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1.  Specific Patterns of Allergic Sensitization in Early Childhood and Asthma & Rhinitis Risk 
BACKGROUND
Specific patterns of allergic sensitization as well as quantification of the in vitro IgE response in early life may provide relevant clinical insight into future rhinitis and asthma risk.
OBJECTIVE
To define relationships among established sensitization to particular aeroallergens, quantitative analyses of allergen-specific IgE levels, pet exposure and sensitization, and asthma and rhinitis risk.
METHODS
Children at high-risk for the development of asthma and allergic diseases were enrolled at birth into the Childhood Origins of ASThma (COAST) study. Allergen-specific IgE was assessed at ages 1, 3, 6, and 9 years by fluoroenzyme immunoassay (Unicap® 100, Pharmacia Diagnostics). Current asthma and rhinitis were diagnosed at age 6 and 8 years.
RESULTS
Sensitization to dog was strongly associated with increased asthma risk (p < 0.0001). Sensitization to perennial compared to seasonal allergens was more strongly associated with asthma risk, while sensitization to seasonal allergens was more closely associated with rhinitis risk. Increased levels of specific IgE to perennial allergens were associated with an increased asthma risk (p = 0.05), while any detectable level of IgE to seasonal allergens was associated with increased rhinitis risk (p = 0.0009). While dog and cat sensitization were both independently associated with increased asthma and rhinitis risk, dog exposure at birth was associated with a reduced risk of asthma, regardless of dog sensitization status during the first 6 years of life (p = 0.05).
CONCLUSIONS & CLINICAL RELEVANCE
Analyzing specific patterns of an individual’s allergic sensitization profile reveals additional relevant associations with asthma and rhinitis risk as opposed to the information gained from characterizing an individual as “atopic” by the presence of any demonstrable sensitization alone. Further, protective mechanisms of dog exposure with regards to asthma risk appear to be unrelated to the prevention of sensitization.
doi:10.1111/cea.12050
PMCID: PMC3557802  PMID: 23331564
asthma; rhinitis; children; IgE; allergic sensitization; pet exposure
2.  Infections and Their Role in Childhood Asthma Inception 
Summary
The association of early onset wheezing with common viral and bacterial infections has raised significant interest in the role of infections in childhood asthma inception. This article serves to review these relationships among infections, host factors, and asthma inception in childhood.
doi:10.1111/pai.12147
PMCID: PMC3977202  PMID: 24236893
inception; asthma; infection; wheezing; virus; childhood; genetics
3.  Genome Sequences of Rhinovirus A Isolates from Wisconsin Pediatric Respiratory Studies 
Genome Announcements  2014;2(2):e00200-14.
Full-length or nearly full-length RNA genome sequences for 98 rhinovirus (RV) A isolates (from the Enterovirus genus of the Picornaviridae family), representing 43 different genotypes, were resolved as part of ongoing studies to define RV genetic diversity and its potential link to respiratory disease.
doi:10.1128/genomeA.00200-14
PMCID: PMC3968333  PMID: 24675855
4.  Genome Sequences of Rhinovirus B Isolates from Wisconsin Pediatric Respiratory Studies 
Genome Announcements  2014;2(2):e00202-14.
Nearly full-length RNA genome sequences for 39 rhinovirus B isolates (RV-B), representing 13 different genotypes, were resolved as part of ongoing studies at the University of Wisconsin that attempt to link rhinovirus (RV) diversity and respiratory disease in infants.
doi:10.1128/genomeA.00202-14
PMCID: PMC3968335  PMID: 24675857
5.  Genome Sequences of Rhinovirus C Isolates from Wisconsin Pediatric Respiratory Studies 
Genome Announcements  2014;2(2):e00203-14.
Human rhinovirus (RV) isolates from the RV-C species are recently discovered infectious agents that are closely linked to asthma and wheezing etiologies in infants. Clinical study samples collected at the University of Wisconsin–Madison describe 41 nearly complete genome sequences representing 21 RV-C genotypes.
doi:10.1128/genomeA.00203-14
PMCID: PMC3968336  PMID: 24675858
6.  Evaluation of the Modified Asthma Predictive Index in High-Risk Preschool Children 
The journal of allergy and clinical immunology in practice  2012;1(2):10.1016/j.jaip.2012.10.008.
