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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.  Respiratory Reviews in Asthma 2013 
From January 2012 up until March 2013, many articles with huge clinical importance in asthma were published based on large numbered clinical trials or meta-analysis. The main subjects of these studies were the new therapeutic plan based on the asthma phenotype or efficacy along with the safety issues regarding the current treatment guidelines. For efficacy and safety issues, inhaled corticosteroid tapering strategy or continued long-acting beta agonists use was the major concern. As new therapeutic trials, monoclonal antibodies or macrolide antibiotics based on inflammatory phenotypes have been under investigation, with promising preliminary results. There were other issues on the disease susceptibility or genetic background of asthma, particularly for the "severe asthma" phenotype. In the era of genome and pharmacogenetics, there have been extensive studies to identify susceptible candidate genes based on the results of genome wide association studies (GWAS). However, for severe asthma, which is where most of the mortality or medical costs develop, it is very unclear. Moreover, there have been some efforts to find important genetic information in order to predict the possible disease progression, but with few significant results up until now. In conclusion, there are new on-going aspects in the phenotypic classification of asthma and therapeutic strategy according to the phenotypic variations. With more pharmacogenomic information and clear identification of the "severe asthma" group even before disease progression from GWAS data, more adequate and individualized therapeutic strategy could be realized in the future.
doi:10.4046/trd.2014.76.3.105
PMCID: PMC3982236  PMID: 24734097
Asthma; Phenotype; Pharmacogenetics; Therapeutics
3.  Pharmacogenomic Approaches to Asthma Treatment 
Major classes of medication in asthma management include bronchodilating β2-agonists, anti-inflammatory inhaled corticosteroids, leukotriene modifiers and theophyllines. However, all asthmatics do not respond to the same extent to a given medication. Available data suggest that a substantial range of individual variability, as much as 70%, may be due to genetic characteristics of each patient. Pharmacogenomics offers the potential to optimize medications for individual asthmatics by using genetic information to improve efficacy or avoid adverse effects. The best-studied case of the potential contribution of pharmacogenomics to treatment response in asthma comes from studies on human β2 adrenergic receptors. In addition, genetic variation in β2-adrenergic receptor (Arg16Gly) may predict response to anticholinergics for the treatment of asthma. In case of inhaled corticosteroids, a recent investigation using a traditional SNP-based approach identified a gene for corticotropin releasing hormone receptor 1 as a potential marker of response. Another major pathway that has been investigated is the pathway underlying response to cysteinyl leukotriene receptor antagonist. It is likely that in the near future, pharmacogenomic approaches based on individual genetic information will be introduced into an asthma treatment guideline and this guideline will allow us to identify those who have the best chance to respond to a specific medication.
doi:10.4168/aair.2010.2.3.177
PMCID: PMC2892049  PMID: 20592916
Asthma; pharmacogenomics; treatment response
4.  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
5.  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
6.  Pharmacogenetics of the β2-Adrenergic Receptor Gene 
Asthma is a complex genetic disease with multiple genetic and environmental determinants contributing to the observed variability in response to common anti-asthma therapies. Asthma pharmacogenetic research has focused on multiple candidate genes including the β2-adrenergic receptor gene (ADRβ2) and its effect on individual responses to beta agonist therapy. At present, knowledge about the effects of ADRβ2 variation on therapeutic responses is evolving and should not alter current Asthma Guideline approaches consisting of the use of short acting beta agonists for as-needed symptom based therapy and the use of a regular long-acting beta agonist in combination with inhaled corticosteroid therapy for optimal control of asthma symptoms in those asthmatics who are not controlled on inhaled corticosteroid alone. This approach is based upon studies showing a consistent pharmacogenetic response to regular use of short acting beta agonists (SABA) and less consistent findings in studies evaluating long acting beta agonist (LABA). While emerging pharmacogenetic studies are provocative and should lead to functional approaches, conflicting data with responses to LABA therapy may be caused by factors that include small sample sizes of study populations and differences in experimental design that may limit the conclusions that may be drawn from these clinical trials at the present time.
doi:10.1016/j.iac.2007.09.007
PMCID: PMC2736101  PMID: 17996583
7.  Dual specificity phosphatase-1 as a pharmacogenetic modifier of inhaled steroid response among asthma patients 
Background
Inhaled corticosteroids (ICS) are considered first-line treatment for persistent asthma; yet, there is significant variability in treatment response. Dual specificity phosphatase-1 (DUSP1) appears to mediate the anti-inflammatory action of corticosteroids.
