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1.  Role of biomarkers in understanding and treating children with asthma: towards personalized care 
Asthma is one of the most common chronic diseases affecting children. Despite publicized expert panels on asthma management and the availability of high-potency inhaled corticosteroids, asthma continues to pose an enormous burden on quality of life for children. Research into the genetic and molecular origins of asthma are starting to show how distinct disease entities exist within the syndrome of “asthma”. Biomarkers can be used to diagnose underlying molecular mechanisms that can predict the natural course of disease or likely response to drug treatment. The progress of personalized medicine in the care of children with asthma is still in its infancy. We are not yet able to apply stratified asthma treatments based on molecular phenotypes, although that time may be fast approaching. This review discusses some of the recent advances in asthma genetics and the use of current biomarkers that can help guide improved treatment. For example, the fraction of expired nitric oxide and serum Immunoglobulin E (IgE) (including allergen-specific IgE), when evaluated in the context of recurrent asthma symptoms, are general predictors of allergic airway inflammation. Biomarker assays for secondhand tobacco smoke exposure and cysteinyl leukotrienes are both promising areas of study that can help personalize management, not just for pharmacologic management, but also education and prevention efforts.
doi:10.2147/PGPM.S30626
PMCID: PMC3760446  PMID: 24019751
asthma; biomarkers; children; management
2.  Number of Patients Studied Prior to Approval of New Medicines: A Database Analysis 
PLoS Medicine  2013;10(3):e1001407.
In an evaluation of medicines approved by the European Medicines Agency 2000 to 2010, Ruben Duijnhoven and colleagues find that the number of patients evaluated for medicines approved for chronic use are inadequate for evaluation of safety or long-term efficacy.
Background
At the time of approval of a new medicine, there are few long-term data on the medicine's benefit–risk balance. Clinical trials are designed to demonstrate efficacy, but have major limitations with regard to safety in terms of patient exposure and length of follow-up. This study of the number of patients who had been administered medicines at the time of medicine approval by the European Medicines Agency aimed to determine the total number of patients studied, as well as the number of patients studied long term for chronic medication use, compared with the International Conference on Harmonisation's E1 guideline recommendations.
Methods and Findings
All medicines containing new molecular entities approved between 2000 and 2010 were included in the study, including orphan medicines as a separate category. The total number of patients studied before approval was extracted (main outcome). In addition, the number of patients with long-term use (6 or 12 mo) was determined for chronic medication. 200 unique new medicines were identified: 161 standard and 39 orphan medicines. The median total number of patients studied before approval was 1,708 (interquartile range [IQR] 968–3,195) for standard medicines and 438 (IQR 132–915) for orphan medicines. On average, chronic medication was studied in a larger number of patients (median 2,338, IQR 1,462–4,135) than medication for intermediate (878, IQR 513–1,559) or short-term use (1,315, IQR 609–2,420). Safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least 6 and 12 mo in 46.4% and 58.3% of new medicines, respectively. Among the 84 medicines intended for chronic use, 68 (82.1%) met the guideline recommendations for 6-mo use (at least 300 participants studied for 6 mo and at least 1,000 participants studied for any length of time), whereas 67 (79.8%) of the medicines met the criteria for 12-mo patient exposure (at least 100 participants studied for 12 mo).
Conclusions
For medicines intended for chronic use, the number of patients studied before marketing is insufficient to evaluate safety and long-term efficacy. Both safety and efficacy require continued study after approval. New epidemiologic tools and legislative actions necessitate a review of the requirements for the number of patients studied prior to approval, particularly for chronic use, and adequate use of post-marketing studies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Before any new medicine is marketed for the treatment of a human disease, it has to go through extensive laboratory and clinical research. In the laboratory, scientists investigate the causes of diseases, identify potential new treatments, and test these interventions in disease models, some of which involve animals. The safety and efficacy of potential new interventions is then investigated in a series of clinical trials—studies in which the new treatment is tested in selected groups of patients under strictly controlled conditions, first to determine whether the drug is tolerated by humans and then to assess its efficacy. Finally, the results of these trials are reviewed by the government body responsible for drug approval; in the US, this body is the Food and Drug Administration, and in the European Union, the European Medicines Agency (EMA) is responsible for the scientific evaluation and approval of new medicines.
Why Was This Study Done?
Clinical trials are primarily designed to test the efficacy—the ability to produce the desired therapeutic effect—of new medicines. The number of patients needed to establish efficacy determines the size of a clinical trial, and the indications for which efficacy must be shown determine the trial's duration. However, identifying adverse effects of drugs generally requires the drug to be taken by more patients than are required to show efficacy, so the information about adverse effects is often relatively limited at the end of clinical testing. Consequently, when new medicines are approved, their benefit–risk ratios are often poorly defined, even though physicians need this information to decide which treatment to recommend to their patients. For the evaluation of risk or adverse effects of medicines being developed for chronic (long-term) treatment of non-life-threatening diseases, current guidelines recommend that at least 1,000–1,500 patients are exposed to the new drug and that 300 and 100 patients use the drug for six and twelve months, respectively, before approval. But are these guidelines being followed? In this database analysis, the researchers use data collected by the EMA to determine how many patients are exposed to new medicines before approval in the European Union and how many are exposed for extended periods of time to medicines intended for chronic use.