BACKGROUND
Prediction of subsequent school-age asthma during the preschool years has proven challenging.
OBJECTIVE
To confirm in a post hoc analysis the predictive ability of the modified Asthma Predictive Index (mAPI) in a high-risk cohort and a theoretical unselected population. We also tested a potential mAPI modification with a 2-wheezing episode requirement (m2API) in the same populations.
METHODS
Subjects (n = 289) with a family history of allergy and/or asthma were used to predict asthma at age 6, 8, and 11 years with the use of characteristics collected during the first 3 years of life. The mAPI and the m2API were tested for predictive value.
RESULTS
For the mAPI and m2API, school-age asthma prediction improved from 1 to 3 years of age. The mAPI had high predictive value after a positive test (positive likelihood ratio ranging from 4.9 to 55) for asthma development at years 6, 8, and 11. Lowering the number of wheezing episodes to 2 (m2API) lowered the predictive value after a positive test (positive likelihood ratio ranging from 1.91 to 13.1) without meaningfully improving the predictive value of a negative test. Posttest probabilities for a positive mAPI reached 72% and 90% in unselected and high-risk populations, respectively.
CONCLUSIONS
In a high-risk cohort, a positive mAPI greatly increased future asthma probability (eg, 30% pretest probability to 90% posttest probability) and is a preferred predictive test to the m2API. With its more favorable positive posttest probability, the mAPI can aid clinical decision making in assessing future asthma risk for preschool-age children.
doi:10.1016/j.jaip.2012.10.008
PMCID: PMC3811153  PMID: 24187656
Asthma; Wheezing; Children; Asthma predictive index; Modified asthma predictive index
7.  Pulmonary 3He Magnetic Resonance Imaging of Childhood Asthma 
Background
Magnetic resonance imaging (MRI) with 3He does not require ionizing radiation and has been shown to detect regional abnormalities in lung ventilation and structure in adult asthma, but the method has not been extended to childhood asthma. Measurements of regional lung ventilation and microstructure in childhood asthma could advance our understanding of disease mechanisms.
Objective
To determine whether 3He MRI in children can identify abnormalities related to diagnosis of asthma or prior history of respiratory illness.
Methods
Forty-four children aged 9-10 years were recruited from a birth cohort at increased risk of developing asthma and allergic diseases. For each subject a time-resolved three-dimensional (3D) image series and a 3D diffusion-weighted image were acquired in separate breathing maneuvers. The number and size of ventilation defects were scored, and regional maps and statistics of average 3He diffusion length were calculated.
Results
Children with mild to moderate asthma had lower average diffusion length, Xrms¯ (p=0.004), increased regional standard deviation of diffusion length (p=0.03), and higher defect scores (p=0.03) than those without asthma. Children with histories of wheezing illness with rhinovirus infection prior to the third birthday had lower Xrms¯ (p=0.01) and higher defect score (p=0.05).
Conclusion
MRI with 3He detected more and larger regions of ventilation defect and a greater degree of restricted gas diffusion in children with asthma compared to those without asthma. These measures are consistent with regional obstruction and smaller and more regionally variable dimensions of the peripheral airways and alveolar spaces.
doi:10.1016/j.jaci.2012.10.032
PMCID: PMC3563846  PMID: 23246019
asthma; pediatric; hyperpolarized MRI; apparent diffusion coefficient
9.  Comparison of the Etiology of Viral Respiratory Illnesses in Inner-City and Suburban Infants 
The Journal of Infectious Diseases  2012;206(9):1342-1349.
Background. The risk of developing childhood asthma has been linked to the severity and etiology of viral respiratory illnesses in early childhood. Since inner-city infants have unique environmental exposures, we hypothesized that patterns of respiratory viral infections would also be distinct.
Methods. We compared the viral etiology of respiratory illnesses in 2 groups: a cohort of 515 infants from 4 inner-city areas and a cohort of 285 infants from mainly suburban Madison, Wisconsin. Nasal secretions were sampled during periods of respiratory illness and at 1 year of age and were analyzed for viral pathogens by multiplex polymerase chain reaction.
