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1.  Association of Adenotonsillectomy with Asthma Outcomes in Children: A Longitudinal Database Analysis 
PLoS Medicine  2014;11(11):e1001753.
Rakesh Bhattacharjee and colleagues use data from a US private health insurance database to compare asthma severity measures in children one year before and one year after they underwent adenotonsillectomy with asthma measures in those who did not undergo adenotonsillectomy.
Please see later in the article for the Editors' Summary
Background
Childhood asthma and obstructive sleep apnea (OSA), both disorders of airway inflammation, were associated in recent observational studies. Although childhood OSA is effectively treated by adenotonsillectomy (AT), it remains unclear whether AT also improves childhood asthma. We hypothesized that AT, the first line of therapy for childhood OSA, would be associated with improved asthma outcomes and would reduce the usage of asthma therapies in children.
Methods and Findings
Using the 2003–2010 MarketScan database, we identified 13,506 children with asthma in the United States who underwent AT. Asthma outcomes during 1 y preceding AT were compared to those during 1 y following AT. In addition, 27,012 age-, sex-, and geographically matched children with asthma without AT were included to examine asthma outcomes among children without known adenotonsillar tissue morbidity. Primary outcomes included the occurrence of a diagnostic code for acute asthma exacerbation (AAE) or acute status asthmaticus (ASA). Secondary outcomes included temporal changes in asthma medication prescriptions, the frequency of asthma-related emergency room visits (ARERs), and asthma-related hospitalizations (ARHs). Comparing the year following AT to the year prior, AT was associated with significant reductions in AAE (30.2%; 95% CI: 25.6%–34.3%; p<0.0001), ASA (37.9%; 95% CI: 29.2%–45.6%; p<0.0001), ARERs (25.6%; 95% CI: 16.9%–33.3%; p<0.0001), and ARHs (35.8%; 95% CI: 19.6%–48.7%; p = 0.02). Moreover, AT was associated with significant reductions in most asthma prescription refills, including bronchodilators (16.7%; 95% CI: 16.1%–17.3%; p<0.001), inhaled corticosteroids (21.5%; 95% CI: 20.7%–22.3%; p<0.001), leukotriene receptor antagonists (13.4%; 95% CI: 12.9%–14.0%; p<0.001), and systemic corticosteroids (23.7%; 95% CI: 20.9%–26.5%; p<0.001). In contrast, there were no significant reductions in these outcomes in children with asthma who did not undergo AT over an overlapping follow-up period. Limitations of the MarketScan database include lack of information on race and obesity status. Also, the MarketScan database does not include information on children with public health insurance (i.e., Medicaid) or uninsured children.
Conclusions
In a very large sample of privately insured children, AT was associated with significant improvements in several asthma outcomes. Contingent on validation through prospectively designed clinical trials, this study supports the premise that detection and treatment of adenotonsillar tissue morbidity may serve as an important strategy for improving asthma control.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma has been rising steadily over the past few decades. Nowadays, about 200–300 million adults and children worldwide are affected by asthma, a chronic condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs). Although asthma can develop at any age, it is often diagnosed in childhood—asthma is one of the commonest chronic diseases in children. In the US, for example, asthma affects around 7.1 million children under the age of 18 years and is the third leading cause of hospitalization of children under the age of 15 years. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke. Exercise, cold air, and infections can trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
Recent studies have found an association between severe childhood asthma and obstructive sleep apnea (OSA). In OSA, airway inflammation promotes hypertrophy (excess growth) of the adenoids and the tonsils, immune system tissues in the upper airway. During sleep, the presence of hypertrophic adenotonsillar tissues predisposes the walls of the throat to collapse, which results in apnea—a brief interruption in breathing. People with OSA often snore loudly and frequently wake from deep sleep as they struggle to breathe. Childhood OSA, which affects 2%–3% of children, can be effectively treated by removal of the adenoids and tonsils (adenotonsillectomy). Given the association between childhood OSA and severe asthma and given the involvement of airway inflammation in both conditions, might adenotonsillectomy also improve childhood asthma? Here, the researchers analyze data from the MarketScan database, a large database of US patients with private health insurance, to investigate whether adenotonsillectomy is associated with improvements in asthma outcomes and with reductions in the use of asthma therapies in children.
What Did the Researchers Do and Find?
The researchers used the database to identify 13,506 children with asthma who had undergone adenotonsillectomy and to obtain information about asthma outcomes among these children for the year before and the year after the operation. Because asthma severity tends to decrease with age, the researchers also used the database to identify 27,012 age-, sex-, and geographically matched children with asthma who did not have the operation so that they could examine asthma outcomes over an equivalent two-year period in the absence of complications related to adenotonsillar hypertrophy. Comparing the year after adenotonsillectomy with the year before the operation, adenotonsillectomy was associated with a 30% reduction in acute asthma exacerbations, a 37.9% reduction in acute status asthmaticus (an asthma attack that is unresponsive to the drugs usually used to treat attacks), a 25.6% reduction in asthma-related emergency room visits, and a 35.8% reduction in asthma-related hospitalizations. By contrast, among the control children, there was only a 2% reduction in acute asthma exacerbations and only a 7% reduction in acute status asthmaticus over an equivalent two-year period. Adenotonsillectomy was also associated with significant reductions (changes unlikely to have occurred by chance) in prescription refills for most types of drugs used to treat asthma, whereas there were no significant reductions in prescription refills among children with asthma who had not undergone adenotonsillectomy. The study was limited by the lack of measures of race and obesity, which are both associated with severity of asthma.
What Do These Findings Mean?
These findings show that in a large sample of privately insured children in the US, adenotonsillectomy was associated with significant improvements in several asthma outcomes. These results do not show, however, that adenotonsillectomy caused a reduction in the severity of childhood asthma. It could be that the children who underwent adenotonsillectomy (but not those who did not have the operation) shared another unknown factor that led to improvements in their asthma over time. To prove a causal link, it will be necessary to undertake a randomized controlled trial in which the outcomes of groups of children with asthma who are chosen at random to undergo or not undergo adenotonsillectomy are compared. However, with the proviso that there are some risks associated with adenotonsillectomy, these findings suggest that the detection and treatment of adenotonsillar hypertrophy may help to improve asthma control in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001753.
The US Centers for Disease Control and Prevention provides information on asthma, including videos, games, and links to other resources for children with asthma
The American Lung Association provides detailed information about asthma and a fact sheet on asthma in children; it also has information about obstructive sleep apnea
The National Sleep Foundation provides information on snoring and obstructive sleep apnea in children
The UK National Health Service Choices website provides information (including some personal stories) about asthma, about asthma in children, and about obstructive sleep apnea
The “Global Asthma Report 2014” will be available in October 2014
MedlinePlus provides links to further information on asthma, on asthma in children, on sleep apnea, and on tonsils and adenoids (in English and Spanish)
doi:10.1371/journal.pmed.1001753
PMCID: PMC4219664  PMID: 25369282
2.  Asthma in adults 
Clinical Evidence  2010;2010:1501.