What Did the Researchers Do and Find?
Using the European Commission's Community Register of Medicinal Products, the researchers identified 161 standard medicines and 39 orphan medicines (medicines to treat or prevent rare life-threatening diseases) that contained new active substances and that were approved in the European Union between 2000 and 2010. They extracted information on the total number of patients studied and on the number exposed to the medicines for six months and twelve months before approval of each medicine from EMA's European public assessment reports. The average number of patients studied before approval was 1,708 for standard medicines and 438 for orphan medicines (marketing approval is easier to obtain for orphan medicines than for standard medicines to encourage drug companies to develop medicines that might otherwise be unprofitable). On average, medicines for chronic use (for example, asthma medications) were studied in more patients (2,338) than those for intermediate use such as anticancer drugs (878), or short-term use such as antibiotics (1,315). The safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least six and twelve months in 46.4% and 58.4% of new medicines, respectively. Finally, among the 84 medicines intended for chronic use, 72 were studied in at least 300 patients for six months, and 70 were studied in at least 100 patients for twelve months.
What Do These Findings Mean?
These findings suggest that although the number of patients studied before approval is sufficient to determine the short-term efficacy of new medicines, it is insufficient to determine safety or long-term efficacy. Any move by drug approval bodies to require pharmaceutical companies to increase the total number of patients exposed to a drug, or the number exposed for extended periods of time to drugs intended for chronic use, would inevitably delay the entry of new products into the market, which likely would be unacceptable to patients and healthcare providers. Nevertheless, the researchers suggest that a reevaluation of the study size and long-term data requirements that need to be met for the approval of new medicines, particularly those designed for long-term use, is merited. They also stress the need for continued study of both the safety and efficacy of new medicines after approval and the importance of post-marketing studies that actively examine safety issues.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001407.
The European Medicines Agency (EMA) provides information about all aspects of the scientific evaluation and approval of new medicines in the European Union; its European public assessment reports are publicly available
The European Commission's Community Register of Medicinal Products is a publicly searchable database of medicinal products approved for human use in the European Union
The US Food and Drug Administration provides information about drug approval in the US for consumers and for health professionals
The US National Institutes of Health provides information (including personal stories) about clinical trials
doi:10.1371/journal.pmed.1001407
PMCID: PMC3601954  PMID: 23526887
3.  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
4.  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
5.  Asthma and depression: a pragmatic review of the literature and recommendations for future research 
Background
Although the association between asthma and psychosocial factors has long been recognised, it is only in the last decade that the impact of coexisting asthma and depression has become the focus of considerable research interest. However, the findings so far have been confusing and often contradictory. This paper sets out a methodical review and appraisal of the literature to date, including suggestions for future research.
Method
PubMed and PsycINFO databases were used to search for English-language articles relating to asthma and depression research. The resulting articles were then reviewed and summarised, creating a report that was used to develop research recommendations.
Results
The main findings from this review included: (a) results are mixed as to whether persons with asthma are more likely to be depressed than those without asthma; (b) asthma and depression may have an 'additive' adverse effect on the normal asthma-related quality of life reductions; (c) subjective measures of asthma severity may be more strongly related to depression than objective measures; (d) specific asthma symptoms appear to be linked to depression; (e) sadness and depression can produce respiratory effects consistent with asthma exacerbations; (f) depression appears to be negatively related to asthma treatment compliance; (g) corticosteroid use in asthma treatment has been associated with depression, though it is unclear how common this problem is in real life; (h) interventions that address the physical, psychological, and social consequences of asthma are likely to lead to the most successful treatment outcomes; (i) treating the depression of individuals with asthma is likely to minimise the negative effects of the coexistence; and (j) a number of common methodological problems were observed in the literature.
Recommendations
There is a large amount of research yet to be undertaken to clarify issues around asthma and depression, with the overdue next step being to design integrated treatment approaches, and carry out large-scale prospective studies to determine the impact of using such approaches to treat individuals with depression and asthma. Such studies will be the only way in which some fundamental questions about the development and coexistence of these two conditions will be answered.
doi:10.1186/1745-0179-1-18
PMCID: PMC1253523  PMID: 16185365
asthma; depression; depressive disorder; research
6.  An Internet Intervention to Improve Asthma Management: Rationale and Protocol of a Randomized Controlled Trial 
JMIR Research Protocols  2013;2(2):e28.
Background
Many studies have shown the effectiveness of self-management for patients with asthma. In particular, possession and use of a written asthma action plan provided by a doctor has shown to significantly improve patients’ asthma control. Yet, uptake of a written asthma action plan and preventative asthma management is low in the community, especially amongst adults.
Objective
A Web-based personally controlled health management system (PCHMS) called Healthy.me will be evaluated in a 2010 CONSORT-compliant 2-group (static websites verse PCHMS) parallel randomized controlled trial (RCT) (allocation ratio 1:1).
Methods
The PCHMS integrates an untethered personal health record with consumer care pathways and social forums. After eligibility assessment, a sample of 300 adult patients with moderate persistent asthma will be randomly assigned to one of these arms. After 12 months of using either Healthy.me or information websites (usual care arm), a post-study assessment will be conducted.