Results. Overall, inner-city infants had lower rates of viral detection. Considering specific viruses, sick urban infants had lower rates of detectable rhinovirus or respiratory syncytial virus infection and higher rates of adenovirus infection. Every urban site had a higher proportion of adenovirus-positive samples associated with illnesses (10%–21%), compared with Madison (6%).
Conclusions. These findings provide evidence that inner-city babies have different patterns of viral respiratory illnesses than babies who grow up in a more suburban location. These findings raise important questions about the etiology of virus-negative illnesses in urban infants and the possibility of long-term consequences of early life infections with adenovirus in this population.
doi:10.1093/infdis/jis504
PMCID: PMC3466995  PMID: 23014674
10.  Human Rhinovirus Species and Season of Infection Determine Illness Severity 
Rationale: Human rhinoviruses (HRVs) consist of approximately 160 types that cause a wide range of clinical outcomes, including asymptomatic infections, common colds, and severe lower respiratory illnesses.
Objectives: To identify factors that influence the severity of HRV illnesses.
Methods: HRV species and types were determined in 1,445 nasal lavages that were prospectively collected from 209 infants participating in a birth cohort who had at least one HRV infection. Questionnaires were used during each illness to identify moderate to severe illnesses (MSI).
Measurements and Main Results: Altogether, 670 HRV infections were identified, and 519 of them were solitary infections (only one HRV type). These 519 viruses belonged to 93 different types of three species: 49 A, 9 B, and 35 C types. HRV-A (odds ratio, 8.2) and HRV-C (odds ratio, 7.6) were more likely to cause MSI compared with HRV-B. In addition, HRV infections were 5- to 10-fold more likely to cause MSI in the winter months (P < 0.0001) compared with summer, in contrast to peak seasonal prevalence in spring and fall. When significant differences in host susceptibility to MSI (P = 0.004) were considered, strain-specific rates of HRV MSI ranged from less than 1% to more than 20%.
Conclusions: Factors related to HRV species and type, season, and host susceptibility determine the risk of more severe HRV illness in infancy. These findings suggest that anti-HRV strategies should focus on HRV-A and -C species and identify the need for additional studies to determine mechanisms for seasonal increases of HRV severity, independent of viral prevalence, in cold weather months.
doi:10.1164/rccm.201202-0330OC
PMCID: PMC3530215  PMID: 22923659
rhinovirus; severe illness; species; type; seasonality
11.  Rhinovirus Wheezing Illness and Genetic Risk of Childhood-Onset Asthma 
The New England journal of medicine  2013;368(15):1398-1407.
BACKGROUND
Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts.
METHODS
We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. Finally, we examined genotype-specific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs).
RESULTS
The 17q21 variants were associated with HRV wheezing illnesses in early life, but not with RSV wheezing illnesses. The associations of 17q21 variants with asthma were restricted to children who had had HRV wheezing illnesses, resulting in a significant interaction effect with respect to the risk of asthma. Moreover, the expression levels of ORMDL3 and of GSDMB were significantly increased in HRV-stimulated PBMCs, as compared with unstimulated PBMCs. The expression of these genes was associated with 17q21 variants in both conditions, although the increase with exposure to HRV was not genotype-specific.
CONCLUSIONS
Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses and with expression of two genes at this locus. The expression levels of both genes increased in response to HRV stimulation, although the relative increase was not associated with the 17q21 genotypes. (Funded by the National Institutes of Health.)
doi:10.1056/NEJMoa1211592
PMCID: PMC3755952  PMID: 23534543
12.  Innate Immune Responses to Rhinovirus are Reduced by the High-Affinity IgE Receptor in Allergic Asthmatic Children 
Background
Children with allergic asthma have more frequent and severe human rhinovirus (HRV)-induced wheezing and asthma exacerbations through unclear mechanisms.
Objective
To determine whether increased high-affinity IgE receptor (FcεRI) expression and cross-linking impairs innate immune responses to HRV, particularly in allergic asthmatic children.
Methods
Peripheral blood mononuclear cells (PBMC) were obtained from 44 children and surface expression of FcεRI on plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), monocytes, and basophils was assessed using flow cytometry. Cells were also incubated with rabbit anti-human IgE to cross-link FcεRI, followed by stimulation with HRV-16, and interferon (IFN)-α and -λ1 were measured by Luminex. The relationships among FcεRI expression and cross-linking, HRV-induced IFN-α and -λ1 production, and childhood allergy and asthma were subsequently analyzed.