Objective
To determine whether variants in the DUSP1 gene are associated with clinical response to ICS treatment.
Methods
Study participants with asthma were drawn from the following multi-ethnic cohorts: the Genetics of Asthma in Latino Americans (GALA) study, the Study of African Americans, Asthma, Genes & Environments (SAGE), and the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). We screened GALA participants for genetic variants that modified the relationship between ICS use and bronchodilator response. We then replicated our findings in SAGE and SAPPHIRE participants. In a group of SAPPHIRE participants treated with ICS for 6 weeks, we examined whether a DUSP1 polymorphism was associated with changes in forced expiratory volume at one second (FEV1) and self-reported asthma control.
Results
DUSP1 polymorphisms, rs881152 and rs34507926, localized to different haplotype blocks and appeared to significantly modify the relationship between ICS use and bronchodilator response among GALA participants. This interaction was also seen for rs881152 among SAPPHIRE, but not SAGE participants. Among the group of SAPPHIRE patients prospectively treated with ICS for 6 weeks, rs881152 genotype was significantly associated with changes in self-reported asthma control but not FEV1.
Conclusion
DUSP1 polymorphisms were associated with clinical response to ICS therapy, and therefore, may be useful in the future to identify asthma patients more likely to respond to this controller treatment.
Clinical implications
These findings further our understanding of ICS pharmacogenetics and will hopefully result in improved tailoring of this controller therapy among individuals with asthma and in better disease control.
Capsule summary
We identified genetic variants in DUSP1 which appeared to mediate the clinical response to inhaled corticosteroid (ICS) medication. These findings may eventually assist in identifying individuals with asthma most likely to respond this controller therapy.
doi:10.1016/j.jaci.2010.06.007
PMCID: PMC2943151  PMID: 20673984
Asthma; inhaled corticosteroids; dual specificity phosphatase-1; DUSP1; corticosteroid responsiveness
8.  Genetics of Asthma Susceptibility and Severity 
Clinics in chest medicine  2012;33(3):431-443.
The interaction of genes and environmental exposures influences the development of asthma and determines asthma severity. This review focuses on recent developments in genetic studies of asthma onset and progression. Genome-wide association studies (GWAS) are currently the most effective approach to study genetics of complex diseases. There have been two large meta-analyses of asthma susceptibility, GABRIEL and EVE, which identified the same four chromosomal regions, many of which had also been identified in previous GWAS: loci in the ORMDL3 region of 17q21, IL1RL/IL18R genes on chromosome 2q, the TSLP gene region on 5q22, and IL33 on chromosome 9p24. These regions were associated with asthma in individuals of different ethnic backgrounds. EVE also identified a novel asthma susceptibility locus, PYHIN1, in individuals of African descent. Genome-wide screens for asthma susceptibility in Asian adults and children both identified genetic variants in the major histocompatiblity complex gene region (HLA region) on chromosome 6p21 as highly associated with asthma risk. This locus was one of the first candidate genes identified for asthma and has been a significant predictor of asthma risk in several GWAS.
There is also a need to understand asthma disease heterogeneity as different phenotypes may reflect several pathogenic pathways. Genes that are associated with phenotypes including lung function, biomarker levels and asthma therapeutic responses provide insight into mechanisms of asthma severity progression. For example, the HHIP gene is a significant predictor of pulmonary function changes in asthma and in the normal population. A joint model of risk variants in lung function genes were highly associated with lower FEV1 and increased asthma severity criteria. In addition, a genome-wide screen to discover pharmacogenetic associations related to response to inhaled glucocorticoids identified two correlated SNPs in the GLCCI1 gene that confer a significant lung function response to this asthma therapy.
