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1.  PEDIATRIC ASTHMA: NATURAL HISTORY, ASSESSMENT AND TREATMENT 
Wheezing and childhood asthma are not synonymous but rather comprise a heterogeneous group of conditions that have different outcomes over the course of childhood. Most infants who wheeze have a transient condition associated with diminished airway function at birth and have no increased risk of asthma later in life. However, children with persistent wheezing throughout childhood and frequent exacerbations represent the main challenge today. Studying the natural history of asthma is important for the understanding and accurate prediction of the clinical course of different phenotypes. To date, a great improvement has been achieved in reducing the frequency of asthma symptoms. However, neither decreased environmental exposure nor controller treatment, as recommended by the recent national asthma education and prevention program, can halt the progression of asthma in childhood or the development of persistent wheezing phenotype. This review focuses on the recent studies that led to the current understanding of asthma phenotypes in childhood and the recommended treatments.
doi:10.1002/msj.20285
PMCID: PMC3172616  PMID: 21913196
asthma; pediatric; phenotypes; exacerbation; treatment; inhaled corticosteroid (ICS); short acting beta agonist (SABA); long acting beta agonist (LABA)
2.  Pediatric Asthma 
Asthma currently affects the lives of more than 30 million Americans from infancy to the elderly. In many ways, pediatric asthma differs from adult asthma, including childhood-onset adult asthma. Despite many advances in our understanding of the disease, the natural history of asthma is not well defined, especially in different subsets of patients. For many with allergic asthma the disease has its origins in early childhood, associated with early sensitization to aeroallergens and exposure to repeated viral infections. These early life exposures, coupled with genetically determined susceptibility, have a major impact on the natural history of the disease. A number of risk factors during the critical early stages in the initiation of asthma have been associated with subsequent outcomes. In addition, protective factors linked to early life experiences have also been delineated which may impact the development of atopy and asthma and reduce the prevalence of these diseases. Cumulatively, the data highlight the critical nature of this early period in which immune/inflammatory responses in the lung are initiated and serve to maintain the disease in subsequent years.
doi:10.1513/pats.200808-090RM
PMCID: PMC2677403  PMID: 19387030
asthma; children; predictors; persistence
3.  Early childhood wheezing: various natural courses and their relationship to later asthma 
Korean Journal of Pediatrics  2012;55(8):259-264.
Wheezing is one of the most frequent complaints that lead to the use of medical resources in younger children. Generally, wheezing is caused by bronchiolitis and resolves spontaneously without recurrence, but sometimes, wheezing can progress into asthma. Early data on the natural history of childhood wheezing was mostly obtained from retrospective reviews of medical records or from questionnaires, which made it difficult to exclude biases. Now that many cohort studies are available, reviewing the results of birth cohort studies makes it possible to understand the natural course of early childhood wheezing and the risk factors for asthma. In this study, we have reviewed the various phenotypes of early childhood wheezing and their natural courses to help select the most appropriate management modalities for the different types of early childhood wheezing.
doi:10.3345/kjp.2012.55.8.259
PMCID: PMC3433561  PMID: 22977437
Asthma; Preschool child; Cohort studies; Infant; Wheezing
4.  Asthma and Chronic Obstructive Pulmonary Disease 
Purpose of the review
In the clinical setting, patients who present with a combination of asthma and chronic obstructive pulmonary disease (COPD) related traits are not uncommon. This review discusses recent advances in the characterization of the natural course, phenotypes, and molecular markers of cases with co-existing asthma and COPD and in the understanding of the nature of the link between these two conditions.
Recent findings
Recent epidemiological evidence indicates that asthma accounts for a substantial proportion of cases of irreversible airflow limitation in the general population and that, in addition to the critical role of environmental exposures in adult age, alterations of developmental processes in childhood may also predispose subjects with asthma to COPD later in life. Findings from clinical and experimental studies emphasize the existence of remarkable heterogeneity within the group of subjects with co-existing asthma and COPD in terms of natural history of lung function, risk factors for disease progression, lung structural changes, and immunological profiles.