Results
FcεRIα expression on pDCs was inversely associated with HRV-induced IFN- α and IFN-λ1 production. Cross-linking FcεRI prior to HRV stimulation further reduced PBMC IFN-α (47% relative reduction, 95% confidence interval [CI], 32–62%, p<0.0001) and IFN-λ1 (81% relative reduction, 95% CI, 69–93%, p<0.0001) secretion. Allergic asthmatic children had higher surface expression of FcεRIα on pDCs and mDCs when compared to non-allergic non-asthmatic children. Further, after FcεRI cross-linking, allergic asthmatic children had significantly lower HRV-induced IFN responses than allergic non-asthmatics (IFN-α, p=0.004; IFN-λ1, p=0.02) and non-allergic non-asthmatics (IFN-α, p=0.002; IFN-λ1, p=0.01).
Conclusions
Allergic asthmatic children have impaired innate immune responses to HRV that correlate with increased FcεRI expression on pDCs and are reduced by FcεRI cross-linking. These effects likely increase susceptibility to HRV-induced wheezing and asthma exacerbations.
doi:10.1016/j.jaci.2012.05.023
PMCID: PMC3437329  PMID: 22766097
asthma; allergic; rhinovirus; interferon; FcεRI; IgE receptor; plasmacytoid dendritic cells
13.  Protection from asthma in a high-risk birth cohort by attenuated P2X7 function 
Background
Viral illnesses are important factors in both asthma inception and exacerbations, and allergic sensitization in early life further enhances asthma risk through unclear mechanisms. Cellular damage due to infection or allergen inhalation increases ATP in the airways with subsequent purinergic receptor activation. The purinergic receptor P2X7 may enhance airway leukocyte recruitment to the airways and P2X7 knockout mice display a reduced asthma-like phenotype.
Objective
Based upon the P2X7 knockout mouse, we hypothesized that children with low functioning P2X7 would have decreased rates of asthma.
Methods
We utilized a functional assay to determine P2X7 pore-producing capacity in whole blood samples in a birth cohort study at high risk for asthma development. The P2X7 assay was validated with known loss-of-function alleles in humans. P2X7 pore status categorization was used to assess asthma and allergy status in the cohort.
Results
Attenuated P2X7 function was associated with lower asthma rates at ages 6 and 8 and the greatest effects were observed in boys. Children with asthma at age 11 who had low P2X7 capacity had less severe disease in the previous year. Attenuated P2X7 function was also associated with sensitization to fewer aeroallergens.
Conclusion
P2X7 functional capacity is associated with asthma risk or disease severity and these relationships appear to be age-related.
doi:10.1016/j.jaci.2012.05.040
PMCID: PMC3551624  PMID: 22743305
asthma; allergy; children; P2X7; ATP
14.  Key Observations from the NHLBI Asthma Clinical Research Network 
Thorax  2012;67(5):450-455.
The National Heart, Lung and Blood Institute (NHLBI) Asthma Clinical Research Network (ACRN) recently completed its work after 20 years of collaboration as a multicentre clinical trial network. When formed, its stated mission was to perform multiple controlled clinical trials for treating patients with asthma by dispassionately examining new and existing therapies, and to rapidly communicate its findings to the medical community. The ACRN conducted 15 major clinical trials. In addition, clinical data, manual of operations, protocols and template informed consents from all ACRN trials are available via NHLBI BioLINCC (https://biolincc.nhlbi.nih.gov/studies/). This network contributed major insights into the use of inhaled corticosteroids, short-acting and long-acting ß-adrenergic agonists, leukotriene receptor antagonists, and novel agents (tiotropium, colchicine and macrolide antibiotics). They also pioneered studies of the variability in drug response, predictors of treatment response and pharmacogenetics. This review highlights the major research observations from the ACRN that have impacted the current management of asthma.
doi:10.1136/thoraxjnl-2012-201876
PMCID: PMC3709602  PMID: 22514237
15.  Increased H1N1 Infection Rate in Children with Asthma 
Rationale: The 2009 H1N1 flu appeared to cause more severe cold symptoms during the 2009–2010 flu season.