Introduction
About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. Patients with severe disease have an increased risk of death, but patients with mild-to-moderate disease are also at risk of exacerbations. Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for chronic asthma? What are the effects of treatments for acute asthma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (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 99 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. For acute asthma: beta2 agonists (plus ipratropium bromide, pressured metered-dose inhalers, short-acting continuous nebulised, short-acting intermittent nebulised, and short-acting intravenous); corticosteroids (inhaled); corticosteroids (single oral, combined inhaled, and short courses); education about acute asthma; generalist care; helium-oxygen mixture (heliox); magnesium sulphate (intravenous and adding isotonic nebulised magnesium to inhaled beta2 agonists); mechanical ventilation; oxygen supplementation (controlled 28% oxygen and controlled 100% oxygen); and specialist care. For chronic asthma: beta2 agonists (adding long-acting inhaled beta2 agonists when asthma is poorly controlled by inhaled corticosteroids, or short-acting inhaled beta2 agonists as needed for symptom relief); inhaled corticosteroids (low dose and increasing dose); leukotriene antagonists (with or without inhaled corticosteroids); and theophylline (when poorly controlled by inhaled corticosteroids).
Key Points
About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. These people have an increased risk of death.
Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions.
Taking short-acting beta2 agonists as needed is as likely to relieve symptoms and improve lung function as a regular dosing schedule in adults with chronic asthma.
Adding long-acting beta2 agonists to inhaled corticosteroids decreases the number of exacerbations and improves symptoms, lung function, and quality of life in people with mild-to-moderate persistent asthma that is poorly controlled with corticosteroids.
CAUTION: Long-acting beta2 agonists have been associated with increased asthma-related mortality, and should always be used with inhaled corticosteroids.
Low-dose inhaled corticosteroids improve symptoms and lung function in persistent asthma compared with placebo or regular inhaled beta2 agonists. Leukotriene antagonists are more effective than placebo at reducing symptoms, but we don't know if adding leukotriene antagonists to inhaled corticosteroids is of benefit in people with chronic asthma.CAUTION: Leukotriene antagonists have been associated with a possible increased risk of neuropsychiatric events.Adding theophylline to inhaled corticosteroids may improve lung function in people with mild or moderate chronic asthma that is poorly controlled with inhaled corticosteroids, but we don't know if they are of benefit compared with long-acting beta2 agonists or leukotriene antagonists.
In people with an acute attack of asthma, supplementation of beta2 agonists with 28% oxygen, systemic corticosteroids (short courses), additional beta2 agonists (various routes of administration), or ipratropium bromide improve symptoms. Inhaled corticosteroids seem to improve lung function in people with acute asthma. However, we don't know whether inhaled corticosteroids are as effective as systemic corticosteroids at improving symptom severity, lung function, and hospital admissions. Inhaled plus oral corticosteroids and oral corticosteroids alone may have similar effects in preventing relapse and improving lung function.Beta2 agonists delivered from a metered-dose inhaler using a spacer are as effective at improving lung function as those given by a nebuliser or given intravenously. Giving beta2 agonists intravenously is more invasive than giving beta2 agonists by nebuliser.In people with severe acute asthma, continuous nebulised short-acting beta2 agonists may also improve lung function more than intermittent nebulised short-acting beta2 agonists.We don't know if intravenous magnesium sulphate, nebulised magnesium alone, or adding nebulised magnesium to inhaled beta2 agonists improves lung function in people with acute asthma.We don't know whether helium-oxygen mixture (heliox) is more effective at improving lung function compared with usual care. Mechanical ventilation may be life saving in severe acute asthma, but it is associated with high levels of morbidity. Specialist care of acute asthma may lead to improved outcomes compared with generalist care.We don't know whether education to help self-manage asthma improves symptom severity, lung function, or quality of life, but it may reduce hospital admissions.
PMCID: PMC2907598  PMID: 21718577
3.  Asthma in adults (acute) 
Clinical Evidence  2011;2011:1513.
Introduction
About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. Patients with severe disease have an increased risk of death, but patients with mild to moderate disease are also at risk of exacerbations. Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute asthma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 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 100 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 (plus ipratropium bromide, pressured metered-dose inhalers, short-acting continuous nebulised, short-acting intermittent nebulised, short-acting iv, and inhaled formoterol); corticosteroids (inhaled); corticosteroids (single oral, combined inhaled, and short courses); education about acute asthma; generalist care; helium–oxygen mixture (heliox); magnesium sulphate (iv and adding isotonic nebulised magnesium to inhaled beta2 agonists); mechanical ventilation; oxygen supplementation (controlled 28% oxygen and controlled 100% oxygen); and specialist care.
Key Points
About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. These people have an increased risk of death.
Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions.
Inhaled short-acting beta2 agonists are considered the mainstay of treatment for acute asthma.
In people with an acute attack of asthma, supplementation of beta2 agonists with low oxygen concentrations, systemic corticosteroids (short courses), additional beta2 agonists (various routes of administration), or ipratropium bromide improves symptoms. Inhaled corticosteroids seem to improve lung function in people with acute asthma. However, we don't know whether inhaled corticosteroids are as effective as systemic corticosteroids at improving symptom severity, lung function, and hospital admissions. Inhaled plus oral corticosteroids and oral corticosteroids alone may have similar effects in preventing relapse.Beta2 agonists delivered from a metered-dose inhaler using a spacer are as effective at improving lung function as those given by a nebuliser or given iv. Giving beta2 agonists iv is more invasive than giving beta2 agonists by nebuliser.In people with severe acute asthma, continuous nebulised short-acting beta2 agonists may also improve lung function more than intermittent nebulised short-acting beta2 agonists.The inhaled long-acting beta2 agonist formoterol seems to be at least equivalent to the short-acting beta2 agonists salbutamol and terbutaline in terms of pulmonary function in moderate to severe acute asthma treatment. On the basis of research undertaken in people with chronic asthma, the FDA has recommended minimising the use of long-acting beta agonists because of an increased risk of asthma exacerbations, hospital admissions, and death. The FDA acknowledges that they do have an important role in helping some patients control asthma symptoms.We don't know if iv magnesium sulphate, nebulised magnesium alone, or adding nebulised magnesium to inhaled beta2 agonists improves lung function in people with acute asthma.We don't know whether helium–oxygen mixture (heliox) is more effective at improving lung function compared with usual care.Mechanical ventilation may be life saving in severe acute asthma, but it is associated with high levels of morbidity. Specialist care of acute asthma may lead to improved outcomes compared with generalist care.We don't know whether education to help self-manage asthma improves symptom severity, lung function, or quality of life, but it may reduce hospital admissions.
PMCID: PMC3661228  PMID: 21463536
4.  Outcomes After Periodic Use of Inhaled Corticosteroids in Children 
Background
Many children with persistent asthma use inhaled corticosteroids on a periodic basis. Clinical trials in adults suggest that periodic use of inhaled corticosteroids may be effective for patients with mild persistent asthma. However, scant information exists on the clinical outcomes of children with asthma who are using inhaled corticosteroids on a periodic basis in real-world settings.
Objective
This prospective cohort study compared clinical outcomes during a 12-month follow-up period between children with persistent asthma whose parents believed that they were supposed to use inhaled steroids either (a) periodically or (b) daily year-round at the start of the period. The clinical outcomes studied were (1) asthma-related emergency department (ED) visits or hospitalizations, (2) uncontrolled asthma based on health care and medication use, and (3) outpatient visits for asthma.
Patients and methods
The study population included children with persistent asthma from two health plans whose parents reported that they were using inhaled corticosteroids during a baseline telephone interview. The interviews collected information on whether the children’s parents believed they were supposed to use inhaled corticosteroids on a periodic or daily basis, as well as baseline asthma symptom status, sociodemographic, and behavioral variables. We used computerized databases to identify clinical events for each child during the 12 months after their baseline interview. Uncontrolled asthma was defined as any asthma-related ED visit or hospitalization, two or more oral steroid prescription fills, or four or more beta-agonists canisters filled during the 12-month period. We compared these outcomes between the periodic versus daily users of inhaled corticosteroids using logistic regression analyses. We conducted both (1) a traditional logistic regression analysis in which we adjusted for selection bias by including covariates such as age, asthma physical status, sociodemographic and behavioral variables, and history of asthma-related health care use during the year before interview and (2) an analysis using propensity scores to more fully adjust for selection bias.