Summary
The phenotypic complexity of cases with co-existing asthma and COPD challenges a rigid categorization of patients into existing diagnostic labels and suggests the importance of integrating clinical, functional, morphologic, immunological, and molecular assessments to tailor and optimize prevention and treatment.
doi:10.1097/ACI.0b013e3283300baf
PMCID: PMC2832909  PMID: 19638929
asthma; chronic obstructive pulmonary disease; chronic bronchitis; emphysema
5.  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
6.  Phenotypes and endotypes of severe asthma in children 
Korean Journal of Pediatrics  2013;56(5):191-195.
Severe childhood asthma is a complicated and heterogeneous disorder with distinct phenotypes. Children with severe asthma have more persistent symptoms despite receiving treatment, more atopy, greater airway obstruction, and more air trapping than those with mild-to-moderate asthma. They also have higher morbidity and substantial airflow limitations that persist throughout adulthood. Identification of the phenotype clusters and endotypes of severe asthma can allow further modulation of the natural history of severe asthma and may provide the pathophysiologic rationale for appropriate management strategies.
doi:10.3345/kjp.2013.56.5.191
PMCID: PMC3668198  PMID: 23741231
Severe asthma; Child; Phenotype; Endotype
7.  New Insights into the Natural History of Asthma: Primary Prevention on the Horizon 
Recent studies of the natural history of asthma have shifted attention towards viral respiratory illness in early life as a major risk factor associated with the development of the most persistent forms of the disease. Although early aeroallergen sensitization is strongly associated with chronic asthma, several trials in which single aeroallergen exposure in pregnancy and early childhood was successfully accomplished and compared with sham avoidance have failed to show any decrease in asthma incidence. New evidence suggests that complex interactions occur between viral infection and aeroallergen sensitization in genetically susceptible subjects, which trigger the immune responses and airway changes that are characteristic of persistent asthma. The finding that exposure to bacterial products among children raised on farms is associated with diminished asthma prevalence during the school years has now been replicated, and experimental studies have suggested that these effects are mediated by the activation of T-regulatory cells in the airway. It is thus plausible to hypothesize that primary prevention of asthma could be attained through surrogate therapeutic interventions that activate similar mechanisms in young children at high risk for asthma.
doi:10.1016/j.jaci.2011.09.020
PMCID: PMC3963825  PMID: 22036094
8.  Examining the association between childhood asthma and parent and grandparent asthma status: Implications for Practice 
Clinical pediatrics  2010;49(6):535-541.
Examination of intergenerational asthma beyond maternal asthma has been limited. The association between childhood asthma and intergenerational asthma status among a national cohort of children was examined.
The genealogical sample (2,552 children) participating in the Child Development Supplement of the Panel Study of Income Dynamics. Multivariate regression was used to determine intergenerational asthma.
Children with a parent with asthma were almost twice as likely (OR=1.96) to have asthma compared to those without a parent with asthma. Children with a parent and grandparent with asthma were over four times more likely to have asthma compared to those without a parent and grandparent with asthma (OR=4.27). Children with a grandparent with asthma were more likely to have asthma (OR=1.52).
A family history of asthma was a significant predictor of physician diagnosed asthma in children regardless of race/ethnicity and socioeconomic status. Findings support the collection of family history, including grandparent asthma status.
doi:10.1177/0009922809356465
PMCID: PMC3020897  PMID: 20507869
asthma; intergenerational; panel study
9.  Viral asthma: implications for clinical practice 
The natural history of asthma appears to be driven primarily by the timing and duration of viral respiratory infections. From the very high rate of infections in childhood, to the more sporadic pattern seen in adults, the cycle of acute injury followed by an inefficient repair process helps explain the clinical patterns of asthma severity currently recognized by asthma guidelines. Why the asthmatic host responds to viral injury in a particular way is largely a mystery and the subject of intense investigation. The role of viruses in asthma extends not just to intermittent but to persistent disease, and to both the atopic as well as nonatopic phenotypes. Future therapeutic strategies should include primary prevention via the development of antiviral innate immunity-enhancing vaccines, as well as secondary prevention via the use of antiviral agents, or immunomodulators designed to boost the antiviral response or interrupt the proinflammatory cascade.