Future genetic studies for asthma susceptibility and severity will incorporate exome or whole-genome sequencing to identify common and rare genetic variants. Using these variants identified in comprehensively phenotyped asthmatics will lead to the development of personalized therapy in individuals with asthma.
doi:10.1016/j.ccm.2012.05.005
PMCID: PMC3431509  PMID: 22929093
Asthma; genetics; susceptibility; severity; personalized medicine; therapy; lung function
9.  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
10.  Asthma and other wheezing disorders in children 
Clinical Evidence  2006;2006:0302.
Introduction
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 anxiety.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute asthma in children? What are the effects of single-agent prophylaxis in children taking as-needed inhaled beta agonists for asthma? What are the effects of additional prophylactic treatments in childhood asthma inadequately controlled by standard-dose inhaled corticosteroids? What are the effects of treatments and of prophylactic treatments for acute wheezing in infants? We searched: Medline, Embase, The Cochrane Library and other important databases up to October 2005 (BMJ 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 84 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, long-acting [inhaled salmeterol], short-acting [oral salbutamol or by nebuliser, or metered-dose inhaler/spacer versus nebuliser]), corticosteroids (oral prednisolone, systemic, inhaled higher or lower doses [beclometasone]), ipratropium bromide (single or multiple dose inhaled), leukotriene receptor antagonists (oral montelukast), nedocromil (inhaled), oxygen, sodium cromoglycate (inhaled), or theophylline (oral or intravenous).
Key Points
Childhood asthma can be difficult to distinguish from viral wheeze and can affect up to 20% of children.
The consensus is that oxygen, high dose nebulised beta2 agonists and systemic corticosteroids should be used to treat an acute asthma attack. High dose beta2 agonists may be equally effective when given intermittently or continuously via a nebuliser, or from a metered dose inhaler using a spacer, in children with an acute asthma attack.Admission to hospital may be averted by adding ipratropium bromide to beta2 agonists, or by using high dose nebulised or oral corticosteroids.
Prophylactic inhaled corticosteroids improve symptoms and lung function in children with asthma. Their effect on final adult height is unclear. Inhaled nedocromil, inhaled long acting beta2 agonists, oral theophylline and oral leukotriene receptor antagonists are less effective than corticosteroids.Inhaled sodium cromoglycate does not seem to improve symptoms.
CAUTION: Monotherapy with long acting beta2 agonists reduces the frequency of asthma episodes, but may increase the chance of severe asthma episodes and death when those episodes occur. Intravenous theophylline may improve lung function in children with severe asthma, but can cause cardiac arrhythmias and convulsions.
We don't know whether adding higher doses of corticosteroids, long acting beta2 agonists, oral leukotriene receptor antagonists or oral theophylline to standard treatment improves symptoms or lung function in children with uncontrolled asthma.
In infants with acute wheeze, short acting beta2 agonists via a nebuliser or a spacer may improve symptoms, but we don't know whether high dose inhaled or oral corticosteroids or inhaled ipratropium bromide are beneficial.
Oral short acting beta2 agonists and inhaled high dose corticosteroids may prevent or improve wheeze in infants but can cause adverse effects. We don't know whether lower dose inhaled or oral corticosteroids, inhaled ipratropium bromide or inhaled short acting beta2 agonists improve wheezing episodes in infants.
PMCID: PMC2907635
11.  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
12.  Pharmacogenetics of asthma 
Purpose of review
Patient response to the asthma drug classes, bronchodilators, inhaled corticosteroids and leukotriene modifiers, are characterized by a large degree of heterogeneity, which is attributable in part to genetic variation. Herein, we review and update the pharmacogenetics and pharmaogenomics of common asthma drugs.