Results
The primary outcome measure is possession of or revision of an asthma action plan during the study. Secondary outcome measures include: (1) adherence to the asthma action plan, (2) rate of planned and unplanned visits to healthcare providers for asthma issues, (3) usage patterns of Healthy.me and attrition rates, (4) asthma control and asthma exacerbation scores, and (5) impact of asthma on life and competing demands, and days lost from work.
Conclusions
This RCT will provide insights into whether access to an online PCHMS will improve uptake of a written asthma action plan and preventative asthma actions.
Trial Registration
Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12612000716864; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362714 (Archived by WebCite at http://www.webcitation.org/6IYBJGRnW).
doi:10.2196/resprot.2695
PMCID: PMC3742402  PMID: 23942523
asthma management; Internet intervention; personalized health record; personally controlled health management system; eHealth; asthma action plan
7.  Environmental air toxics: role in asthma occurrence? 
Environmental Health Perspectives  2002;110(Suppl 4):501-504.
The National Urban Air Toxics Research Center (NUATRC) hosted its first scientific workshop in 1994 that focused on possible relationships between air toxics and asthma. From that meeting came recommendations for future research including a need for more complete individual personal exposure assessments so that determinations of personal exposures to pollutants could be made. In the spring of 2001, NUATRC held a second such workshop to review progress made in this area during the intervening 7 years. Peer-reviewed articles from the workshop are published in this issue of (italic)Environmental Health Perspectives Supplements(/italic). As in 1994, academic, government, and industry scientists participated. Dave Guinnup of the Environmental Protection Agency discussed the nature of air toxics, their definition, and the basis for federal regulation. George Leikauf from the University of Cincinnati reviewed the 1994 workshop and subsequent research in this field. Current research funded by NUATRC that is addressing individual personal exposure was presented by Clifford Weisel (Environmental and Occupational Health Sciences Institute, University of Medicine and Dentistry of New Jersey), Patrick Kinney (Columbia University) and Candis Claiborn (Washington State University). David Corry from Baylor College of Medicine highlighted new insights into asthma pathogenesis while Stephen Redd from the Centers for Disease Control presented an overview of asthma epidemiology as well as the societal costs of the disease. Mary White (Agency for Toxic Substances and Disease Registry) discussed recent epidemiologic investigations by public health agencies into community concerns about asthma and hazardous air pollutants. David Peden (University of North Carolina) reviewed scientific studies into the links between asthma and air toxics as well as criteria air pollutants. In a session on occupational asthma, Lee Petsonk (National Institute for Occupational Safety and Health) discussed risk factors for work-related asthma, whereas Ralph Delfino (University of California, Irvine) addressed limitations of extrapolating from occupational asthma to asthma in the general population. These presentations were followed by panel discussions focusing on future research programs, both for NUATRC and similar research institutions. Recommendations for future research included improved assessments of personal exposure to air toxics as well as research focused on specific hazardous air pollutants. The latter recommendation was based on medical literature that suggests certain pollutants from the list of 188 air toxics are most likely to adversely affect respiratory health.
PMCID: PMC1241199  PMID: 12194880
8.  The Role of Parent Health Literacy Among Urban Children with Persistent Asthma 
Patient education and counseling  2009;75(3):368-375.
Health literacy (HL) affects adult asthma management, yet less is known about how parent HL affects child asthma care.
Objective
To examine associations between parent HL and measures related to child asthma.
Methods
Parents of 499 school-age urban children with persistent asthma in Rochester, New York completed home interviews. Measures: The Rapid Estimate of Adult Literacy in Medicine for parent HL; NHLBI criteria for asthma severity, and validated measures of asthma knowledge, beliefs, and experiences. Analyses: Bivariate and multivariate analyses of associations between parent HL measures related to child asthma.
Results
Response rate: 72%, mean child age: 7.0 years. Thirty-two percent had a Hispanic parent; 88% had public insurance. Thirty-three percent had a parent with limited HL. Low parent HL was independently associated with greater parent worry parent perception of greater asthma burden, and lower parent-reported quality of life. Measures of health care use (e.g., emergency care, preventive medicines) were not associated with parent HL.
Conclusions
Parents with limited HL worried more and perceived greater overall burden from the child’s asthma, even though reported health care use did not vary.
Practice Implications
Improved parent understanding and provider-parent communication about child asthma could reduce parent-perceived asthma burden, alleviate parent worry, and improve parent quality of life.
doi:10.1016/j.pec.2009.01.004
PMCID: PMC3712512  PMID: 19233588
Health Literacy; asthma; asthma care; child health; child asthma; health behavior; health beliefs; provider-patient communication; pediatric care; medical care; REALM; poverty; low-income; PACQOL; asthma burden; urban children
9.  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
10.  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
11.  Increased Asthma Risk and Asthma-Related Health Care Complications Associated With Childhood Obesity 
American Journal of Epidemiology  2013;178(7):1120-1128.