PMCID: PMC3047911  PMID: 21437037
asthma; rhinoviruses; exacerbations; epidemiology; phenotypes; clinical trials
10.  Asthma in childhood: a complex, heterogeneous disease 
Asthma in childhood is a heterogeneous disease with different phenotypes and variable clinical manifestations, which depend on the age, gender, genetic background, and environmental influences of the patients. Several longitudinal studies have been conducted to classify the phenotypes of childhood asthma, on the basis of the symptoms, triggers of wheezing illness, or pathophysiological features of the disease. These studies have provided us with important information about the different wheezing phenotypes in young children and about potential mechanisms and risk factors for the development of chronic asthma. The goal of these studies was to provide a better insight into the causes and natural course of childhood asthma. It is well-known that complicated interactions between genes and environmental factors contribute to the development of asthma. Because childhood is a period of rapid growth in both the lungs and the immune system, developmental factors should be considered in the pathogenesis of childhood asthma. The pulmonary system continues to grow and develop until linear growth is completed. Longitudinal studies have reported significant age-related immune development during postnatal early life. These observations suggest that the phenotypes of childhood asthma vary among children and also in an individual child over time. Improved classification of heterogeneous conditions of the disease will help determine novel strategies for primary and secondary prevention and for the development of individualized treatment for childhood asthma.
doi:10.3345/kjp.2011.54.1.1
PMCID: PMC3040359  PMID: 21359053
Asthma; Phenotype; Child
11.  Developing Asthma in Childhood from Exposure to Secondhand Tobacco Smoke: Insights from a Meta-Regression 
Environmental Health Perspectives  2007;115(10):1394-1400.
Objective
Studies have identified associations between household secondhand tobacco smoke (SHS) exposure and induction of childhood asthma. However, the true nature and strength of this association remains confounded in many studies, producing inconsistent evidence. To look for sources of potential bias and try to uncover consistent patterns of relative risk estimates (RRs), we conducted a meta-analysis of studies published between 1970 and 2005.
Data sources
Through an extensive literature search, we identified 38 epidemiologic studies of SHS exposure and the development of childhood asthma (that also controlled for atopy history) from 300 potentially relevant articles.
Data synthesis
We observed substantial heterogeneity within initial summary RRs of 1.48 [95% confidence interval (CI), 1.32–1.65], 1.25 (1.21–1.30), and 1.21 (1.08–1.36), for ever, current, and incident asthma, respectively. Lack of control for type of atopy history (familial or child) and child’s own smoking status within studies and age category altered summary RRs in separate meta-regressions. After adjusting for these confounding characteristics, consistent patterns of association emerged between SHS exposure and childhood asthma induction. Our summary RR of 1.33 (95% CI, 1.14–1.56) from studies of incident asthma among older children (6–18 years of age) is 1.27 times the estimate from studies of younger children and higher than estimates reported in earlier meta-analyses.
Conclusions
This new finding indicates that exposure duration may be a more important factor in the induction of asthma than previously understood, and suggests that SHS could be a more fundamental and widespread cause of childhood asthma than some previous meta-analyses have indicated.
doi:10.1289/ehp.10155
PMCID: PMC2022647  PMID: 17938726
childhood asthma; environmental tobacco smoke; ETS; meta-analysis; meta-regression; relative risk; secondhand tobacco smoke; SHS
12.  ADULT-ONSET ASTHMA IS ASSOCIATED WITH INCREASED CAROTID ATHEROSCLEROSIS AMONG WOMEN IN THE ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY 
Atherosclerosis  2006;195(1):129-137.
Some studies have suggested that asthma may be a risk factor for coronary heart disease and stroke, particularly in women. Child and adult-onset asthma differ according to inflammatory characteristics and gender distribution. We examined whether childhood-onset and adult-onset asthma were associated with carotid artery intima-media thickness (IMT) in men and women in the Atherosclerosis Risk in Communities (ARIC) study. In unadjusted analyses, the weighted mean far wall IMT thickness for women with history of adult-onset asthma was significantly greater than that of women without history of asthma (0.731mm vs. 0.681mm; p<0.0001) while IMT for women with history of childhood-onset asthma (IMT=0.684mm) did not differ substantially from non-asthmatic women. Mean IMT did not differ significantly according to asthma history among men. When the data were fitted to a linear model, the interaction between asthma status and gender was significant (p=0.006). After adjusting for age, race, BMI, smoking status, smoking pack years, diabetes, hypertension, physical activity, education level, and high and low density lipoprotein levels, the mean IMT difference between women with adult-onset asthma and no history of asthma was attenuated but remained significant (0.713mm vs. 0.687mm, p=0.008). In conclusion, adult-onset asthma but not child-onset asthma is associated with increased carotid atherosclerosis among women but not among men.