Objectives: We evaluated H1N1 infections during peak viral season in children with and without asthma to determine whether the H1N1 infectivity rate and illness severity were greater in subjects with asthma.
Methods: One hundred and eighty children, 4–12 years of age, provided eight consecutive weekly nasal mucus samples from September 5 through October 24, 2009, and scored cold and asthma symptoms daily. Viral diagnostics were performed for all nasal samples.
Measurements and Main Results: One hundred and sixty-one children (95 with asthma, 66 without asthma) completed at least 6 of the 8 nasal samples. The incidence of H1N1 infection was significantly higher in children with asthma (41%) than in children without asthma (24%; odds ratio, 4; 95% confidence interval, 1.8–9; P < 0.001), but rates of human rhinovirus infection (90% each) and other viral infections (47 vs. 41%) were similar. In children with asthma, there was a nonsignificant trend for increased loss of asthma control during H1N1 infections compared with human rhinovirus infections (38 vs. 21%; odds ratio, 2.6; 95% confidence interval, 0.9–7.2; P = 0.07).
Conclusions: During peak 2009 H1N1 flu season, children with asthma were infected almost twice as often with H1N1 compared with other respiratory viruses. H1N1 infection also caused increased severity of cold symptoms compared with other viral infections. Given the increased susceptibility of children with asthma to infection, these findings reinforce the need for yearly influenza vaccination to prevent infection, and raise new questions about the mechanism for enhanced susceptibility to influenza infection in asthma.
doi:10.1164/rccm.201109-1635OC
PMCID: PMC3381233  PMID: 22366048
asthma; viral infection; influenza
16.  Recurrent Severe Exacerbations in Early Life and Reduced Lung Function at School Age 
Summary
Severe wheezing exacerbations during the preschool years, a critical time in lung growth and development, may lead to airway damage and remodeling. Our study linked these events to a partially reversible reduction in lung function present at school age.
doi:10.1016/j.jaci.2011.11.046
PMCID: PMC3319175  PMID: 22236729
exacerbation; lung function; childhood; wheezing; corticosteroids
17.  Asthma: Clinical Expression and Molecular Mechanisms 
The Journal of allergy and clinical immunology  2010;125(2 Suppl 2):S95-102.
Asthma is a heterogenous disorder that is characterized by variable airflow obstruction, airway inflammation and hyperresponsiveness, and reversibility either spontaneously or as a result of treatment. Multiple etiologies no doubt exist for both its inception and symptom exacerbation once the disease is established. Factors underlying inception can range from viral respiratory tract infections in infancy(1,2) to occupational exposures in adults.(3) Factors underlying asthma exacerbations include allergen exposure in sensitized individuals, viral infections, exercise, irritants, ingestion of nonsteroidal anti-inflammatory agents, among others. Exacerbating factors may include one or all of these exposures, and vary both among and within patients. Asthma treatment is determined to a large extent following an initial assessment of severity and subsequent establishment of control, both of which can be variable over time and assessed in two domains: impairment (current) and risk (long term consequences).(4) Unfortunately, despite the availability of effective therapies, suboptimal asthma control exists in many patients on a world-wide basis.(5) The future development of novel therapies and treatment paradigms should address these disparities.
doi:10.1016/j.jaci.2009.10.047
PMCID: PMC2853245  PMID: 20176271
Asthma; Respiratory syncytial virus; Rhinovirus; Allergen; Prevention; Exacerbation; Inception; Treatment
18.  Evidence for a Causal Relationship between Allergic Sensitization and Rhinovirus Wheezing in Early Life 
Rationale: Aeroallergen sensitization and virus-induced wheezing are risk factors for asthma development during early childhood, but the temporal developmental sequence between them is incompletely understood.
Objective: To define the developmental relationship between aeroallergen sensitization and virus-induced wheezing.
Methods: A total of 285 children at high risk for allergic disease and asthma were followed prospectively from birth. The timing and etiology of viral respiratory wheezing illnesses were determined, and aeroallergen sensitization was assessed annually for the first 6 years of life. The relationships between these events were assessed using a longitudinal multistate Markov model.