Asthma is the most common chronic condition of childhood, yet the relationship between obesity and asthma risk and the impact of obesity on clinical asthma outcomes are not well understood. For this population-based, longitudinal study, demographic and clinical data were extracted from administrative and electronic health records of 623,358 patients aged 6–19 years who were enrolled in the Kaiser Permanente Southern California health plan in 2007–2011. Crude asthma incidence ranged from 16.9 per 1,000 person-years among normal-weight youth to 22.3 per 1,000 person-years among extremely obese youth. The adjusted risks of asthma for overweight, moderately obese, and extremely obese youth relative to those of normal weight youth were 1.16 (95% confidence interval: 1.13, 1.20), 1.23 (95% confidence interval: 1.19, 1.28), and 1.37 (95% confidence interval: 1.32, 1.42), respectively (Ptrend < 0.0001). The relationship between obesity and asthma risk was strongest in Asian/Pacific Islanders and in the youngest girls (aged 6–10 years), compared with other groups. Among youth who developed asthma, those who were moderately or extremely obese had more frequent asthma exacerbations requiring emergency department services and/or treatment with oral corticosteroids. In conclusion, obese youth are not only more likely to develop asthma, but they may be more likely to have severe asthma, resulting in a greater need for health care utilization and aggressive asthma treatment.
doi:10.1093/aje/kwt093
PMCID: PMC3857927  PMID: 23924576
asthma; body mass index; cohort studies; obesity; overweight; severe asthma
12.  The function of medication beliefs as mediators between personality traits and adherence behavior in people with asthma 
Background
There is evidence that both personality traits and personal beliefs about medications affect adherence behavior. However, limited research exists on how personality and beliefs about asthma medication interact in influencing adherence behavior in people with asthma. To extend our knowledge in this area of adherence research, we aimed to determine the mediating effects of beliefs about asthma medication between personality traits and adherence behavior.
Methods
Asthmatics (n=516) selected from a population-based study called West Sweden Asthma Study completed the Neuroticism, Extraversion and Openness to Experience Five-Factor Inventory, the Medication Adherence Report Scale, and the Beliefs about Medicines Questionnaire. Data were analyzed using confirmatory factor analysis and structural equation modeling.
Results
Three of the five investigated personality traits – agreeableness, conscientiousness, and neuroticism – were associated with both concerns about asthma medication and adherence behavior. Concerns functioned as a partial mediator for the influencing effects of agreeableness, conscientiousness, and neuroticism on adherence behavior.
Conclusion
The findings suggest that personality traits could be used to identify individuals with asthma who need support with their adherence behavior. Additionally, targeting concerns about asthma medication in asthmatics with low levels of agreeableness or conscientiousness or high levels of neuroticism could have a favorable effect on their adherence behavior.
doi:10.2147/PPA.S49725
PMCID: PMC3808229  PMID: 24174872
adherence; individual differences; medication concerns; health behavior
13.  Self-Management of Acute Asthma among Low-Income Urban Adults 
One approach to address asthma disparities has been to create evidence-based guidelines to standardize asthma care and education. However, the adoption of these recommendations has been suboptimal among many providers. As a result, low-income minority patients may not be receiving adequate instruction in asthma self-management. In addition, these patients may fail to follow guideline-based recommendations. We conducted 25 interviews to identify the extent to which urban low-income adults have received training in, and implement, self-management protocols for acute asthma. Twenty-five adults (92% female; 76% African American; mean age 39) were enrolled. Only one subject had received asthma self-management training and only 10 (40%) used short-acting beta-2 agonist-based (SABA) self-management protocols for the early treatment of acute asthma. No subject used a peak flow meter or an asthma action plan. Most (52%) chose to initially treat acute asthma with complementary and alternative medicine (CAM) despite the availability of SABAs. Importantly, 21 (84%) preferred an integrated approach using both conventional and CAM treatments. Four themes associated with acute asthma self-management emerged from the qualitative analysis. The first theme safety reflected subjects’ perception that CAM was safer than SABA. Severity addressed the calculation that subjects made in determining if SABA or CAM was indicated based on the degree of symptoms they were experiencing. The third theme speed and strength of the combination described subjects’ belief in the superiority of integrating CAM and SABA for acute asthma self-management. The final themesense of identity spoke to the ability of CAM to provide a customized self-management strategy that subjects desired. It is unclear if subjects’ greater use of CAM or delays in using SABA-based self-management protocols were functions of inadequate instruction or personal preference. Regardless, delays in, or under use of, conventional self-management protocols may increase the risk for an untoward outcome. To that end, all patents’ acute asthma self-management strategies should be evaluated for their timeliness and appropriateness. This would be of particular importance for vulnerable populations who bear a disproportionate burden of the disease and who have the fewest resources.
doi:10.1080/02770900903029788
PMCID: PMC2751633  PMID: 19657906
acute asthma; self-management; complementary and alternative medicine (CAM); minority; health disparities; qualitative
14.  Advances in Pediatric Asthma in 2010: Addressing the Major Issues 
Last year’s Advances in Pediatric Asthma concluded with the following statement “If we can close these [remaining] gaps through better communication, improvements in the health care system and new insights into treatment, we will move closer to better methods to intervene early in the course of the disease and induce clinical remission as quickly as possible in most children”. This year’s summary will focus on recent advances in pediatric asthma that take steps moving forward as reported in Journal of Allergy and Clinical Immunology publications in 2010.
Some of those recent reports show us how to improve asthma management through steps to better understand the natural history of asthma, individualize asthma care, reduce asthma exacerbations, manage inner city asthma, and some potential new ways to use available medications to improve asthma control. It is clear that we have made many significant gains in managing asthma in children but we have a ways to go to prevent asthma exacerbations, alter the natural history of the disease, and to reduce health disparities in asthma care.