Recent findings
Early studies suggest that bronchodilator reversibility and asthma worsening in patients on continuous short-acting and long-acting β-agonists are related to the Gly16Arg genotype for the ADRB2. More recent studies including genome-wide association studies implicate variants in other genes contribute to bronchodilator response heterogeneity and fail to replicate asthma worsening associated with continuous β-agonist use. Genetic determinants of the safety of long-acting β-agonist require further study. Variants in CRHR1, TBX21, and FCER2 contribute to variability in response for lung function, airways responsiveness, and exacerbations in patients taking inhaled corticosteroids. Variants in ALOX5, LTA4H, LTC4S, ABCC1, CYSLTR2, and SLCO2B1 contribute to variability in response to leukotriene modifiers.
Summary
Identification of novel variants that contribute to response heterogeneity supports future studies of single nucleotide polymorphism discovery and include gene expression and genome-wide association studies. Statistical models that predict the genomics of response to asthma drugs will complement single nucleotide polymorphism discovery in moving toward personalized medicine.
doi:10.1097/MCP.0b013e32831da8be
PMCID: PMC2754311  PMID: 19077707
asthma; genes; personalized medicine; polymorphisms; response heterogeneity
13.  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
14.  Allergic rhinitis: evidence for impact on asthma 
BMC Pulmonary Medicine  2006;6(Suppl 1):S4.
Background
This paper reviews the current evidence indicating that comorbid allergic rhinitis may have clinically relevant effects on asthma.
Discussion
Allergic rhinitis is very common in patients with asthma, with a reported prevalence of up to 100% in those with allergic asthma. While the temporal relation of allergic rhinitis and asthma diagnoses can be variable, the diagnosis of allergic rhinitis often precedes that of asthma. Rhinitis is an independent risk factor for the subsequent development of asthma in both atopic and nonatopic individuals. Controlled studies have provided conflicting results regarding the benefits for asthma symptoms of treating comorbid allergic rhinitis with intranasal corticosteroids. Effects of other treatments for comorbid allergic rhinitis, including antihistamines, allergen immunotherapy, systemic anti-IgE therapy, and antileukotriene agents, have been examined in a limited number of studies; anti-IgE therapy and antileukotriene agents such as the leukotriene receptor antagonists have benefits for treating both allergic rhinitis and asthma. Results of observational studies indicate that treating comorbid allergic rhinitis results in a lowered risk of asthma-related hospitalizations and emergency visits. Results of several retrospective database studies in the United States and in Europe indicate that, for patients with asthma, the presence of comorbid allergic rhinitis is associated with higher total annual medical costs, greater prescribing frequency of asthma-related medications, as well as increased likelihood of asthma-related hospital admissions and emergency visits. There is therefore evidence suggesting that comorbid allergic rhinitis is a marker for more difficult to control asthma and worsened asthma outcomes.
Conclusion
These findings highlight the potential for improving asthma outcomes by following a combined therapeutic approach to comorbid allergic rhinitis and asthma rather than targeting each condition separately.
doi:10.1186/1471-2466-6-S1-S4
PMCID: PMC1698497  PMID: 17140422
15.  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
16.  Pharmacogenetics and the Development of Personalized Approaches for Combination Therapy in Asthma 
Current allergy and asthma reports  2013;13(5):10.1007/s11882-013-0372-x.
Asthma is a common, chronic disease of the airways that is treated with a combination of different therapies. The combination of LABA and ICS therapy results in a synergistic interaction that is efficacious in improving asthma symptom control; however, genetic variation has the potential to alter therapeutic efficacy. Both agents mediate complex molecular pathways consisting of gene variation that has been investigated with the analysis of candidate genes in the β2-adrenergic receptor and glucocorticoid pathway. These pharmacogenetic studies have been limited to retrospective analyses of clinical trial cohorts and a small number of prospective, genotype-stratified trials. More recently, genome-wide association studies in combination with replication in additional cohorts and in vitro cell-based models have been used to identify novel pathway-related pharmacogenetic variations. This review of the pharmacogenetics of the β2-adrenergic receptor and glucocorticoid pathways highlights the genotypic effects of variation in multiple genes from interacting pathways which may contribute to differential responses to inhaled beta agonists and glucocorticoids. As our understanding of these genetic mechanisms improves, panels of biomarkers may be developed to determine which combination therapies are the most effective with the least risk to an individual asthma patient. Before we can usher in an era of personalized medicine for asthma, it is first important to improve our ability to analyze large volumes of genetic data in large clinical trial cohorts using a combination of study designs, analytical methods, and in vitro functional studies.