Results
Of a total of 476 children in the study, 55% of parents believed their children were supposed to be using inhaled corticosteroids on a periodic basis and 45% believed their children were supposed to be using them daily year-round based on the baseline parent interview. At baseline, periodic inhaled corticosteroid users had less severe asthma than daily users based on several measures including better asthma physical status scores on the Children’s Health Survey for Asthma (mean 87 ± 16.0 vs. 81 ± 17.4, p = < 0.0001). During the year before the baseline interview, periodic users compared with daily users were less likely to have an ED visit or hospitalization (10% vs. 23%, p = 0.0001) and less likely to have had five or more albuterol prescription fills (13% vs. 31%, p < 0.0001). During the follow-up year, those who believed inhaled steroids were for periodic use were less likely than those who believed inhaled steroids were for daily use to have an ED visit or hospitalization for asthma (OR 0.36, 95% CI: 0.18–0.73), even after adjusting for baseline asthma status and other covariates. Similarly, those who believed inhaled steroids were for periodic use were less likely to have uncontrolled asthma, OR 0.38 (95% CI: 0.24–0.62). Analyses using propensity score adjustment yielded similar results to the logistic regression analyses.
Conclusion
Children whose parents believed they were supposed to use inhaled corticosteroids on a periodic basis had less severe asthma at baseline than those whose parents believed they were supposed to be using them daily. Periodic users were less likely than daily users to have adverse asthma outcomes during 1-year follow-up. This suggests that clinicians may be applying appropriate selection criteria by choosing patients with less severe asthma for periodic inhaled corticosteroid regimens.
doi:10.1080/02770900802468517
PMCID: PMC4004094  PMID: 19544175
asthma; periodic inhaled corticosteroids; children
5.  Influences on hospital admission for asthma in south Asian and white adults: qualitative interview study 
BMJ : British Medical Journal  2001;323(7319):962.
Objective
To explore reasons for increased risk of hospital admission among south Asian patients with asthma.
Design
Qualitative interview study using modified critical incident technique and framework analysis.
Setting
Newham, east London, a deprived area with a large mixed south Asian population.
Participants
58 south Asian and white adults with asthma (49 admitted to hospital with asthma, 9 not admitted); 17 general practitioners; 5 accident and emergency doctors; 2 out of hours general practitioners; 1 asthma specialist nurse.
Main outcome measures
Patients' and health professionals' views on influences on admission, events leading to admission, general practices' organisation and asthma strategies, doctor-patient relationship, and cultural attitudes to asthma.
Results
South Asian and white patients admitted to hospital coped differently with asthma. South Asians described less confidence in controlling their asthma, were unfamiliar with the concept of preventive medication, and often expressed less confidence in their general practitioner. South Asians managed asthma exacerbations with family advocacy, without systematic changes in prophylaxis, and without systemic corticosteroids. Patients describing difficulty accessing primary care during asthma exacerbations were registered with practices with weak strategies for asthma care and were often south Asian. Patients with easy access described care suggesting partnerships with their general practitioner, had better confidence to control asthma, and were registered with practices with well developed asthma strategies that included policies for avoiding hospital admission.
Conclusions
The different ways of coping with asthma exacerbations and accessing care may partly explain the increased risk of hospital admission in south Asian patients. Interventions that increase confidence to control asthma, confidence in the general practitioner, understanding of preventive treatment, and use of systemic corticosteroids in exacerbations may reduce hospital admissions. Development of more sophisticated asthma strategies by practices with better access and partnerships with patients may also achieve this.
What is already known on this topicSouth Asian patients with asthma are at increased risk of hospital admission with asthma compared with white patientsNo consistent differences in severity or prevalence of asthma, prescribed drugs, or asthma education have been described, and interventions to reduce admission rates in Asian patients have met with variable successWhat this study addsCompared with white patients, south Asian patients admitted to hospital with asthma had less confidence to control asthma, were unfamiliar with the concept of preventive medication, and had less confidence in their general practitionersSouth Asian patients managed asthma attacks through family advocacy and without systematic changes in prophylaxis and without systemic corticosteroidsPatients reporting difficulty in accessing primary care during attacks were often south Asian
PMCID: PMC59689  PMID: 11679384
6.  Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study 
PLoS Medicine  2014;11(7):e1001669.
In this study, Granell and colleagues used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in the Avon Longitudinal Study of Parents and Children (ALSPAC) and found that higher BMI increases the risk of asthma in mid-childhood.
Please see later in the article for the Editors' Summary
Background
Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.
Methods and Findings
We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.
Conclusions
Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma, a chronic (long-term) condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs), has been rising steadily over the past few decades. It is estimated that, nowadays, 200–300 million adults and children worldwide are affected by asthma. Although asthma can develop at any age, it is often diagnosed in childhood—asthma is the most common chronic disease in children. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke, becoming narrower so that less air can enter the lungs. Exercise, cold air, and infections can also trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
We cannot halt the ongoing rise in global asthma rates without understanding the causes of asthma. Some experts think obesity may be one cause of asthma. Obesity, like asthma, is increasingly common, and observational studies (investigations that ask whether individuals exposed to a suspected risk factor for a condition develop that condition more often than unexposed individuals) in children have reported that body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) is positively associated with asthma. Observational studies cannot prove that obesity causes asthma because of “confounding.” Overweight children with asthma may share another unknown characteristic (confounder) that actually causes both obesity and asthma. Moreover, children with asthma may be less active than unaffected children, so they become overweight (reverse causality). Here, the researchers use “Mendelian randomization” to assess whether BMI has a causal effect on asthma. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if a higher BMI leads to asthma, genetic variants associated with increased BMI should be associated with an increased risk of asthma.
What Did the Researchers Do and Find?
The researchers investigated causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in 4,835 children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC, a long-term health project that started in 1991). They calculated an allele score for each child based on 32 BMI-related genetic variants, and estimated associations between this score and BMI, fat mass and lean mass (both measured using a special type of X-ray scanner; in children BMI is not a good indicator of “fatness”), and asthma. They report that the allele score was strongly associated with BMI, fat mass, and lean mass, and with childhood asthma. The estimated causal relative risk (risk ratio) for the effect of BMI on asthma was 1.55 per kg/m2. That is, the relative risk of asthma increased by 55% for every extra unit of BMI. The estimated causal relative risks for the effects of fat mass and lean mass on asthma were 1.41 per 0.5 kg and 2.25 per kg, respectively.
What Do These Findings Mean?
These findings suggest that a higher BMI increases the risk of asthma in mid-childhood and that global increases in BMI toward the end of the 20th century may have contributed to the global increase in asthma that occurred at the same time. It is possible that the observed association between BMI and asthma reported in this study is underpinned by “genetic pleiotropy” (a potential limitation of all Mendelian randomization analyses). That is, some of the genetic variants included in the BMI allele score could conceivably also increase the risk of asthma. Nevertheless, these findings suggest that public health interventions designed to reduce obesity may also help to limit the global rise in asthma.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001669.