Perhaps new directions in personalized medicine and improved health care access and communication will help maintain steady progress in alleviating the burden of this disease in children, especially young children.
doi:10.1016/j.jaci.2010.11.018
PMCID: PMC3032272  PMID: 21211645
asthma; asthma control; asthma impairment; asthma risk; asthma severity; early intervention in asthma; biomarkers; genetics; inhaled corticosteroids; leukotriene receptor antagonists; long-acting β-adrenergic agonists; omalizumab; personalized medicine; therapeutics
15.  Pharmacogenetics of asthma in children 
Allergic diseases such as bronchial asthma and atopic dermatitis develop by a combination of genetic and environmental factors. Several candidate causative genes of asthma and atopy have been reported as the genetic factors. The clinical features of patients and causes of diseases vary. Therefore, personalized medicine (tailor-made medicine) is necessary for the improvement of quality of life (QOL) and for asthma cure. Pharmacogenetics is very important for personalized medicine. Here, we present the genetics and pharmacogenetics of asthma in children. Finally, we show the guideline for personalized medicine for asthma, particularly in childhood, including the pharmacogenetics of anti-asthmatic drugs, preliminarily produced by the authors.
doi:10.4168/aair.2010.2.1.14
PMCID: PMC2831608  PMID: 20224673
Pharmacogenetics; asthma; individualized medicine
16.  Using an electronic medical record (EMR) to conduct clinical trials: Salford Lung Study feasibility 
Background
Real-world data on the benefit/risk profile of medicines is needed, particularly in patients who are ineligible for randomised controlled trials conducted for registration purposes. This paper describes the methodology and source data verification which enables the conduct of pre-licensing clinical trials of COPD and asthma in the community using the electronic medical record (EMR), NorthWest EHealth linked database (NWEH-LDB) and alert systems.
Methods
Dual verification of extracts into NWEH-LDB was performed using two independent data sources (Salford Integrated Record [SIR] and Apollo database) from one primary care practice in Salford (N = 3504). A feasibility study was conducted to test the reliability of the NWEH-LDB to support longitudinal data analysis and pragmatic clinical trials in asthma and COPD. This involved a retrospective extraction of data from all registered practices in Salford to identify a cohort of patients with a diagnosis of asthma (aged ≥18) and/or COPD (aged ≥40) and ≥2 prescriptions for inhaled bronchodilators during 2008. Health care resource utilisation (HRU) outcomes during 2009 were assessed. Exacerbations were defined as: prescription for oral corticosteroids (OCS) in asthma and prescription of OCS or antibiotics in COPD; and/or hospitalisation for a respiratory cause.
Results
Dual verification demonstrated consistency between SIR and Apollo data sources: 3453 (98.6%) patients were common to both systems; 99.9% of prescription records were matched and of 29,830 diagnosis records, one record was missing from Apollo and 272 (0.9%) from SIR. Identified COPD patients were also highly concordant (Kappa coefficient = 0.98).
A total of 7981 asthma patients and 4478 COPD patients were identified within the NWEH-LDB. Cohort analyses enumerated the most commonly prescribed respiratory medication classes to be: inhaled corticosteroids (ICS) (42%) and ICS plus long-acting β2-agonist (LABA) (40%) in asthma; ICS plus LABA (55%) and long-acting muscarinic antagonists (36%) in COPD. During 2009 HRU was greater in the COPD versus asthma cohorts, and exacerbation rates in 2009 were higher in patients who had ≥2 exacerbations versus ≤1 exacerbation in 2008 for both asthma (137.5 vs. 20.3 per 100 person-years, respectively) and COPD (144.6 vs. 41.0, respectively).
Conclusion
Apollo and SIR data extracts into NWEH-LDB showed a high level of concordance for asthma and COPD patients. Longitudinal data analysis characterized the COPD and asthma populations in Salford including medications prescribed and health care utilisation outcomes suitable for clinical trial planning.
doi:10.1186/s12911-015-0132-z
PMCID: PMC4331140
Asthma; COPD; Electronic medical record; EMR; Real-world data; Primary and secondary healthcare; Dual verification
17.  Effects of Air Pollutants on Childhood Asthma 
Yonsei Medical Journal  2005;46(2):239-244.
Epidemiologic studies have suggested the association between environmental exposure to volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs) and the increased risk of incurring asthma. Yet there is little data regarding the relationship between personal exposure to air pollution and the incidence of asthma in children. This study was designed to evaluate the effect of exposure to air pollution on children with asthma by using exposure biomarkers. We assessed the exposure level to VOCs by measuring urinary concentrations of hippuric acid and muconic acid, and PAHs by 1-OH pyrene and 2-naphthol in 30 children with asthma and 30 children without asthma (control). The mean level of hippuric acid was 0.158 ± 0.169 µmol/mol creatinine in the asthma group and 0.148 ± 0.249 µmol/mol creatinine in the control group, with no statistical significance noted (p=0.30). The mean concentration of muconic acid was higher in the asthma group than in the control group (7.630 ± 8.915 µmol/mol creatinine vs. 3.390 ± 4.526 µmol/mol creatinine p=0.01). The mean level of urinary 1-OHP was higher in the asthma group (0.430 ± 0.343 µmol/mol creatinine) than the control group (0.239 ± 0.175 µmol/mol creatinine), which was statistically significant (p=0.03). There was no difference in the mean concentration of 2-NAP between the two groups (9.864 ± 10.037 µmol/mol in the asthma group vs. 9.157 ± 9.640 µmol/mol in the control group, p=0.96). In conclusion, this study suggests that VOCs and PAHs have some role in asthma.
doi:10.3349/ymj.2005.46.2.239
PMCID: PMC2823020  PMID: 15861497
VOCs; PAHs; asthma
18.  Effects of Depressive Symptoms on Health-Related Quality of Life in Asthma Patients 
OBJECTIVE
To assess the effects of depressive symptoms on asthma patients' reports of functional status and health-related quality of life.