doi:10.1007/s11882-013-0372-x
PMCID: PMC3878163  PMID: 23912588
Pharmacogenetics; Genes; Asthma; Response heterogeneity; SNP; Combination therapy; Glucocorticoid pathway
17.  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
18.  Role of pharmacogenomics in drug discovery and development 
Indian Journal of Pharmacology  2008;40(4):137-143.
Pharmacogenetics and pharmacogenomics are two major emerging trends in medical sciences, which influence the success of drug development and therapeutics. In current times, though pharmacogenetic studies are being done extensively for research, its application for drug development needs to get started on a large scale. The major determinants of success of a new drug compound, viz safety and efficacy, have become more predictable, with the advent of pharmacogenetic studies. There is a need felt for pharmacogenomic studies, where the effects of multiple genes are assessed with the study of entire genome.
Pharmacogenetic studies can be used at various stages of drug development. The effect of drug target polymorphisms on drug response can be assessed and identified. In clinical studies, pharmacogenetic tests can be used for stratification of patients based on their genotype, which corresponds to their metabolizing capacity. This prevents the occurrence of severe adverse drug reactions and helps in better outcome of clinical trials. This can also reduce attrition of drug compounds. Further, the variations in drug response can be better studied with the wider application of pharmacogenomic methods like genome wide scans, haplotype analysis and candidate gene approaches. The cost of pharmacogenetic testing has become very low, with the advent of newer high throughput genotyping systems. However, the cost of pharmacogenomic methods continues to be very high. As the treatment with several drugs is being more and more pharmacogeneticaly guided (e.g. warfarin and irinotecan), the FDA has laid down guidelines for pharmaceutical firms regarding submission of pharmacogenetic data for their drug products in labelling.
doi:10.4103/0253-7613.43158
PMCID: PMC2792612  PMID: 20040945
Drug; genotype; pharmaceuticals; pharmacogenetics; pharmacogenomics
19.  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
20.  Achieving Symptom Control in Patients with Moderate Asthma 
Disease severity in asthma can be classified as mild, moderate or severe based upon the frequency of symptoms or the severity of airflow obstruction. This review will focus on the treatment of youths greater than 12 years of age and adults with moderate persistent asthma. Moderate asthmatics may have daily symptoms that cause some limitation with normal daily activities and require use of a rescue inhaled short-acting beta2-agonist inhaler or experience nocturnal awakenings secondary to asthma that occur more than once per week. Furthermore, spirometry may reveal airflow obstruction with a reduction in FEV1 to between 60% and 80% of predicted. Although inhaled corticosteroids (ICS) are the primary controller medication used to modify symptoms in moderate asthmatics, additional controller medications, such as inhaled long-acting beta2-agonists (LABA), leukotriene receptor antagonists (LTRA) or theophylline, are often needed to obtain optimal disease control. While the addition of an inhaled LABA to an ICS is very effective at improving disease control in moderate asthma, concerns have arisen over the safety of LABAs, in particular the risk of asthma-related death. Therefore, consideration may be given to initially adding a LTRA, rather than a LABA, to ICS when asthma symptoms are not adequately controlled by ICS alone. Furthermore, individualization of medication regimens, treatment of co-morbid conditions, and patient education are crucial to optimizing compliance with therapy, improving disease control, and reducing the risk of exacerbations. Lastly, the development of new asthma treatments, perhaps based upon personalized medicine, may revolutionize the future treatment of moderate asthma.