doi:10.1016/j.atherosclerosis.2006.09.004
PMCID: PMC2128256  PMID: 17045272
13.  Paternal History of Asthma and Airway Responsiveness in Children with Asthma 
Rationale: Little is known regarding the relationship between parental history of asthma and subsequent airway hyperresponsiveness (AHR) in children with asthma. Objectives: We evaluated this relationship in 1,041 children with asthma participating in a randomized trial of antiinflammatory medications (the Childhood Asthma Management Program [CAMP]). Methods: Methacholine challenge testing was performed before treatment randomization and once per year over an average of 4.5 years postrandomization. Cross-sectional and longitudinal repeated measures analyses were performed to model the relationship between PC20 (the methacholine concentration causing a 20% fall in FEV1) with maternal, paternal, and joint parental histories of asthma. Models were adjusted for potential confounders. Measurements and Main Results: At baseline, AHR was strongly associated with a paternal history of asthma. Children with a paternal history of asthma demonstrated significantly greater AHR than those without such history (median logePC20, 0.84 vs. 1.13; p = 0.006). Although maternal history of asthma was not associated with AHR, children with two parents with asthma had greater AHR than those with no parents with asthma (median logePC20, 0.52 vs. 1.17; p = 0.0008). Longitudinal multivariate analysis of the relation between paternal history of asthma and AHR using repeated PC20 measurements over 44 months postrandomization confirmed a significant association between paternal history of asthma and AHR among children in CAMP. Conclusions: Our findings suggest that the genetic contribution of the father is associated with AHR, an important determinant of disease severity among children with asthma.
doi:10.1164/rccm.200501-010OC
PMCID: PMC2718530  PMID: 15937295
airway responsiveness; asthma; genetics; longitudinal analysis; parent of origin
14.  Asthma and lung structure on CT: The MESA Lung Study 
Background
The potential consequences of asthma in childhood and young adulthood on lung structure in older adults have not been studied in a large, population-based cohort.
Objective
The authors hypothesized that a history of asthma onset in childhood (age 18 or before) or young adulthood (age 19 to 45) was associated with altered lung structure on computed tomography (CT) in later life.
Methods
The Multi-Ethnic Study of Atherosclerosis Lung Study recruited 3,965 participants and assessed asthma history using standardized questionnaires, spirometry following guidelines, and segmental airway dimensions and percent low attenuation areas on CT scans.
Results
Asthma with onset in childhood and young adulthood was associated with large decrements in the forced expiratory volume in one second among participants with a mean age of 66 years (−365 ml and −343 ml, respectively; P<0.001). Asthma with onset in childhood and young adulthood was associated with increased mean airway wall thickness standardized to an internal perimeter of 10 mm (Pi10) (0.1 mm, P<0.001 for both), predominantly from narrower segmental airway lumens (−0.39 mm and −0.34 mm, respectively; P<0.001). Asthma with onset in childhood and young adulthood also was associated with a greater percentage of low attenuation areas (1.69% and 4.30%, respectively; P<0.001). Findings were similar among never smokers except that differential percentage of low attenuation areas in child-onset asthma was not seen in them.
Conclusion
Asthma with onset in childhood or young adulthood, was associated with reduced lung function, narrower airways and, among asthmatics who smoked, greater percentage of low attenuation areas in later life.
doi:10.1016/j.jaci.2012.11.036
PMCID: PMC3564253  PMID: 23374265
airway remodeling; airway structure; asthma; emphysema; epidemiology
15.  Changes in Environmental Tobacco Smoke Exposure and Asthma Morbidity Among Urban School Children 
Chest  2008;135(4):911-916.
Background:
Environmental tobacco smoke (ETS) exposure is associated with poor asthma outcomes in children. However, little is known about natural changes in ETS exposure over time in children with asthma and how these changes may affect health-care utilization. This article documents the relationship between changes in ETS exposure and childhood asthma morbidity among children enrolled in a clinical trial of supervised asthma therapy.
Methods:
Data for this analysis come from a large randomized clinical trial of supervised asthma therapy in which 290 children with persistent asthma were randomized to receive either usual care or supervised asthma therapy. No smoking cessation counseling or ETS exposure education was provided to caregivers; however, children were given 20 min of asthma education, which incorporated discussion of the avoidance of asthma triggers, including ETS. Asthma morbidity and ETS exposure data were collected from caregivers via telephone interviews at baseline and at the 1-year follow-up.