DESIGN
Cross-sectional study.
SETTING
Primary care internal medicine practice at a tertiary care center in New York City.
PATIENTS
We studied 230 outpatients between the ages of 18 and 62 years with moderate asthma.
MEASUREMENTS AND MAIN RESULTS
Patients were interviewed in person in English or Spanish with two health-related quality-of-life measures, the disease-specific Asthma Quality of Life Questionnaire (AQLQ) (possible score range, 1 to 7; higher scores reflect better function) and the generic Medical Outcomes Study SF-36 (general population mean is 50 for both the Physical Component Summary [PCS] score and Mental Component Summary [MCS] score). Patients also completed a screen for depressive symptoms, the Geriatric Depression Scale (GDS), and a global question regarding current disease activity. Stepwise multivariate analyses were conducted with the AQLQ and SF-36 scores as the dependent variables and depressive symptoms, comorbidity, asthma, and demographic characteristics as independent variables. The mean age of patients was 41 ±SD 11 years and 83% were women. The mean GDS score was 11 ±SD 8 (possible range, 0 to 30; higher scores reflect more depressive symptoms), and a large percentage of patients, 45%, scored above the threshold considered positive for depression screening. Compared with patients with a negative screen for depressive symptoms, patients with a positive screen had worse composite AQLQ scores (3.9 ±SD 1.3 vs 2.8 ±SD 0.8, P < .0001) and worse PCS scores (40 ±SD 11 vs 34 ±SD 8, P < .0001) and worse MCS scores (48 ±SD 11 vs 32 ±SD 10, P < .0001) scores. In stepwise analyses, current asthma activity and GDS scores had the greatest effects on patient-reported health-related quality of life, accounting for 36% and 11% of the variance, respectively, for the composite AQLQ, and 11% and 38% of the variance, respectively, for the MCS in multivariate analyses.
CONCLUSIONS
Nearly half of asthma patients in this study had a positive screen for depressive symptoms. Asthma patients with more depressive symptoms reported worse health-related quality of life than asthma patients with similar disease activity but fewer depressive symptoms. Given the new emphasis on functional status and health-related quality of life measured by disease-specific and general health scales, we conclude that psychological status indicators should also be considered when patient-derived measures are used to assess outcomes in asthma.
doi:10.1046/j.1525-1497.2000.07006.x
PMCID: PMC1495457  PMID: 10840265
asthma; depressive symptoms; quality of life; global measure
19.  e-Health, m-Health and healthier social media reform: the big scale view 
Introduction
In the upcoming decade, digital platforms will be the backbone of a strategic revolution in the way medical services are provided, affecting both healthcare providers and patients. Digital-based patient-centered healthcare services allow patients to actively participate in managing their own care, in times of health as well as illness, using personally tailored interactive tools. Such empowerment is expected to increase patients’ willingness to adopt actions and lifestyles that promote health as well as improve follow-up and compliance with treatment in cases of chronic illness. Clalit Health Services (CHS) is the largest HMO in Israel and second largest world-wide. Through its 14 hospitals, 1300 primary and specialized clinics, and 650 pharmacies, CHS provides comprehensive medical care to the majority of Israel’s population (above 4 million members). CHS e-Health wing focuses on deepening patient involvement in managing health, through personalized digital interactive tools. Currently, CHS e-Health wing provides e-health services for 1.56 million unique patients monthly with 2.4 million interactions every month (August 2011). Successful implementation of e-Health solutions is not a sum of technology, innovation and health; rather it’s the expertise of tailoring knowledge and leadership capabilities in multidisciplinary areas: clinical, ethical, psychological, legal, comprehension of patient and medical team engagement etc. The Google Health case excellently demonstrates this point. On the other hand, our success with CHS is a demonstration that e-Health can be enrolled effectively and fast with huge benefits for both patients and medical teams, and with a robust business model.
CHS e-Health core components
They include:
1. The personal health record layer (what the patient can see) presents patients with their own medical history as well as the medical history of their preadult children, including diagnoses, allergies, vaccinations, laboratory results with interpretations in layman’s terms, medications with clear, straightforward explanations regarding dosing instructions, important side effects, contraindications, such as lactation etc., and other important medical information. All personal e-Health services require identification and authorization.
2. The personal knowledge layer (what the patient should know) presents patients with personally tailored recommendations for preventative medicine and health promotion. For example, diabetic patients are push notified regarding their yearly eye exam. The various health recommendations include: occult blood testing, mammography, lipid profile etc. Each recommendation contains textual, visual and interactive content components in order to promote engagement and motivate the patient to actually change his health behaviour.
