 142 lb, respectively; P = .001) increased statistically significantly during the study for all patients combined. CONCLUSION This study did not show further benefits of additional resistance exercise on long-term somatic protein accretion above and beyond nutritional supplementation alone. When both treatments groups were combined, body weight and muscle strength improved during the study.

Angiotensin II and Aldosterone stimulating NF-κB and AP-1 activation in hepatic fibrosis of rat

BACKGROUND/AIMS Intrahepatic renin-angiotensin-aldosterone system (RAAS) plays a key role in the fibrogenesis of liver. However, the signal transduction mechanism underlying effects of Angiotensin II (Ang II) and Aldosterone (Aldo) on Nuclear Factor-kappaB (NF-kappaB) and active protein-1 (AP-1) pathway in hepatic fibrogenesis remains to be fully elucidated. The present study aims to investigate the signal transduction mechanism underlying effects of Ang II and Aldo on NF-kappaB and AP-1 pathway during hepatic fibrogenesis. METHODS To assess the effect of AECI and Angiotensin II type 1 receptor (AT-1 receptor) blocker on NF-kappaB activity in liver, a model of fibrosis was performed in rat. In vitro, hepatic stellate cells (HSCs)-T6 cells were preincubated for 1 h or not with U0126, a specific inhibitor of extracellular signal regulated kinase (ERK), irbesartan, and N-acetylcysteine prior to exposure to Ang II or Aldo for the indicated times. DNA binding activity of NF-kappaB and AP-1 were analyzed by Electrophoretic mobility shift assay (EMSA). Western blot was used to detect expression of IkappaBalpha and Phospho-P42/44. RT-PCR was used to detect the expressions of tumor necrosis factor alpha (TNFalpha) mRNA and alpha1 (I) procollagen mRNA. RESULTS AECI and AT-1 receptor blocker exert anti-fibrosis effect through inhibiting NF-kappaB activation in liver. Ang II and Aldo increase HSCs NF-kappaB activity and NF-kappaB target gene-TNFalpha expression by inhibiting IkappaBalpha expression in a redox-sensitive manner. Ang II and Aldo also markedly increase HSCs AP-1 activity and AP-1 target gene-alpha1 (I) procollagen mRNA expression via ERK1/2 pathway in a redox-sensitive manner. CONCLUSIONS These results show that stimulation of NF-kappaB and AP-1 pathway mediate hepatic fibrogenesis induced by intrahepatic RAAS.

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

Provision of Antioxidant Therapy in Hemodialysis (PATH): A Randomized Clinical Trial

Increased markers of oxidative stress and acute-phase inflammation are prevalent in patients undergoing maintenance hemodialysis therapy (MHD), and are associated with increased mortality and hospitalization rates and decreased erythropoietin responsiveness. No adequately powered studies have examined the efficacy of antioxidant therapies on markers of inflammation and oxidative stress. We tested the hypothesis that oral antioxidant therapy over 6 months would decrease selected biomarkers of acute-phase inflammation and oxidative stress and improve erythropoietic response in prevalent MHD patients. In total, 353 patients were enrolled in a prospective, placebo-controlled, double-blind clinical trial and randomly assigned to receive a combination of mixed tocopherols (666 IU/d) plus α-lipoic acid (ALA; 600 mg/d) or matching placebos for 6 months (NCT00237718); 238 patients completed the study. High-sensitivity C-reactive protein (hsCRP) and IL-6 concentration were measured as biomarkers of systemic inflammation, and F2 isoprostanes and isofurans were measured as biomarkers of oxidative stress. The groups did not significantly differ at baseline. At 3 and 6 months, the treatment had no significant effect on plasma hsCRP, IL-6, F2 isoprostane, or isofuran concentrations and did not improve the erythropoietic response. No major adverse events were related to the study drug, and both groups had similar mortality and hospitalization rates during the study. In conclusion, the administration of mixed tocopherols and ALA was generally safe and well tolerated, but did not influence biomarkers of inflammation and oxidative stress or the erythropoietic response.