Results:
At baseline, 28% of caregivers reported ETS exposure in the home and 19% reported exposure outside of the primary household only. Among children whose ETS exposure decreased from baseline, fewer hospitalizations (p = 0.034) and emergency department (ED) visits (p ≤ 0.001) were reported in the 12 months prior to the second interview compared to the 12 months prior to the first interview. Additionally, these children were 48% less likely (p = 0.042) to experience an episode of poor asthma control (EPAC).
Conclusions:
This is the first study to demonstrate an association between ETS exposure reduction and fewer EPACs, respiratory-related ED visits, and hospitalizations. These findings emphasize the importance of ETS exposure reduction as a mechanism to improve asthma control and morbidity. Potential policy implications include supporting ETS reductions and smoking cessation interventions for parents and caregivers of children with asthma. Research to identify the most cost-effective strategy is warranted.
Trial registration:
Clinicaltrials.gov Identifier: NCT00110383
doi:10.1378/chest.08-1869
PMCID: PMC2763557  PMID: 19017893
asthma; children; environmental tobacco smoke; tobacco smoke pollution
16.  The Heterogeneity of Asthma Phenotypes in Children and Young Adults 
Journal of Allergy  2012;2012:163089.
Objective. Genetic heterogeneity and risk factor distribution was analyzed in two previously proposed asthma phenotypes. Method. A sample of 412 subjects was investigated at 7-8, 12-13, and 21-22 years of age with questionnaires, skin prick tests, and genetic analysis of IL-4 receptor (IL4R) single-nucleotide polymorphisms. The sample was subdivided in one group with no asthma, and two groups with asthma separated by age of onset of symptoms, namely, early onset asthma (EOA) and late onset asthma (LOA). Risk factors and IL4R markers were analyzed in respect to asthma phenotypes. Results. EOA and LOA groups were both associated with atopy and a maternal history of asthma. Female gender was more common in LOA, whereas childhood eczema, frequent colds in infancy, and a paternal history of asthma were more common in EOA. The AA genotype of rs2057768 and the GG genotype of rs1805010 were more common in LOA, whereas the GG genotype of rs2107356 was less common in EOA. Conclusion. Our data suggest that early and late onset asthma may be of different endotypes and genotypes.
doi:10.1155/2012/163089
PMCID: PMC3332210  PMID: 22577403
17.  The Urban Environment and Childhood Asthma Study 
Childhood asthma is not distributed evenly throughout the population, and children who grow up in crowded urban neighborhoods have higher rates of asthma and experience greater morbidity due to asthma. There are several environmental and lifestyle factors associated with urban living that are suspected to promote the development of asthma, particularly in the first few years of life. Collectively, this information suggests the hypothesis that exposure in early life to adverse environmental and lifestyle factors associated with disadvantaged urban environments modifies immune development to increase the risk for allergic diseases and asthma. The Urban Environment and Childhood Asthma birth cohort study was initiated in 2004 to test this hypothesis. The study population was recruited prenatally, and consisted of 560 families from four urban areas who were at high risk for allergies and/or asthma on the basis of parental histories, along with an additional 49 families without atopic parents. Immune development, respiratory illnesses, and exposure to stress, indoor pollutants, microbial products, and allergens were measured prospectively, and the major study outcomes are recurrent wheeze at three years of age and asthma at age seven. This review summarizes the study design, methods, and early findings of the URECA study.
doi:10.1016/j.jaci.2010.01.037
PMCID: PMC2860857  PMID: 20226291
18.  Intraregional differences in asthma prevalence and risk factors for asthma among adolescents in Split-Dalmatia County, Croatia 
Summary
Background
Our aim was to assess the differences in intraregional prevalence of asthma in adolescents in Split-Dalmatia County to determine asthma risk factors in our population and estimate the specificity and sensitivity of the questionnaire used.
Material/Methods
We conducted the study using the European Community Respiratory Health Survey II short questionnaire supplemented by some questions from the International Study of Asthma in Childhood questionnaire. The participants suspected to have asthma were invited for examination by an asthma specialist who established the final diagnosis of asthma according to the medical history, physical examination, skin-prick tests, and peak flow measurements.