3. The personal health services layer (what the patient can do) enables patients to schedule clinic visits, order chronic prescriptions, e-consult their physician via secured e-mail, set SMS medication reminders, e-consult a pharmacist regarding personal medications. Consultants’ answers are sent securely to the patients’ personal mobile device.
On December 2009 CHS launched secured, web based, synchronous medical consultation via video conference. Currently 11,780 e-visits are performed monthly (May 2011). The medical encounter includes e-prescription and referral capabilities which are biometrically signed by the physician. On December 2010 CHS launched a unique mobile health platform, which is one of the most comprehensive personal m-Health applications world-wide. An essential advantage of mobile devices is their potential to bridge the digital divide. Currently, CHS m-Health platform is used by more than 45,000 unique users, with 75,000 laboratory results views/month, 1100 m-consultations/month and 9000 physician visit scheduling/month.
4. The Bio-Sensing layer (what physiological data the patient can populate) includes diagnostic means that allow remote physical examination, bio-sensors that broadcast various physiological measurements, and smart homecare devices, such as e-Pill boxes that gives seniors, patients and their caregivers the ability to stay at home and live life to its fullest. Monitored data is automatically transmitted to the patient’s Personal Health Record and to relevant medical personnel.
The monitoring layer is embedded in the chronic disease management platform, and in the interactive health promotion and wellness platform. It includes tailoring of consumer-oriented medical devices and service provided by various professional personnel—physicians, nurses, pharmacists, dieticians and more.
5. The Social layer (what the patient can share). Social media networks triggered an essential change at the humanity ‘genome’ level, yet to be further defined in the upcoming years. Social media has huge potential in promoting health as it combines fun, simple yet extraordinary user experience, and bio-social-feedback. There are two major challenges in leveraging health care through social networks:
a. Our personal health information is the cornerstone for personalizing healthier lifestyle, disease management and preventative medicine. We naturally see our personal health data as a super-private territory. So, how do we bring the power of our private health information, currently locked within our Personal Health Record, into social media networks without offending basic privacy issues?
b. Disease management and preventive medicine are currently neither considered ‘cool’ nor ‘fun’ or ‘potentially highly viral’ activities; yet, health is a major issue of everybody’s life. It seems like we are missing a crucial element with a huge potential in health behavioural change—the Fun Theory. Social media platforms comprehends user experience tools that potentially could break current misconception, and engage people in the daily task of taking better care of themselves.
CHS e-Health innovation team characterized several break-through applications in this unexplored territory within social media networks, fusing personal health and social media platforms without offending privacy. One of the most crucial issues regarding adoption of e-health and m-health platforms is change management. Being a ‘hot’ innovative ‘gadget’ is far from sufficient for changing health behaviours at the individual and population levels.
CHS health behaviour change management methodology includes 4 core elements:
1. Engaging two completely different populations: patients, and medical teams. e-Health applications must present true added value for both medical teams and patients, engaging them through understanding and assimilating “what’s really in it for me”. Medical teams are further subdivided into physicians, nurses, pharmacists and administrative personnel—each with their own driving incentive. Resistance to change is an obstacle in many fields but it is particularly true in the conservative health industry. To successfully manage a large scale persuasive process, we treat intra-organizational human resources as “Change Agents”. Harnessing the persuasive power of ~40,000 employees requires engaging them as the primary target group. Successful recruitment has the potential of converting each patient-medical team interaction into an exposure opportunity to the new era of participatory medicine via e-health and m-health channels.
2. Implementation waves: every group of digital health products that are released at the same time are seen as one project. Each implementation wave leverages the focus of the organization and target populations to a defined time span. There are three major and three minor implementation waves a year.
3. Change-Support Arrow: a structured infrastructure for every implementation wave. The sub-stages in this strategy include:
Cross organizational mapping and identification of early adopters and stakeholders relevant to the implementation wave
Mapping positive or negative perceptions and designing specific marketing approaches for the distinct target groups
Intra and extra organizational marketing
Conducting intensive training and presentation sessions for groups of implementers
Running conflict-prevention activities, such as advanced tackling of potential union resistance
Training change-agents with resistance-management behavioural techniques, focused intervention for specific incidents and for key opinion leaders
Extensive presence in the clinics during the launch period, etc.
The entire process is monitored and managed continuously by a review team.
4. Closing Phase: each wave is analyzed and a “lessons-learned” session concludes the changes required in the modus operandi of the e-health project team.
PMCID: PMC3571141
e-Health; mobile health; personal health record; online visit; patient empowerment; knowledge prescription
20.  Factors predicting inhaled corticosteroid responsiveness in African American patients with asthma 
Background
African American patients suffer disproportionately from uncontrolled asthma. Treatment with an inhaled corticosteroid (ICS) is considered first-line therapy for persistent asthma.
Objective
To determine the degree to which African American patients respond to ICS medication and whether the level of response is influenced by other factors, including genetic ancestry.
Methods
Patients aged 12-56 years who received care from a large health system in southeast Michigan and who resided in Detroit were recruited to participate if they had a diagnosis of asthma. Patients were treated with 6 weeks of inhaled beclomethasone dipropionate, and pulmonary function was re-measured after treatment. Ancestry was determined by genotyping ancestry informative markers. The main outcome measure was ICS responsiveness defined as the change in pre-bronchodilator FEV1 over the 6-week course of treatment.