Measurements and Main Results: Children who were sensitized to aeroallergens had greater risk of developing viral wheeze than nonsensitized children (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.2–3.1). Allergic sensitization led to an increased risk of wheezing illnesses caused by human rhinovirus (HRV) but not respiratory syncytial virus. The absolute risk of sensitized children developing viral wheeze was greatest at 1 year of age; however, the relative risk was consistently increased at every age assessed. In contrast, viral wheeze did not lead to increased risk of subsequent allergic sensitization (HR, 0.76; 95% CI, 0.50–1.1).
Conclusions: Prospective, repeated characterization of a birth cohort demonstrated that allergic sensitization precedes HRV wheezing and that the converse is not true. This sequential relationship and the plausible mechanisms by which allergic sensitization can lead to more severe HRV-induced lower respiratory illnesses support a causal role for allergic sensitization in this developmental pathway. Therefore, therapeutics aimed at preventing allergic sensitization may modify virus-induced wheezing and the development of asthma.
doi:10.1164/rccm.201104-0660OC
PMCID: PMC3297109  PMID: 21960534
virus; wheezing; allergic sensitization; RSV; human rhinovirus
19.  IFNG genotype and sex interact to influence risk of childhood asthma 
Background
Asthma is a complex disease characterized by sex-specific differences in incidence, prevalence and severity, but little is known about the molecular basis of these sex differences. Objective: To investigate the genetic architecture of sex differences in asthma risk, we evaluated i) associations between polymorphisms in the interferon-gamma (IFNG) gene and childhood onset asthma in combined and sex-specific samples, and ii) interactions between polymorphisms and sex on asthma risk.
Methods
Main and sex-interaction effects of IFNG genetic diversity on asthma risk and IFN-γ levels were examined in a birth cohort of children at high risk for asthma and allergic diseases. Replication of the genetic association was assessed in an independent sample of asthma cases.
Results
Significant genotype-by-sex interactions on asthma were observed for two IFNG SNPs, rs2069727 and rs2430561, which were in strong linkage disequilibrium with each other. In contrast, none of the ten IFNG SNPs showed significant main effects on asthma. The observed genotype-by-sex interaction on asthma was characterized by non-additivity, i.e. heterozygote boys had the highest risk for asthma, while heterozygote girls had the lowest risk. The interaction effect was robust to other asthma risk factors but was limited to children who experienced wheezing illnesses with viral infections during the first three years of life. Genotype-by-sex interactions were also observed in IFN-γ response to LPS in the first year of life. Finally, the sex interaction effect was replicated in an independent population of childhood asthma cases.
Conclusions
These results provide insight into the genetic basis of sex differences in asthma and highlight the potential importance of interactions among sex, genotype, and environmental factors in asthma pathogenesis.
doi:10.1016/j.jaci.2011.06.016
PMCID: PMC3548570  PMID: 21798578
IFN-γ; asthma; children; sex differences; single nucleotide polymorphism; association study
20.  Asthma Therapies Revisited 
Asthma is a heterogenous disorder related to numerous biologic, immunologic, and physiologic components that generate multiple clinical phenotypes. Further, genetic and environmental factors interact in ways that produce variability in both disease onset and severity and differential expression based on both the age and sex of the patient. Thus, the natural history of asthma is complex in terms of disease expression, remission, relapse, and progression. As such, therapy for asthma is complicated and has been approached from the standpoints of primary, secondary, and tertiary prevention. Presently, asthma cannot be cured but can be controlled in most patients, an indication that most of the success clinical research strategies have realized has been in the area of tertiary prevention. Since for many adult patients with asthma their disease had its roots in early life, much recent research has focused on events during early childhood that can be linked to subsequent asthma development with the hopes of creating appropriate interventions to alter its natural history of expression. These research approaches can be categorized into three questions. Who is the right patient to treat? When is the right time to begin treatment? And finally, what is the appropriate treatment to prescribe?