The US Centers for Disease Control and Prevention provides information on asthma and on all aspects of overweight and obesity (in English and Spanish)
The World Health Organization provides information on asthma and on obesity (in several languages)
The UK National Health Service Choices website provides information about asthma, about asthma in children, and about obesity (including real stories)
The Global Asthma Report 2011 is available
The Global Initiative for Asthma released its updated Global Strategy for Asthma Management and Prevention on World Asthma Day 2014
Information about the Avon Longitudinal Study of Parents and Children is available
MedlinePlus provides links to further information on obesity in children, on asthma, and on asthma in children (in English and Spanish
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001669
PMCID: PMC4077660  PMID: 24983943
7.  Prescribing patterns of asthma controller therapy for children in UK primary care: a cross-sectional observational study 
Background
Asthma management guidelines recommend a stepwise approach to instituting and adjusting anti-inflammatory controller therapy for children with asthma. The objective of this retrospective observational study was to describe prescribing patterns of asthma controller therapies for children in a primary care setting.
Methods
Data from the UK General Practice Research Database were examined for children with recorded asthma or recurrent wheezing who, from September 2006 through February 2007, were ≤ 14 years old at the time of a first asthma controller prescription after ≥ 6 months without a controller prescription. We evaluated demographic characteristics, asthma duration, comorbidities, asthma-related health care resource use, and prescribed daily dose of controller medication. In addition, physicians for 635 randomly selected patients completed a survey retrospectively classifying asthma severity at the prescription date and describing therapy and health care utilization for 6 prior months.
Results
We identified 10,004 children, 5942 (59.4%) of them boys, of mean (SD) age of 8.0 (3.8) years. Asthma controller prescriptions were for inhaled corticosteroid (ICS) monotherapy for 9059 (90.6%) children; ICS plus long-acting β2-agonist (LABA) for 698 (7.0%); leukotriene antagonist monotherapy for 91 (0.9%); ICS plus leukotriene antagonist for 55 (0.6%); and other therapy for 101 (1.0%), including 45 (0.45%) children who were prescribed LABA as monotherapy. High doses of ICS (> 400 μg) were prescribed for 44/2140 (2.1%) children < 5 years old and for 420/7452 (5.6%) children ≥ 5 years. Physicians reported asthma severity as intermittent for 346/635 (55%) patients and as mild, moderate, and severe persistent for 159 (25%), 71 (11%), and 11 (2%), respectively (severity data missing for 48 [8%]). The baseline characteristics and controller therapy prescriptions of the survey cohort were similar to those of the full cohort.
Conclusions
Physician classifications of asthma severity did not always correspond to guideline recommendations, as leukotriene receptor antagonists were rarely used and high-dose ICS or add-on LABA was prescribed even in intermittent and mild disease. In UK primary care, monotherapy with ICS is the most common controller therapy at all levels of asthma severity.
doi:10.1186/1471-2466-10-29
PMCID: PMC2882363  PMID: 20470409
8.  Value of Inhaled Corticosteroid Therapy In Long-Term Asthma Management 
Pharmacy and Therapeutics  2010;35(7):377-416.
Asthma, which affects more than 22 million people in the U.S. every year, poses a significant clinical and economic burden to our health care system. Patients, health care practitioners, and payers require a variety of resources to ensure optimal disease management and positive clinical outcomes while also managing costs. In addition, decision makers in health care must determine the most appropriate and cost-efficient therapy or class of agents to achieve asthma control. As such, payers rely on evidence-based medicine, including guidelines to determine the right therapy for the right patient.
Inhaled corticosteroid (ICS) therapy plays a critical role in the management of mild-to-moderate persistent asthma. Despite national treatment guidelines that cite ICS therapy as the most effective and safest long-term treatment option for persistent asthma, ICS monotherapy continues to be underused. One retrospective claims study found that 55.2% of children with mild-to-moderate asthma received prescriptions for combination therapy (ICS and long-acting beta-agonists) as initial controller treatment. This practice is contrary to national treatment guidelines, which recommend a step-therapy approach. These prescribing patterns result in higher pharmacy costs, do not always ensure control of symptoms, and sometimes expose patients to potential safety risks.
This article addresses the importance of ICS therapy in the treatment of mild-to-moderate asthma, as advocated by the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3 guidelines; the role of small airway disease in asthma pathophysiology; and the clinical and economic benefits of ICS therapy.
PMCID: PMC2912006  PMID: 20689625
asthma; inhaled corticosteroid; disease management; cost effectiveness
9.  276 A 4-Year Follow-up in Children With Moderate/Severe Asthma after Withdrawal 1 Year Omalizumab Treatment 
Background
Asthma guidelines include omalizumab in the step up management in those patients with severe non-controlled asthma despite the use of the inhaled corticosteroids (ICS) at the highest dose recommended and/or oral corticosteroids (OCS) courses. This communication describes the 4 year follow up of children with moderate/severe allergic asthma treated for 1 year with add-on omalizumab after discontinuation.
Methods
7 children (6 to <12 years) with moderate/severe uncontrolled asthma following strict inclusion/exclusion criteria. The patients completed a 1 year treatment with omalizumab according to the DBPC CIGE025 clinical study protocol. Four years follow up after discontinuation of the study medication was performed. It included clinical assessment, different asthma-related outcomes and lung function in outpatient hospital office
Results
All patients that received xolair during the study period achieved good asthma control and high dose ICS (mean dose fluticasone 500 mcg) were could be discontinued. Surprisingly, the 7 patients that received Xolair for one year were completely free of asthma symptoms during the first 3 years of follow up. They did not use any additional asthma medication. After the third year of follow up, only 2 out of 7 (28%) patients begun with persistent asthma symptoms and exacerbations. These patients have required rescue medication and then regular controller medication (budesonide 400 mcg). We could not identified any risk factor helping in predicting those who had symptoms relapsing. Lung function, number of exacerbation, number of hospitalization, eosinophilia, IgE levels or previous treatments with OCS
Conclusions
Most of these patients 5 out of 7 still remain asymptomatic 4 years after discontinuation Xolair without regular ICS treatment. They are still not using any controller medication only 2 patients had exacerbations and at present show persistent mild asthma controlled with medium ICS therapy. This follow up would generate the hypothesis that omalizumab could have a potential as a modifier of the natural history of asthma beyond the improvement of symptoms control in children with moderate/severe uncontrolled asthma. Further studies are needed to test this hypothesis.
doi:10.1097/01.WOX.0000412033.47007.6f
PMCID: PMC3512580
10.  Socioeconomic, Family, and Pediatric Practice Factors Affecting the Level of Asthma Control 
Pediatrics  2009;123(3):829-835.
Background
Multiple issues bear on effective control of childhood asthma.
Objective
To identify factors related to the level of asthma control in children receiving asthma care from community pediatricians.
Patients and Methods
Data for 362 children participating in an intervention study to reduce asthma morbidity were collected by telephone administered questionnaire. Level of asthma control (“well controlled,” partially controlled,” or “poorly controlled”) was derived from measures of recent impairment (symptoms, activity limitations, albuterol use) and the number of exacerbations in a 12 month period. Data also included demographic characteristics, asthma-related quality of life, pediatric management practices, and medication usage. Univariable and multivariable analyses were used to identify factors associated with poor asthma control and to explore the relationship between control and use of daily controller medications.