doi:10.4137/CCRPM.S5100
PMCID: PMC3256747  PMID: 22259262
asthma; inhaled corticosteroids; long-acting beta2-agonists; leukotriene modifiers; leukotriene receptor antagonists; theophylline
21.  A review of anti-IgE monoclonal antibody (omalizumab) as add on therapy for severe allergic (IgE-mediated) asthma 
Bronchial asthma is recognized as a highly prevalent health problem in the developed and developing world with significant social and economic consequences. Increased asthma severity is not only associated with enhanced recurrent hospitalization and mortality but also with higher social costs. The pathogenetic background of allergic-atopic bronchial asthma is characterized by airway inflammation with infiltration of several cells (mast cells, basophils, eosinophils, monocytes, and T-helper (Th)2 lymphocytes). However, in atopic asthma the trigger factors for acute attacks and chronic worsening of bronchial inflammation are aeroallergens released by pollens, dermatophagoides, and pets, which are able to induce an immune response by interaction with IgE antibodies. Currently anti-inflammatory treatments are effective for most asthma patients, but there are asthmatic subjects whose disease is not completely controlled by inhaled or systemic corticosteroids and who account for a significant portion of the healthcare costs of asthma. A novel therapeutic approach to asthma and other allergic respiratory diseases involves interference in the action of IgE, and this antibody has been viewed as a target for novel immunological drug development in asthma. Omalizumab is a humanized recombinant monoclonal anti-IgE antibody approved for treatment of moderate to severe IgE-mediated (allergic) asthma. This non-anaphylactogenic anti-IgE antibody inhibits IgE functions, blocking free serum IgE and inhibiting their binding to cellular receptors. By reducing serum IgE levels and IgE receptor expression on inflammatory cells in the context of allergic cascade, omalizumab represents a new class of mast cells stabilizing drugs; it is a novel approach to the treatment of atopic asthma. Omalizumab therapy is well tolerated and significantly improves symptoms and disease control, reducing asthma exacerbations and the need to use high dosage of inhaled corticosteroids. Moreover, omalizumab improves quality of life of patients with severe persistent allergic asthma which is inadequately controlled by currently available asthma medications. In conclusion omalizumab may fulfil an important need in patients with moderate to severe asthma.
PMCID: PMC2374942  PMID: 18472983
airway hyper-reactivity; asthma; allergic respiratory diseases; atopic respiratory diseases; anti-IgE therapy; hypersensitivity; monoclonal anti-IgE antibody; omalizumab
22.  Safety of bronchodilators and corticosteroids for asthma during pregnancy: what we know and what we need to do better 
Asthma is a common medical condition complicating pregnancy with potentially serious effects on pregnancy outcome. The aim of this review is to provide an update on efficacy and safety of asthma medications, primarily bronchodilators and corticosteroids, used during pregnancy with focus on pregnancy outcome, and, furthermore, to discuss limitations of available studies and point to possible improvements in future studies. A planned series of systematic searches was conducted using the PubMed database. Use of short-acting β2-agonists has generally been established as safe, and the few studies stating otherwise appear to have, perhaps critical, methodological limitations. The safety of long-acting β2-agonists remains to be further investigated, and the few available studies have methodological limitations and, therefore, provide no definite answers, although a very recent study supports the safety of add-on long-acting β2-agonists to inhaled corticosteroids. Inhaled corticosteroids are generally found to be safe, although further research is needed to investigate both the efficacy and safety of high dose therapy with inhaled corticosteroids. Studies have reported associations between the use of systemic corticosteroids and adverse perinatal outcomes, such as preterm birth, low birth weight, and pre-eclampsia. This must, however, be weighed against the potential serious impact of severe, uncontrolled asthma itself on pregnancy outcome. The main obstacle to a valid interpretation of several of the available studies is the inadequate stratification for asthma severity and control. Overall, asthma in itself and not just poor asthma control poses a greater risk to pregnancy outcomes than asthma medication. Nonetheless, more studies focusing on disentangling the effects of asthma alone and asthma medications are needed. Increased use of stratified risk assessments, taking the concept of asthma severity into greater consideration, is much warranted in future studies.
doi:10.2147/JAA.S52592
PMCID: PMC3833838  PMID: 24259987
asthma; pregnancy; perinatal outcomes; asthma management; bronchodilators; inhaled corticosteroids; systemic corticosteroids
23.  Secondary Outcomes of a Pilot Randomized Trial of Azithromycin Treatment for Asthma 
PLoS Clinical Trials  2006;1(2):e11.