doi:10.1513/pats.200806-055RM
PMCID: PMC2677407  PMID: 19387036
asthma; therapy; inhaled corticosteroids; β-agonists
21.  Approaches to Stepping-Up and Stepping-Down Care in Asthma 
The variability in symptom control is a challenging feature of asthma that necessitates careful monitoring and the need to step-up and step-down individualized therapeutic regimens over time. This stepwise concept in asthma therapy can be considered in at least three contexts. For lack of control that is persistent over long periods of time, an increase in the overall medication or a “step-up long-term (SLT)” is indicated. A second approach, “step-up short-term (SST)”, may be utilized during a temporary loss of acceptable control, such as at the onset of a viral respiratory tract illness. In these cases, a step-up in therapy is usually terminated in 3–10 days once asthma control has been satisfactorily achieved. Finally, for treating symptoms related to the variability of asthma on a day to day basis, ICS used concomitantly with a beta agonist has been evaluated, though not currently approved in the United States. We will term this particular intervention as “step-up intermittent (SUI).” Here we summarize the existing data regarding these three approaches to step-up care, step-down management, as well as identify areas where more comparative studies are necessary to provide further guidance to clinicians regarding proper step-up and step-down strategies in the care of asthma.
doi:10.1016/j.jaci.2011.07.014
PMCID: PMC3205296  PMID: 21855125
asthma; step-up; step-down; stepwise; guidelines; severity; control; step-up intermittent; step-up short-term; step-up long-term
22.  Growth of Preschool Children at High Risk for Asthma Two Years after Discontinuation of Fluticasone 
Background
The effect on linear growth of daily long-term inhaled corticosteroid (ICS) therapy in preschool-aged children with recurrent wheezing is controversial.
Objective
To determine the effect of daily ICS given for 2 years on linear growth in preschool children with recurrent wheezing.
Methods
Children ages 2 and 3 years with recurrent wheezing and positive modified asthma predictive indices were randomized to a two-year treatment period of fluticasone propionate CFC (176 mcg/day) or masked-placebo delivered by valved chamber with mask and then followed 2 years off study medication. Height growth determined by stadiometry was compared between treatment groups.
Results
In the study cohort as a whole, the fluticasone group did not have significantly less linear growth than the placebo-group [change in height from baseline difference (ΔHt) of −0.2 cm (95% CI, −1.1, 0.6)] two years after discontinuation of study treatment. In post-hoc analyses, children 2 years old and who weighed < 15 kg at enrollment treated with fluticasone had less linear growth compared to placebo [ΔHt of −1.6 cm (95% CI, −2.8, −0.4), p=0.009].
Conclusion
Linear growth was not significantly different in high-risk, recurrent wheezing preschool age children treated with CFC fluticasone 176 mcg/day compared to placebo 2 years after fluticasone is discontinued. However, post-hoc subgroup analyses revealed that children who are younger in age and of lesser weight relative to the entire study cohort had significantly less linear growth, possibly due to a higher relative fluticasone exposure.
doi:10.1016/j.jaci.2011.06.027
PMCID: PMC3224818  PMID: 21820163
Asthma predictive index; atopy; clinical trials; early childhood asthma; fluticasone; inhaled corticosteroids; intermittent wheezing; linear growth; research network
23.  Most Nocturnal Asthma Symptoms Occur Outside of Exacerbations and Associate with Morbidity 
Background
Although nocturnal awakenings help categorize asthma severity and control, their clinical significance has not been thoroughly studied.
Objective
To determine the clinical consequences of nocturnal asthma symptom(s) requiring albuterol in children with mild-to-moderate persistent asthma outside of periods when oral corticosteroids were used for worsening asthma symptoms.
Methods
285 children ages 6 to 14 years with mild-to-moderate persistent asthma were randomized to receive one of three controller regimens and completed daily symptom diaries for 48 weeks. Diary responses were analyzed for the frequency and consequences of nocturnal asthma symptoms requiring albuterol.
Results
Nocturnal asthma symptoms requiring albuterol occurred in 72.2% of participants at least once and in 24.3% ≥13 times. 81.3% of nocturnal symptoms occurred outside of exacerbation periods and were associated the next day with the following events: albuterol use (56.9% of days preceded by nocturnal symptoms versus 18.1% of days not preceded by nocturnal symptoms, Relative Risk (RR) 2.3, 95%CI: 2.2,2.4), school absence (5.0% versus 0.3%, RR 10.6, 95%CI: 7.8,14.4), and doctor contact (3.7% versus 0.2%, RR 8.8, 95%CI:6.1,12.5). Similar findings were noted during exacerbation periods (RR 1.7 for albuterol use, 5.5 for school absence, and 4.9 for doctor contact). Nocturnal symptoms did not predict the onset of exacerbations.