Results
Asthma was “well controlled” for 24% of children, “partially controlled” for 20%, and “poorly controlled” for 56%. Medicaid insurance (p=0.016), the presence of another family member with asthma (p=0.0168), and outside the home maternal employment, (p=0.025), were significant univariable factors associated with poor asthma control. Medicaid insurance had an independent association with poor control (OR 0.49, 95% CI 0.28-0.9). Seventy-six percent of children were reported by parents as receiving a daily controller medication. Comparison of guidelines recommended controller medication with level of control indicated that a higher step level of medication would have been appropriate for 74% of these children. Significantly lower overall quality of life scores were observed in both parents and children with poor control. (ANOVA, p<0.05)
Conclusion
Despite substantial use of daily controller medication, children with asthma continue to experience poorly controlled asthma and reduced quality of life. While Medicaid insurance and aspects of family structure are significant factors associated with poorly controlled asthma, attention to medication use and quality of life indicators may further reduce morbidity.
doi:10.1542/peds.2008-0504
PMCID: PMC2723164  PMID: 19255010
Childhood asthma; asthma control; asthma outcomes
11.  Asthma in adults (chronic) 
Clinical Evidence  2011;2011:1512.
Introduction
About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. Patients with severe disease have an increased risk of death, but patients with mild-to-moderate disease are also at risk of exacerbations. Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for chronic asthma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 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 54 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: adding anti-IgE treatment; beta2 agonists (adding long-acting inhaled beta2 agonists when asthma is poorly controlled by inhaled corticosteroids, or short-acting inhaled beta2 agonists as needed for symptom relief); inhaled corticosteroids (low dose and increasing dose); leukotriene antagonists (with or without inhaled corticosteroids); and theophylline (when poorly controlled by inhaled corticosteroids).
Key Points
About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. These people have an increased risk of death.
Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions.
Taking short-acting beta2 agonists as needed is as likely to relieve symptoms and improve lung function as a regular dosing schedule in adults with chronic asthma.
Adding long-acting beta2 agonists to inhaled corticosteroids decreases the number of exacerbations and improves symptoms, lung function, and quality of life in people with mild-to-moderate persistent asthma that is poorly controlled with corticosteroids.
CAUTION: Long-acting beta2 agonists have been associated with increased asthma-related mortality, and should always be used with inhaled corticosteroids.
Low-dose inhaled corticosteroids improve symptoms and lung function in persistent asthma compared with placebo or regular inhaled beta2 agonists. Leukotriene antagonists are more effective than placebo at reducing symptoms, but we don't know if adding leukotriene antagonists to low-dose inhaled corticosteroids is of benefit in people with chronic asthma.CAUTION: Leukotriene antagonists have been associated with a possible increased risk of neuropsychiatric events.Adding theophylline to inhaled corticosteroids may improve lung function in people with mild or moderate chronic asthma that is poorly controlled with inhaled corticosteroids, but we don't know if they are of benefit compared with long-acting beta2 agonists or leukotriene antagonists. Anti-IgE treatment (omalizumab) as an adjunct to treatment with inhaled and oral corticosteroids improves symptom severity, decreases exacerbation frequency, and may decrease hospital admission rates in people with chronic moderate to severe asthma.
PMCID: PMC3275169  PMID: 21749735
12.  Health care utilization and medical costs for childhood asthma in Taiwan: using Taiwan National Health Insurance Research Database 
Asia Pacific Allergy  2012;2(3):167-171.
Asthma is an important health problem worldwide and the prevalence is increasing in most part of the world. The burden of this disease to governments, health-care systems, and patients and their families have been greater more than ever despite efforts advocated by Global Initiative for Asthma for total asthma controls. Using Taiwan National Health Insurance Research Database, in this review, the population-based prospective studies showed the costs and health care utilization of childhood asthma in Taiwan was 2 folds higher than non-asthmatic children, and the prescription patterns of anti-asthmatic medications among physician in different discipline were all far from satisfied. The appropriateness of combinational therapy of inhaled corticosteroids and long acting β-agonists for moderate to severe childhood asthma was only 62%. In a government-sponsored disease management program for asthmatic patients within national health insurance, though the total mean costs (26.5%) and outpatient costs (26.1%) increased, the mean emergency department visits and hospitalization rates were significantly reduced by 34.4% and 51.74%, respectively, compared to the previous year. Therefore, in the real-world situation, asthmatic patients as well as medical professions who take care of asthmatic children still have much space for their symptoms controls and knowledge improvement to reduce the burden of asthma. From the experience of care and management of childhood asthma in Taiwan may reveal same problems of childhood asthma care in the similar cultural and ecological environments of Asian pacific countries, and suggest government-sponsored program may also have significant impact aimed at improving the care of patients with asthma.
doi:10.5415/apallergy.2012.2.3.167
PMCID: PMC3406295  PMID: 22872818
Childhood asthma; Health care utilization; Disease management; National health insurance
13.  Asthma Control in Oman 
Objectives:
The Asthma Insights and Reality (AIR) study in the Gulf and Near East (one of a worldwide series of surveys conducted in adults and children to assess asthma control) was conducted in Oman to assess how closely asthma control meets international guidelines recommendations.
Methods:
From January 2007 to March 2008, asthmatics receiving treatment or currently suffering from asthma symptoms were interviewed among nationals randomly surveyed from the most populated urban areas in Oman (Muscat, Sohar and Nizwa). The standard AIR questionnaire was used to assess symptom severity, health care utilisation, limitation of activity and medication use.
Results:
From 201 asthmatic participants, 21% were under 16 years and 43% were female. Tobacco use was low in our asthmatics. Disparity in asthma perception was wide in Oman; while 57% of asthmatics perceived their asthma as well or completely controlled, actually 54% had poorly or not well controlled asthma. All recommendations for asthma control by the Global Initiative for Asthma were largely unmet, especially in child asthmatics, with 44% reporting night awakenings due to asthma during the previous 4 weeks and 47% exercise-induced asthma in the previous 12 months. Overall, 32.6% of children and 34.8% of adults reported absence due to asthma from school/work during the previous year. Use of preventive inhaled corticosteroids was only 5.0%, one of the lowest even within the AIR Gulf and Near East study, producing an unacceptable ratio ICS/SABA (inhaled corticosteroid/short acting beta-agonist) of 0.054 in Omani asthmatics.
Conclusion:
Asthma control in Oman falls far below the goals of current international guidelines therefore corrective strategies are needed.
PMCID: PMC3074685  PMID: 21509207
Asthma; Oman; Health survey; Asthma Prevention & Control; Adult; Child
14.  Asthma and other recurrent wheezing disorders in children (acute) 
Clinical Evidence  2012;2012:0300.
Introduction
Acute childhood asthma is a common clinical emergency presenting across a range of ages and with a range of severities.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute asthma in children? 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 35 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 (high-dose nebulised, metered-dose inhaler plus spacer device versus nebuliser, intravenous), corticosteroids (systemic, high-dose inhaled), ipratropium bromide (single- or multiple-dose inhaled), magnesium sulphate, oxygen, and theophylline or aminophylline.
Key Points
Not all acute wheeze is due to asthma/bronchospasm, particularly in children aged <2 years. If bronchodilators do not improve symptoms, alternative diagnoses (e.g., infection, foreign body) should be considered.
Although no evidence exists to support the use of oxygen in acute asthma, it is known to be effective and should be administered when oxygen saturations fall below 94% in all cases of acute asthma.
Although there is little evidence to support the use of inhaled bronchodilators, they remain one of the first-line treatment choices for acute asthma. In mild to moderate acute asthma, beta2 agonists may be equally as effective from a metered-dose inhaler/spacer combination compared with nebuliser for control of acute symptoms and may be associated with a shorter duration of stay in the emergency department and reduced side effects.In severe acute asthma, we don't know whether there is a difference between continuous and intermittent nebulised beta2 agonists.CAUTION: Inhaled salbutamol has been associated with hypokalaemia and tremor.