Objectives:
The respiratory pathogen Chlamydia pneumoniae (C. pneumoniae) produces acute and chronic lung infections and is associated with asthma. Evidence for effectiveness of antichlamydial antibiotics in asthma is limited. The primary objective of this pilot study was to investigate the feasibility of performing an asthma clinical trial in practice settings where most asthma is encountered and managed. The secondary objectives were to investigate (1) whether azithromycin treatment would affect any asthma outcomes and (2) whether C. pneumoniae serology would be related to outcomes. This report presents the secondary results.
Design:
Randomized, placebo-controlled, blinded (participants, physicians, study personnel, data analysts), allocation-concealed parallel group clinical trial.
Setting:
Community-based health-care settings located in four states and one Canadian province.
Participants:
Adults with stable, persistent asthma.
Interventions:
Azithromycin (six weekly doses) or identical matching placebo, plus usual community care.
Outcome Measures:
Juniper Asthma Quality of Life Questionnaire (Juniper AQLQ), symptom, and medication changes from baseline (pretreatment) to 3 mo posttreatment (follow-up); C. pneumoniae IgG and IgA antibodies at baseline and follow-up.
Results:
Juniper AQLQ improved by 0.25 (95% confidence interval; −0.3, 0.8) units, overall asthma symptoms improved by 0.68 (0.1, 1.3) units, and rescue inhaler use decreased by 0.59 (−0.5, 1.6) daily administrations in azithromycin-treated compared to placebo-treated participants. Baseline IgA antibodies were positively associated with worsening overall asthma symptoms at follow-up (p = 0.04), but IgG was not (p = 0.63). Overall asthma symptom improvement attributable to azithromycin was 28% in high IgA participants versus 12% in low IgA participants (p for interaction = 0.27).
Conclusions:
Azithromycin did not improve Juniper AQLQ but appeared to improve overall asthma symptoms. Larger community-based trials of antichlamydial antibiotics for asthma are warranted.
Editorial Commentary
Background: Chlamydia pneumoniae is a common bacterium thought to be responsible for a substantial proportion of community-acquired pneumonia and bronchitis infections. There is some observational evidence associating chronic C. pneumoniae infection with more severe symptoms in people with asthma. However, there are very little data from clinical trials determining whether treatment with antibiotics active against C. pneumoniae has an effect on the control of asthma.
What this trial shows: In this trial, the researchers randomized 45 adults who were being treated for asthma in primary care to receive either azithromycin (an antibiotic active against C. pneumoniae) or placebo, in addition to their usual asthma care. Participants were followed up for 3 mo after completion of treatment, during which time participants recorded data relating to their overall symptoms and daily activities on a 5-point scale, and use of bronchodilators. At the start of the trial, and at 3-mo follow-up, participants also completed a quality-of-life questionnaire using a validated scale. The primary objective of this trial was to investigate the feasibility of running an asthma trial in the primary care setting, and in using IVR telephone systems to collect the outcome data, reported in [13]. In this paper, the asthma outcomes are reported. Participants receiving azithromycin did not show a significant improvement in quality of life at 3-mo follow-up as compared to participants receiving placebo. However, the investigators did see a significant improvement in the overall symptoms recorded by participants receiving azithromycin, as compared to placebo.
Strengths and limitations: The randomization methods in the trial were appropriate, as was the choice of placebo as a comparison for azithromycin. However, the number of participants in the trial was small, and it is likely that many more participants would need to be recruited to conclusively demonstrate or disprove an effect of azithromycin on asthma-related quality of life. Further, the trial used three different measures for asthma outcomes: (1) the quality-of-life questionnaire, (2) measurement of symptoms and daily activities on a 5-point scale, and (3) bronchodilator use. Only the quality-of-life questionnaire is validated, making it difficult to compare the results with those of other asthma trials.