Results
A total of 4027 students (51.2% male) participated in the study. According to the prevalence of wheezing during the last 12 months, asthma prevalence was estimated at 9.7%. The total prevalence of asthma confirmed by an asthma specialist in the selected population was 5.60% (95% CI, 4.93–6.36%); 6.18% in Split (95% CI, 5.37–7.09), 5.63% in Imotski (95% CI, 3.48–8.58), and 2.90% in Sinj (95% CI, 1.67–4.68) (P=0.0028). We found sensitization to aeroallergens and peanuts, and active smoking to be independent risk factors for asthma.
Conclusions
Split-Dalmatia County has moderate asthma prevalence, with a significant intraregional difference. Asthma prevalence estimated by a questionnaire (9.7%) overestimates the prevalence of asthma confirmed by an asthma specialist (5.6%) in adolescents in Croatia. Our data confirmed the need of a more complex questionnaire to evaluate the accurate prevalence of current asthma or the need for subsequent clinical evaluation of the questionnaire obtained data. Allergic sensitization to aeroallergens and active smoking were important risk factors for asthma.
doi:10.12659/MSM.882609
PMCID: PMC3560826  PMID: 22460102
asthma; prevalence; ISAAC; ECRHS; Croatia; intraregional; risk factors
19.  Childhood asthma and indoor allergens in Native Americans in New York 
Environmental Health  2006;5:22.
Background
The objective of this study was to assess the correlation between childhood asthma and potential risk factors, especially exposure to indoor allergens, in a Native American population.
Methods
A case-control study of St. Regis Mohawk tribe children ages 2–14 years, 25 diagnosed with asthma and 25 controls was conducted. Exposure was assessed based on a personal interview and measurement of mite and cat allergens (Der p 1, Fel d 1) in indoor dust.
Results
A non-significant increased risk of childhood asthma was associated with self-reported family history of asthma, childhood environmental tobacco smoke exposure, and air pollution. There was a significant protective effect of breastfeeding against current asthma in children less than 14 years (5.2 fold lower risk). About 80% of dust mite and 15% of cat allergen samples were above the threshold values for sensitization of 2 and 1 μg/g, respectively. The association between current asthma and exposure to dust mite and cat allergens was positive but not statistically significant.
Conclusion
This research identified several potential indoor and outdoor risk factors for asthma in Mohawks homes, of which avoidance may reduce or delay the development of asthma in susceptible individuals.
doi:10.1186/1476-069X-5-22
PMCID: PMC1552054  PMID: 16859546
20.  Asthma and other recurrent wheezing disorders in children (chronic) 
Clinical Evidence  2012;2012:0302.
Introduction
Childhood asthma is the most common chronic paediatric illness. There is no cure for asthma but good treatment to palliate symptoms is available. Asthma is more common in children with a personal or family history of atopy, increased severity and frequency of wheezing episodes, and presence of variable airway obstruction or bronchial hyperresponsiveness. Precipitating factors for symptoms and acute episodes include infection, house dust mites, allergens from pet animals, exposure to tobacco smoke, and exercise.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of single-agent prophylaxis in children taking as-needed inhaled beta2 agonists for asthma? What are the effects of additional prophylactic treatments in childhood asthma inadequately controlled by standard-dose inhaled corticosteroids? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 48 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: beta2 agonists (long-acting), corticosteroids (inhaled standard or higher doses), leukotriene receptor antagonists (oral), omalizumab, and theophylline (oral).
Key Points
Childhood asthma can be difficult to distinguish from viral wheeze and can affect up to 20% of children.
Regular monotherapy with inhaled corticosteroids improves symptoms, reduces exacerbations, and improves physiological outcomes in children with asthma symptoms requiring regular short-acting beta2 agonist treatment. Their effect on final adult height is minimal and when prescribed within recommended doses have an excellent safety record. Regular monotherapy with other treatments is not superior to low-dose inhaled corticosteroids.
Leukotriene receptor antagonists may have a role as first-line prophylaxis in very young children.
There is consensus that long-acting beta2 agonists should not be used for first-line prophylaxis. CAUTION: Monotherapy with long-acting beta2 agonists does not reduce asthma exacerbations but may increase the chance of severe asthma episodes.