The only indication for ipratropium bromide for acute childhood asthma is in combination with salbutamol for acute severe wheeze.
Although there is little evidence to support the use of oral corticosteroids, they remain one of the first-line treatment choices for acute asthma. In mild to moderate asthma, oral corticosteroids are known to be more effective than placebo. We don't know whether high-dose inhaled corticosteroids and oral corticosteroids differ in effectiveness as we found insufficient evidence.
For severe asthma, addition of intravenous salbutamol, aminophylline, or magnesium sulphate are all effective compared with the addition of placebo. In severe acute asthma, we don't know whether intravenous aminophylline and salbutamol differ in effectiveness as we found insufficient evidence from one small RCT.CAUTION: Intravenous salbutamol and aminophylline have been associated with cardiac arrhythmias. Salbutamol has been associated with hypokalaemia and aminophylline has been associated with nausea. Intravenous theophylline can cause cardiac arrhythmias and convulsions if therapeutic blood concentrations are exceeded.
PMCID: PMC3390594  PMID: 24807832
15.  The Effect of Budesonide/Formoterol Pressurized Metered-Dose Inhaler on Predefined Criteria for Worsening Asthma in Four Different Patient Populations with Asthma 
Drugs in R&d  2012;12(1):9-14.
Background Previous studies have shown disparities between Black and Hispanic patients compared with other populations in response to asthma medications.
Objective: The aim of this analysis was to assess the effect of budesonide/formoterol pressurized metered-dose inhaler (BUD/FM pMDI) and BUD on predefined criteria for asthma worsening, an asthma control metric generally aligned with definitions of moderate asthma exacerbations, across four different populations.
Methods: Data were from four 12-week, randomized, double-blind,US studies of BUD/FM pMDI treatment in patients aged 12 years or older with varying asthma severities and of varying races. Predefined asthma events and withdrawals due to predefined events were assessed as secondary study endpoints. Study I (NCT00651651) includes data from predominantly White patients with mild to moderate asthma who were randomized to BUD/FM pMDI 160/9 μg twice daily (bid; n = 123) or BUDpMDI 160 μg bid (n = 121). Study II (NCT00652002) includes data from predominantly White patients withmoderate to severe asthma who were randomized to BUD/FM pMDI 320/9 μg bid (n = 124) or BUD pMDI 320 μg bid (n = 109). Study III (NCT00702325) included self-reported Black patients with moderate to severe asthma who were randomized to BUD/FM pMDI 320/9 μg bid (n = 153) or BUD dry powder inhaler 360 μg bid (n = 148). Study IV (NCT00419757) included self-reported Hispanic patients with moderate to severe asthma who were randomized to BUD/FM pMDI 320/9 μg bid (n = 127) or BUD pMDI 320 μg bid (n = 123). Patients were to be withdrawn from the studies if they developed an asthma event, as determined by predefined criteria, except for night-time awakenings, where withdrawal was left to the study physician’s judgment.
Results: Overall, fewer patients in the studies (study I, II, III, and IV, respectively) experienced ≧1 asthma event in the BUD/FM group (18.7%, 29.8%, 37.3%, 25.2%) versus the BUD group (21.5%, 44.0%, 45.3%, 31.7%); only study II results showed a statistically significant difference between treatments. Fewer patients with moderate to severe asthma (studies II, III, and IV) were withdrawn due to ≧1 asthma event in the BUD/FM group (10.5%, 11.8%, 3.1%, respectively) than in the BUD group (20.2%, 18.9%, 6.5%, respectively); however, percentages were similar in the BUD/FM (7.3%) and BUD (6.6%) groups in patients with mild to moderate asthma (study I).
Conclusions: Predefined asthma event rates were numerically or significantly lower for patients with asthma receiving BUD/FMpMDI versusBUD, regardless of race or disease severity. Differences between the BUD/FM pMDI and BUD groupswere smaller in patients with mild to moderate asthma than in those with moderate to severe asthma, most likely because patients with milder disease had lower asthma event rates. Overall, these findings support the efficacy of BUD/FM pMDI in achieving asthma control in patients with moderate to severe asthma.
doi:10.2165/11630600-000000000-00000
PMCID: PMC3586061  PMID: 22329608
16.  The Effect of Budesonide/Formoterol Pressurized Metered-Dose Inhaler on Predefined Criteria for Worsening Asthma in Four Different Patient Populations with Asthma 
Drugs in R&D  2012;12(1):9-14.
Background Previous studies have shown disparities between Black and Hispanic patients compared with other populations in response to asthma medications.
Objective: The aim of this analysis was to assess the effect of budesonide/formoterol pressurized metered-dose inhaler (BUD/FM pMDI) and BUD on predefined criteria for asthma worsening, an asthma control metric generally aligned with definitions of moderate asthma exacerbations, across four different populations.
Methods: Data were from four 12-week, randomized, double-blind,US studies of BUD/FM pMDI treatment in patients aged 12 years or older with varying asthma severities and of varying races. Predefined asthma events and withdrawals due to predefined events were assessed as secondary study endpoints. Study I (NCT00651651) includes data from predominantly White patients with mild to moderate asthma who were randomized to BUD/FM pMDI 160/9 μg twice daily (bid; n = 123) or BUDpMDI 160 μg bid (n = 121). Study II (NCT00652002) includes data from predominantly White patients withmoderate to severe asthma who were randomized to BUD/FM pMDI 320/9 μg bid (n = 124) or BUD pMDI 320 μg bid (n = 109). Study III (NCT00702325) included self-reported Black patients with moderate to severe asthma who were randomized to BUD/FM pMDI 320/9 μg bid (n = 153) or BUD dry powder inhaler 360 μg bid (n = 148). Study IV (NCT00419757) included self-reported Hispanic patients with moderate to severe asthma who were randomized to BUD/FM pMDI 320/9 μg bid (n = 127) or BUD pMDI 320 μg bid (n = 123). Patients were to be withdrawn from the studies if they developed an asthma event, as determined by predefined criteria, except for night-time awakenings, where withdrawal was left to the study physician’s judgment.
Results: Overall, fewer patients in the studies (study I, II, III, and IV, respectively) experienced ≧1 asthma event in the BUD/FM group (18.7%, 29.8%, 37.3%, 25.2%) versus the BUD group (21.5%, 44.0%, 45.3%, 31.7%); only study II results showed a statistically significant difference between treatments. Fewer patients with moderate to severe asthma (studies II, III, and IV) were withdrawn due to ≧1 asthma event in the BUD/FM group (10.5%, 11.8%, 3.1%, respectively) than in the BUD group (20.2%, 18.9%, 6.5%, respectively); however, percentages were similar in the BUD/FM (7.3%) and BUD (6.6%) groups in patients with mild to moderate asthma (study I).
Conclusions: Predefined asthma event rates were numerically or significantly lower for patients with asthma receiving BUD/FMpMDI versusBUD, regardless of race or disease severity. Differences between the BUD/FM pMDI and BUD groupswere smaller in patients with mild to moderate asthma than in those with moderate to severe asthma, most likely because patients with milder disease had lower asthma event rates. Overall, these findings support the efficacy of BUD/FM pMDI in achieving asthma control in patients with moderate to severe asthma.
doi:10.2165/11630600-000000000-00000
PMCID: PMC3586061  PMID: 22329608
17.  Asthma Diagnosis, Severity, Control and Medication Use In Low Income Minority Preteens 
Background
Asthma severity, control, type of medical regimen provided and compliance with it are not well understood in minority patients at the transition stage from childhood to adolescence.