Contribution to the evidence: This trial provides suggestive evidence that azithromycin may have benefits in the treatment of asthma, but should not on its own lead to a change in practice. The study provides a good basis for a larger randomized trial of such treatments, which would need to assess reliably the effect of these drugs not only on symptoms but also on quality of life. Information gained from this trial would help to design several aspects of future studies, e.g., their size, follow-up duration, and suitable outcome measures.
doi:10.1371/journal.pctr.0010011
PMCID: PMC1488900  PMID: 16871333
24.  Pharmacogenetics: Implications of Race and Ethnicity on Defining Genetic Profiles for Personalized Medicine 
Pharmacogenetics is being used to develop personalized therapies specific to individuals from different ethnic or racial groups. Pharmacogenetic studies to date have been primarily performed in trial cohorts consisting of non-Hispanic whites of European descent. A “bottleneck” or collapse of genetic diversity associated with the first human colonization of Europe during the Upper Paleolithic period, followed by the recent mixing of African, European, and Native American ancestries has resulted in different ethnic groups with varying degrees of genetic diversity. Differences in genetic ancestry may introduce genetic variation which has the potential to alter the therapeutic efficacy of commonly used asthma therapies, for example β2-adrenergic receptor agonists (beta agonists). Pharmacogenetic studies of admixed ethnic groups have been limited to small candidate gene association studies of which the best example is the gene coding for the receptor target of beta agonist therapy, ADRB2. Large consortium-based sequencing studies are using next-generation whole-genome sequencing to provide a diverse genome map of different admixed populations which can be used for future pharmacogenetic studies. These studies will include candidate gene studies, genome-wide association studies, and whole-genome admixture-based approaches which account for ancestral genetic structure, complex haplotypes, gene-gene interactions, and rare variants to detect and replicate novel pharmacogenetic loci.
doi:10.1016/j.jaci.2013.10.040
PMCID: PMC3933289  PMID: 24369795
asthma; genes; pharmacogenetics; response heterogeneity; single nucleotide polymorphism; admixture mapping; ethnic group
25.  New drugs targeting Th2 lymphocytes in asthma 
Asthma represents a profound worldwide public health problem. The most effective anti-asthmatic drugs currently available include inhaled β2-agonists and glucocorticoids and control asthma in about 90-95% of patients. The current asthma therapies are not cures and symptoms return soon after treatment is stopped even after long term therapy. Although glucocorticoids are highly effective in controlling the inflammatory process in asthma, they appear to have little effect on the lower airway remodelling processes that appear to play a role in the pathophysiology of asthma at currently prescribed doses. The development of novel drugs may allow resolution of these changes. In addition, severe glucocorticoid-dependent and resistant asthma presents a great clinical burden and reducing the side-effects of glucocorticoids using novel steroid-sparing agents is needed. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Drug development for asthma has been directed at improving currently available drugs and findings new compounds that usually target the Th2-driven airway inflammatory response. Considering the apparently central role of T lymphocytes in the pathogenesis of asthma, drugs targeting disease-inducing Th2 cells are promising therapeutic strategies. However, although animal models of asthma suggest that this is feasible, the translation of these types of studies for the treatment of human asthma remains poor due to the limitations of the models currently used. The myriad of new compounds that are in development directed to modulate Th2 cells recruitment and/or activation will clarify in the near future the relative importance of these cells and their mediators in the complex interactions with the other pro-inflammatory/anti-inflammatory cells and mediators responsible of the different asthmatic phenotypes. Some of these new Th2-oriented strategies may in the future not only control symptoms and modify the natural course of asthma, but also potentially prevent or cure the disease.
doi:10.1186/1745-6673-3-S1-S6
PMCID: PMC2259400  PMID: 18315837

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