Theophylline was used as first-line prevention before the introduction of inhaled corticosteroids. Although there is weak evidence that theophylline is superior to placebo, theophylline should no longer be used as first-line prophylaxis in childhood asthma because of clear evidence of the efficacy and safety of inhaled corticosteroids. Theophylline has serious adverse effects (cardiac arrhythmia, convulsions) if therapeutic blood concentrations are exceeded.
When low-dose inhaled corticosteroids fail to control asthma, most older children will respond to one of the add-on options available, which include addition of long-acting beta2 agonists, addition of leukotriene receptor antagonists, addition of theophylline, or increased dose of inhaled corticosteroid. However, we don't know for certain how effective these additional treatments are because we found no/limited RCT evidence of benefit compared with adding placebo/no additional treatments. Addition of long-acting beta2 agonists may reduce symptoms and improve physiological measures compared with increased dose of corticosteroids in older children. Long-acting beta2 agonists are not currently licensed for use in children under 5 years of age.Consensus suggests that younger children are likely to benefit from addition of leukotriene receptor antagonists. Although there is weak evidence that addition of theophylline to inhaled corticosteroids does improve symptom control and reduce exacerbations, theophylline should only be added to inhaled corticosteroids in children aged over 5 years when the addition of long-acting beta2 agonists and leukotriene receptor antagonists have both been unsuccessful.
Omalizumab may be indicated in the secondary care setting for older children (aged over 5 years) with poorly controlled allergic asthma despite use of intermediate- and high-dose inhaled corticosteroids once the diagnosis is confirmed and compliance and psychological issues are addressed. However, we need more data to draw firm conclusions.
PMCID: PMC3285219  PMID: 22305975
21.  Key findings and clinical implications from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study 
Patients with severe or difficult-to-treat asthma are an understudied population but account for considerable asthma morbidity, mortality, and costs. The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study was a large, 3-year, multicenter, observational cohort study of 4756 patients (n = 3489 adults ≥18 years of age, n = 497 adolescents 13-17 years of age, and n = 770 children 6-12 years of age) with severe or difficult-to-treat asthma. TENOR's primary objective was to characterize the natural history of disease in this cohort. Data assessed semiannually and annually included demographics, medical history, comorbidities, asthma control, asthma-related health care use, medication use, lung function, IgE levels, self-reported asthma triggers, and asthma-related quality of life. We highlight the key findings and clinical implications from more than 25 peer-reviewed TENOR publications. Regardless of age, patients with severe or difficult-to-treat asthma demonstrated high rates of health care use and substantial asthma burden despite receiving multiple long-term controller medications. Recent exacerbation history was the strongest predictor of future asthma exacerbations. Uncontrolled asthma, as defined by the 2007 National Heart, Lung, and Blood Institute guidelines’ impairment domain, was highly prevalent and predictive of future asthma exacerbations; this assessment can be used to identify high-risk patients. IgE and allergen sensitization played a role in the majority of severe or difficult-to-treat asthmatic patients.
doi:10.1016/j.jaci.2012.04.014
PMCID: PMC3622643  PMID: 22694932
TENOR; severe or difficult-to-treat asthma; asthma control; asthma exacerbations; burden; medication; quality of life; allergy; IgE
22.  The Impact of Respiratory Viral Infection on Wheezing Illnesses and Asthma Exacerbations 
The etiology and morbidity associated with asthma are thought to stem from both genetic factors and potentially modifiable environmental factors, such as viral infections.[1-7] Although it is unclear whether respiratory viral infections cause asthma, observational studies have demonstrated a high rate of asthma in children with a history of severe viral lower respiratory tract infections during infancy, and viruses are the associated with the majority of asthma exacerbations among both children and adults. This review will discuss the pathogens associated with virus-induced wheezing illnesses during infancy and early childhood, the association of bronchiolitis during infancy with an increased risk of childhood asthma, and the association of respiratory viruses with asthma exacerbations in older children and adults.
doi:10.1016/j.iac.2008.03.001
PMCID: PMC2504766  PMID: 18572106
viruses; respiratory tract infections; asthma
23.  530 Atopic Phenotype in Children under 6 Years with Persistent Wheezing in El Salvador 
Background
Asthma is the most common chronic disease of childhood and the leading cause of childhood morbidity1. Even if an early intervention could improve their symptoms, the diagnosis of asthma in the first years of age is difficult. This study is the first effort to describe the atopic profile and the risk of developing asthma in a group of children from El Salvador with recurrent wheezing.