Conclusion
Nocturnal symptoms requiring albuterol in children with mild-to-moderate persistent asthma receiving controller therapy occurred predominantly outside of exacerbation periods. Despite being poor predictors of exacerbations, they were associated with increases in albuterol use, school absences, and doctor contacts the day after nocturnal symptom occurrences.
doi:10.1016/j.jaci.2011.07.018
PMCID: PMC3408598  PMID: 21855126
asthma; nocturnal symptoms; exacerbation
24.  Decreased Lung Function After Preschool Wheezing Rhinovirus Illnesses in Children At Risk to Develop Asthma 
Background
Preschool rhinovirus wheezing illnesses predict an increased risk of childhood asthma; however, it is not clear how specific viral illnesses in early life relate to lung function later on in childhood.
Objective
To determine the relationshipof virus-specific wheezing illnesses and lung function in a longitudinal cohort of children at risk for asthma.
Methods
Two hundred thirty-eight children were followed prospectivelyfrom birth to 8 years of age. Early life viral wheezing respiratory illnesses were assessed using standard techniques and lung function was assessed annually by spirometry and impulse oscillometry (IOS). The relationshipsof these virus-specific wheezing illnesses and lung function were assessed by mixed-effect linear regression.
Results
Children who wheezed with rhinovirus (RV) demonstrated significantly decreased spirometry values [FEV1 (p=0.001), FEV0.5 (p<0.001), FEF25–75 (p<0.001)], and also had abnormal IOS measures [more negative Reactance at 5 Hz (p<0.001)] compared to those who did not wheeze with RV. Children who wheezed with RSV or other viral illnesses did not have any significant differences in spirometric or IOS indices when compared to children who did not. Children diagnosed with asthma at ages 6 or 8 years had significantly decreased FEF25–75 (p=0.05) compared to children without asthma.
Conclusion
Among outpatient viral wheezing illnesses in early childhood, those caused by RV infections are the mostsignificant predictors of decreased lung functionup to age 8 years in a high-risk birth cohort. Whether low lung function is a cause and/or effect of RV wheezing illnesses has yet to be determined.
doi:10.1016/j.jaci.2011.06.037
PMCID: PMC3233203  PMID: 21878241
rhinovirus; respiratory syncytial virus; wheezing; asthma; spirometry; impulse oscillometry
25.  Daily or Intermittent Budesonide in Preschool Children with Recurrent Wheezing 
The New England journal of medicine  2011;365(21):1990-2001.
BACKGROUND
Daily inhaled glucocorticoids are recommended for young children at risk for asthma exacerbations, as indicated by a positive value on the modified asthma predictive index (API) and an exacerbation in the preceding year, but concern remains about daily adherence and effects on growth. We compared daily therapy with intermittent therapy.
METHODS
We studied 278 children between the ages of 12 and 53 months who had positive values on the modified API, recurrent wheezing episodes, and at least one exacerbation in the previous year but a low degree of impairment. Children were randomly assigned to receive a budesonide inhalation suspension for 1 year as either an intermittent high-dose regimen (1 mg twice daily for 7 days, starting early during a predefined respiratory tract illness) or a daily low-dose regimen (0.5 mg nightly) with corresponding placebos. The primary outcome was the frequency of exacerbations requiring oral glucocorticoid therapy.
RESULTS
The daily regimen of budesonide did not differ significantly from the intermittent regimen with respect to the frequency of exacerbations, with a rate per patient-year for the daily regimen of 0.97 (95% confidence interval [CI], 0.76 to 1.22) versus a rate of 0.95 (95% CI, 0.75 to 1.20) for the intermittent regimen (relative rate in the intermittent-regimen group, 0.99; 95% CI, 0.71 to 1.35; P=0.60). There were also no significant between-group differences in several other measures of asthma severity, including the time to the first exacerbation, or adverse events. The mean exposure to budesonide was 104 mg less with the intermittent regimen than with the daily regimen.
CONCLUSIONS
A daily low-dose regimen of budesonide was not superior to an intermittent high-dose regimen in reducing asthma exacerbations. Daily administration led to greater exposure to the drug at 1 year.
doi:10.1056/NEJMoa1104647
PMCID: PMC3247621  PMID: 22111718

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