Objective
Identify factors in clinical practice and patient behavior associated with negative outcomes for children at this developmentally significant period.
Methods
Parents of 1292 children with asthma among 6827 pre-teens in 19 middle schools in predominantly African American (94%), low income neighborhoods in Detroit, Michigan were enrolled. Data collected through self administered survey and telephone interviews were useable for 936 parents. Study queries related to demographics, asthma symptoms, and medication use. Mixed effects models with a random intercept for school used to determine severity and control and association of medical regimens to these.
Results
Sixty-seven percent children with probable asthma had received a physician's diagnosis. Being female was associated with being undiagnosed (p=0.02); 47% with no diagnosis had persistent asthma and 68% with a diagnosis and asthma medicines were not controlled. Over half with a diagnosis and no medicine were not controlled. Thirty nine percent had controller medicine; 40% were not compliant with controller use; 9% nebulized controller medicine. Compliant use of controller medicine was not associated with asthma control (p=0.001).
Conclusions
Lack of an asthma diagnosis was significant in these low income communities. Adolescent girls were at risk for not receiving a diagnosis. Regimens provided children at an important stage in their development were not consistent with therapies recommended for asthma control. Patient compliance with asthma regimens was low. Both clinical and patient education regarding effective asthma management is needed regarding pre teens in low income minority communities.
Clinical Implications
Diagnosis and medical therapy choices for low income, African American pre-adolescents may not account for the actual level of their symptoms. Asthma is likely to be uncontrolled at this significant developmental stage in this population. Girls may be at risk for diagnosis failure.
doi:10.3109/02770900903483824
PMCID: PMC3098616  PMID: 20170321
Asthma; Pre-Adolescents; Intervention; Self-Management; Middle School; African-American; Low Income
18.  Long-Term Budesonide or Nedocromil Treatment, Once Discontinued, Does Not Alter the Course of Mild to Moderate Asthma in Children and Adolescents 
The Journal of pediatrics  2009;154(5):682-687.
Objectives
To determine whether long-term, continuous use of inhaled anti-inflammatory medications affects asthma outcomes in children with mild-moderate asthma after use is discontinued.
Study design
Of 1,041 participants in the Childhood Asthma Management Program randomized clinical trial, 941 (90%) were followed to determine whether 4.3 years of twice daily budesonide or nedocromil (each compared with placebo) affected subsequent asthma outcomes during a 4.8 year post-trial period in which treatment was managed by the participant's physician.
Results
The groups treated continuously during the trial with either budesonide or nedocromil did not differ from placebo in lung function, control of asthma, or psychological status at the end of 4.8 years of post-trial follow-up; however, the decreased mean height in the budesonide group relative to the placebo group at the end of the trial (1.1 cm, P=0.005) remained statistically significant (0.9 cm, P=0.01) after an additional 4.8 years and was more pronounced in girls (1.7 cm; P=0.001) than boys (0.3 cm; P=0.49). Participants used inhaled corticosteroids during 30% of the post-trial period in all groups.
Conclusions
Clinically meaningful improvements in control of asthma and improvements in airway responsiveness achieved during continuous treatment with inhaled corticosteroids do not persist after continuous treatment is discontinued.
doi:10.1016/j.jpeds.2008.11.036
PMCID: PMC2942076  PMID: 19167726
19.  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
20.  Inflammatory phenotypes underlying uncontrolled childhood asthma despite inhaled corticosteroid treatment: rationale and design of the PACMAN2 study 
BMC Pediatrics  2013;13:94.
Background
The diagnosis of childhood asthma covers a broad spectrum of pathological mechanisms that can lead to similarly presenting clinical symptoms, but may nonetheless require different treatment approaches. Distinct underlying inflammatory patterns are thought to influence responsiveness to standard asthma medication.
Methods/design
The purpose of the PACMAN2 study is to identify inflammatory phenotypes that can discriminate uncontrolled childhood asthma from controlled childhood asthma by measures in peripheral blood and exhaled air. PACMAN2 is a nested, case–control follow-up study to the ongoing pharmacy-based “Pharmacogenetics of Asthma medication in Children: Medication with Anti-inflammatory effects” (PACMAN) study. The original PACMAN cohort consists of children aged 4–12 years with reported use of asthma medication. The PACMAN2 study will be conducted within the larger PACMAN cohort, and will focus on detailed phenotyping of a subset of the PACMAN children. The selected participants will be invited to a follow-up visit in a clinical setting at least six months after their baseline visit based on their adherence to usage of inhaled corticosteroids, their asthma symptoms in the past year, and their age (≥ 8 years). During the follow-up visit, current and long-term asthma symptoms, medication use, environmental factors, medication adherence and levels of exhaled nitric oxide will be reassessed. The following measures will also be examined: pulmonary function, exhaled volatile organic compounds, as well as inflammatory markers in peripheral blood and blood plasma. Comparative analysis and cluster-analyses will be used to identify markers that differentiate children with uncontrolled asthma despite their use of inhaled corticosteroids (ICS) (cases) from children whose asthma is controlled by the use of ICS (controls).
Discussion
Asthmatic children with distinct inflammatory phenotypes may respond differently to anti-inflammatory therapy. Therefore, by identifying inflammatory phenotypes in children with the PACMAN2 study, we may greatly impact future personalised treatment strategies, uncover new leads for therapeutic targets and improve the design of future clinical studies in the assessment of the efficacy of novel therapeutics.
doi:10.1186/1471-2431-13-94
PMCID: PMC3691827  PMID: 23768206
Asthma; Child; Phenotypes; Inflammation; Proteomics; Volatile organic compounds; Corticosteroids
21.  Predictors of Remitting, Periodic, and Persistent Childhood Asthma 
Background
The course of mild to moderate persistent asthma in children is not clearly established.
Objective
To determine the rate and predictors for remitting, periodic, and persistent asthma in adolescence.
Methods
The Childhood Asthma Management Program (CAMP) was a 4.3-year randomized, double-masked, multicenter trial in children with mild to moderate persistent asthma that compared continuous therapy with either budesonide or nedocromil, each to placebo, followed by 4 years observational follow-up period. Asthma activity during the observation period included remitting (no asthma activity in the last year), persistent (asthma activity in every quarter), and periodic asthma (neither remitting nor persistent).
Results
Asthma was identified as remitting in 6%, periodic in 39%, and persistent in 55% of the 909 participants, with no effect noted from earlier anti-inflammatory treatment during the CAMP trial. Within all three asthma activity categories, improvements in airway hyperresponsiveness, eosinophilia, and asthma morbidity were observed over time. Features at entry into CAMP associated with remitting vs. persistent asthma were lack of allergen sensitization and exposure to indoor allergens [OR=3.23, p<0.001], milder asthma [OR=2.01, p=0.03], older age [OR=1.23, p=0.01], less airway hyperresponsiveness (higher log methacholine FEV1 PC20 [OR=1.39, p=0.03]), higher pre-bronchodilator FEV1 % predicted [OR=1.05, p=0.02], and lower FVC % predicted [OR=0.96, p=0.04].
Conclusion
Remission of asthma in adolescence is infrequent and not impacted by 4 years of anti-inflammatory controller therapy. Factors such as sensitization and exposure, low lung function, and airway greater hyperresponsiveness decrease the likelihood of remitting asthma.
doi:10.1016/j.jaci.2009.10.037
PMCID: PMC2844768  PMID: 20159245
Remission; Natural history; Persistent asthma
22.  331 Asthma Management in Latin America: Learnings from the Latin America Asthma Insight and Management (LA AIM) Survey of Patients 
The World Allergy Organization Journal  2012;5(Suppl 2):S123-S124.