Methods
A questionnaire was designed for parents to determine the atopic background, while skin tests were performed in children. We used the modified Asthma Predictive Index (APIm)2 to assess the risk of developing asthma.
Results
65 children under 6 years were evaluated, with an average age of 3.5 years. The average age of onset of wheezing was at 11 months of age. Family history of asthma, chronic rhinitis and eczema were presented respectively at 25%, 19% and 8% of the population. 42% of our population presents allergic rhinitis and 37% eczema. Among the factors related to wheezing risk, we found that one third of the population was born via caesarean section with a breastfeeding average of 3.76 months; also we found the presence of pets in 26% of households, a passive smoking and exposure to wood smoke in 17% and 35% of the studied population respectively. 23 children were sensitized to respiratory allergens. Dust mites were found in 73% of children sensitized. The APIm was positive in 66% of the population.
Conclusions
This is the first cohort of children described under 6 years with recurrent wheezing in El Salvador. We found an early presentation of wheezing, caused not only by viral conditions. These children had strong personal and family atopic background with a high rate of sensitization to respiratory allergens, especially dust mites. Most of the children studied are at risk of presenting asthma in later ages.
doi:10.1097/01.WOX.0000411645.34076.e1
PMCID: PMC3512625
24.  Traffic, Susceptibility, and Childhood Asthma 
Environmental Health Perspectives  2006;114(5):766-772.
Results from studies of traffic and childhood asthma have been inconsistent, but there has been little systematic evaluation of susceptible subgroups. In this study, we examined the relationship of local traffic-related exposure and asthma and wheeze in southern California school children (5–7 years of age). Lifetime history of doctor-diagnosed asthma and prevalent asthma and wheeze were evaluated by questionnaire. Parental history of asthma and child’s history of allergic symptoms, sex, and early-life exposure (residence at the same home since 2 years of age) were examined as susceptibility factors. Residential exposure was assessed by proximity to a major road and by modeling exposure to local traffic-related pollutants. Residence within 75 m of a major road was associated with an increased risk of lifetime asthma [odds ratio (OR) = 1.29; 95% confidence interval (CI), 1.01–1.86], prevalent asthma (OR = 1.50; 95% CI, 1.16–1.95), and wheeze (OR = 1.40; 95% CI, 1.09–1.78). Susceptibility increased in long-term residents with no parental history of asthma for lifetime asthma (OR = 1.85; 95% CI, 1.11–3.09), prevalent asthma (OR = 2.46; 95% CI, 0.48–4.09), and recent wheeze (OR = 2.74; 95% CI, 1.71–4.39). The higher risk of asthma near a major road decreased to background rates at 150–200 m from the road. In children with a parental history of asthma and in children moving to the residence after 2 years of age, there was no increased risk associated with exposure. Effect of residential proximity to roadways was also larger in girls. A similar pattern of effects was observed with traffic-modeled exposure. These results indicate that residence near a major road is associated with asthma. The reason for larger effects in those with no parental history of asthma merits further investigation.
doi:10.1289/ehp.8594
PMCID: PMC1459934  PMID: 16675435
air pollution; asthma; child; epidemiology; traffic
25.  Viral Respiratory Infection and the Link to Asthma 
Viral respiratory infections are closely associated with wheezing illnesses and exacerbations of asthma throughout childhood, and yet there are a number of remaining questions pertaining to the specific nature of this relationship. Infection with an expanding list of respiratory viruses is an important cause of acute wheezing in infancy, and viruses are detected in most exacerbations of asthma throughout childhood. Furthermore, infants who develop severe viral respiratory infections are more likely to have asthma later in childhood. There has been progress in understanding the pathogenesis of viral respiratory illnesses, and this has led to new insights into how these processes might differ in asthma. Several host factors, including respiratory allergy and virus-induced interferon responses, modify the risk of virus-induced wheezing. In the absence of effective antiviral therapies, treatment of virus-induced wheezing and exacerbations of asthma can be challenging, and studies evaluating current treatment strategies are reviewed. Understanding the host-pathogen interactions that determine the severity of respiratory illnesses and long-term sequelae is likely to be of great help in identifying at-risk individuals, and in designing new and more effective treatments.
doi:10.1097/INF.0b013e318168b718
PMCID: PMC3913380  PMID: 18820588
rhinovirus; respiratory syncytial virus; asthma

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