Background
In 2003, the Asthma Insights and Reality in Latin America (AIRLA) survey assessed, in part, perception, knowledge, and attitudes related to asthma.1 In 2011 the Latin America Asthma Insight and Management (LA AIM) survey was designed to ascertain the realities of living with asthma, disconnect between expectations in asthma management and patient experience, and unmet needs. Using results from our survey, we investigated the advances made in asthma care and the challenges that remain for Latin American patients with asthma.
Methods
Asthma patients aged ≥18 years from 4 Latin American countries (Argentina, Brazil, Mexico, Venezuela) and the Commonwealth of Puerto Rico responded to survey questions during 35-minute face-to-face interviews. A sample size of 2000 patients (400 patients/location) provided an accurate national representation of the opinions of asthma patients. Questions probed respondents' views on topics such as patient-reported levels of asthma control, frequency and duration of exacerbations in the past year, and current and recent use of asthma medications. Participants in both surveys had a diagnosis of asthma, had taken asthma medication, or had an asthma attack within 12 months of the survey.
Results
Results from the LA AIM will be available November 2011. A total of 2184 adults or parents of children with asthma took part in AIRLA by phone or face-to-face interviews.1 In AIRLA, 54.0% of respondents reported their disease as well- or completely controlled. However, only 2.4% met all guideline criteria for asthma control. Further, 6% of AIRLA respondents reported their asthma as severe; however, when guideline criteria were applied, 21% had severe asthma.
Conclusions
The responses in LA AIM shed light on whether there have been meaningful changes since the 2003 AIRLA survey in patient perception of their asthma control and that control as defined by guideline criteria. Because asthma morbidity is largely preventable, additional education is required to teach patients that by more closely following asthma management strategies outlined by current guidelines, more patients can achieve adequate asthma control.
doi:10.1097/01.WOX.0000412094.11096.f5
PMCID: PMC3512921
23.  RETRACTED ARTICLE: Inhaled corticosteroids and long-acting beta-agonists in adult asthma: a winning combination in all? 
In the recent years, considerable insight has been gained in to the optimal management of adult asthma. Most adult patients with asthma have mild intermittent and persistent disease, and it is acknowledged that many patients do not reach full control of all symptoms and signs of asthma. Those with mild persistent asthma are usually not well controlled without inhaled corticosteroids (ICS). Studies have provided firm evidence that these patients can be well controlled when receiving ICS, especially when disease is of recent onset. This treatment should be given on a daily basis at a low dose and when providing a good response should be maintained to prevent severe exacerbations and disease deterioration. Intermittent ICS treatment at the time of an exacerbation has also been suggested as a strategy for mild persistent asthma, but it is less effective than low-dose regular treatment for most outcomes. Adding a long-acting beta-agonist (LABA) to ICS appears to be unnecessary in most of these patients for optimising control of their asthma. Patients with moderate persistent asthma can be regarded as those who are not ideally controlled on low-dose ICS alone. The combination of an ICS and LABA is preferred in these patients, irrespective of the brand of medicine, and this combination is better than doubling or even quadrupling the dose of ICS to achieve better asthma control and reduce exacerbation risks. An ICS/LABA combination in a single inhaler represents a safe, effective and convenient treatment option for the management of patients with asthma unstable on inhaled steroids alone. Ideally, once asthma is under full control, the dose of inhaled steroids should be reduced, which is possible in many patients. The duration of treatment before initiating this dose reduction has, however, not been fully established. One of the combinations available to treat asthma (budesonide and formoterol) has also been assessed as both maintenance and rescue therapy with a further reduction in the risk for a severe exacerbation. Clinical effectiveness in the real world now has to be established, since this approach likely improves compliance with regular maintenance therapy.
doi:10.1007/s00210-008-0302-y
PMCID: PMC2493602  PMID: 18500509
Asthma; Beta-2-agonist; Inhaled corticosteroids; Hyperresponsiveness
24.  Early asthma control and maintenance with eformoterol following reduction of inhaled corticosteroid dose 
Thorax  2002;57(9):791-798.
Background: Previous studies have indicated the benefits of adding long acting ß2 agonists to inhaled corticosteroids in the maintenance treatment of moderate to severe asthma. The effects of adding eformoterol to corticosteroids on asthma control and exacerbations in patients with mild to moderate asthma were studied.
Methods: After a run in period of 7–14 days on existing medication, 663 symptomatic patients were randomised to receive budesonide Turbohaler 400 µg twice daily together with either eformoterol Turbohaler 9 µg (delivered dose) or placebo twice daily. After 4 weeks patients whose asthma was well controlled (n=505) were re-randomised to receive budesonide 400 µg daily and either eformoterol 9 µg or placebo twice daily for a further 6 months.
Results: Patients receiving eformoterol achieved asthma control 10 days sooner than those receiving budesonide alone, and improvements in lung function, symptoms, quality of life, and relief ß2 agonist use were significantly greater with eformoterol. During the 6 month follow up the frequency of mild exacerbations was significantly lower in the eformoterol group than in those receiving budesonide alone (7.2 versus 10.5 per patient, 95% confidence interval for ratio 0.49 to 0.96, p=0.03). The time to first day of poorly controlled asthma was 97 days in the eformoterol group compared with 42 days in the placebo group (p=0.003).
Conclusions: Adding eformoterol to a low or moderate dose of budesonide in mild asthma resulted in faster and more effective control than treatment with budesonide alone. Eformoterol allowed the corticosteroid dose to be reduced while also decreasing the rate of mild exacerbations compared with budesonide alone. These data suggest a therapeutic advantage of adding eformoterol to inhaled corticosteroids in patients with mild to moderate asthma.
doi:10.1136/thorax.57.9.791
PMCID: PMC1746437  PMID: 12200524
25.  The Role of the Primary Care Physician in Helping Adolescent and Adult Patients Improve Asthma Control 
Mayo Clinic Proceedings  2011;86(9):894-902.
Many adolescents and adults with asthma continue to have poorly controlled disease, often attributable to poor adherence to asthma therapy. Failure to adhere to recommended treatment may result from a desire to avoid regular reliance on medications, inappropriate high tolerance of asthma symptoms, failure to perceive the chronic nature of asthma, and poor inhaler technique. Primary care physicians need to find opportunities and methods to address these and other issues related to poor asthma control. Few adolescents or adults with asthma currently have asthma “checkup” visits, usually seeking medical care only with an exacerbation. Therefore, nonrespiratory-related office visits represent an important opportunity to assess baseline asthma control and the factors that most commonly lead to poor control. Tools such as the Asthma Control Test, the Asthma Therapy Assessment Questionnaire, the Asthma Control Questionnaire, and the Asthma APGAR provide standardized, patient-friendly ways to capture necessary asthma information. For uncontrolled asthma, physicians can refer to the stepwise approach in the 2007 National Asthma Education and Prevention Program guidelines to adjust medication use, but they must consider step-up decisions in the context of quality of the patient's inhaler technique, adherence, and ability to recognize and avoid or eliminate triggers. For this review, a literature search of PubMed from 2000 through August 31, 2010, was performed using the following terms (or a combination of these terms): asthma, asthma control, primary care, NAEPP guidelines, assessment, uncontrolled asthma, burden, impact, assessment tools, triggers, pharmacotherapy, safety. Studies were limited to human studies published in English. Articles were also identified by a manual search of bibliographies from retrieved articles and from article archives of the author.
doi:10.4065/mcp.2011.0035
PMCID: PMC3257999  PMID: 21878602

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