Results
Among 147 participating African American patients with asthma, average improvement in FEV1 following 6 weeks of ICS treatment was 11.6%. The mean proportion of African ancestry in this group was 78.4%. The degree of baseline bronchodilator reversibility was the only factor consistently associated ICS responsiveness as measured by both an improvement in FEV1 and in patient reported asthma control (P=0.001 and P=0.021, respectively). The proportion of African ancestry was not significantly associated with ICS responsiveness.
Conclusions
While baseline pulmonary function parameters appear to be associated with the likelihood to respond to ICS treatment, the proportion of genetic African ancestry does not. This study suggests that genetic ancestry may not contribute to differences in ICS controller response among African American patients with asthma.
Clinical Implications
Although African American patients suffer disproportionately from asthma-related complications, response to ICS controller therapy does not appear to be dependent on an individual’s proportion of African ancestry.
Capsule summary
Personalized medicine will be most beneficial to groups disproportionately affected by disease complications. Here we find baseline bronchodilator reversibility but not African ancestry to be associated with ICS responsiveness among African American patients with asthma.
doi:10.1016/j.jaci.2010.08.002
PMCID: PMC2998569  PMID: 20864153
inhaled corticosteroids; asthma; race-ethnicity; continental population groups; ancestry; urban health
21.  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
22.  Preterm Birth and Childhood Wheezing Disorders: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(1):e1001596.
In a systematic review and meta-analysis, Jasper Been and colleagues investigate the association between preterm birth and the development of wheezing disorders in childhood.
Please see later in the article for the Editors' Summary
Background
Accumulating evidence implicates early life factors in the aetiology of non-communicable diseases, including asthma/wheezing disorders. We undertook a systematic review investigating risks of asthma/wheezing disorders in children born preterm, including the increasing numbers who, as a result of advances in neonatal care, now survive very preterm birth.
Methods and Findings
Two reviewers independently searched seven online databases for contemporaneous (1 January 1995–23 September 2013) epidemiological studies investigating the association between preterm birth and asthma/wheezing disorders. Additional studies were identified through reference and citation searches, and contacting international experts. Quality appraisal was undertaken using the Effective Public Health Practice Project instrument. We pooled unadjusted and adjusted effect estimates using random-effects meta-analysis, investigated “dose–response” associations, and undertook subgroup, sensitivity, and meta-regression analyses to assess the robustness of associations.
We identified 42 eligible studies from six continents. Twelve were excluded for population overlap, leaving 30 unique studies involving 1,543,639 children. Preterm birth was associated with an increased risk of wheezing disorders in unadjusted (13.7% versus 8.3%; odds ratio [OR] 1.71, 95% CI 1.57–1.87; 26 studies including 1,500,916 children) and adjusted analyses (OR 1.46, 95% CI 1.29–1.65; 17 studies including 874,710 children). The risk was particularly high among children born very preterm (<32 wk gestation; unadjusted: OR 3.00, 95% CI 2.61–3.44; adjusted: OR 2.81, 95% CI 2.55–3.12). Findings were most pronounced for studies with low risk of bias and were consistent across sensitivity analyses. The estimated population-attributable risk of preterm birth for childhood wheezing disorders was ≥3.1%.
Key limitations related to the paucity of data from low- and middle-income countries, and risk of residual confounding.
Conclusions
There is compelling evidence that preterm birth—particularly very preterm birth—increases the risk of asthma. Given the projected global increases in children surviving preterm births, research now needs to focus on understanding underlying mechanisms, and then to translate these insights into the development of preventive interventions.
Review Registration
PROSPERO CRD42013004965
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last around 40 weeks, but worldwide, more than 11% of babies are born before 37 weeks of gestation (the period during which a baby develops in its mother's womb). Preterm birth is a major cause of infant death—more than 1 million babies die annually from preterm birth complications—and the number of preterm births is increasing globally. Multiple pregnancies, infections, and chronic (long-term) maternal conditions such as diabetes can all cause premature birth, but the cause of many preterm births is unknown. The most obvious immediate complication that is associated with preterm birth is respiratory distress syndrome. This breathing problem, which is more common in early preterm babies than in near-term babies, occurs because the lungs of premature babies are structurally immature and lack pulmonary surfactant, a unique mixture of lipids and proteins that coats the inner lining of the lungs and helps to prevent the collapse of the small air sacs in the lungs that absorb oxygen from the air. Consequently, preterm babies often need help with their breathing and oxygen supplementation.
Why Was This Study Done?
Improvements in the management of prematurity mean that more preterm babies survive today than in the past. However, accumulating evidence suggests that early life events are involved in the subsequent development of non-communicable diseases (non-infectious chronic diseases). Given the increasing burden of preterm birth, a better understanding of the long-term effects of preterm birth is essential. Here, the researchers investigate the risks of asthma and wheezing disorders in children who are born preterm by undertaking a systematic review (a study that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical method for combining the results of several studies). Asthma is a chronic condition that is caused by inflammation of the airways. In people with asthma, the airways can react very strongly to allergens such as animal fur and to irritants such as cigarette smoke. Exercise, cold air, and infections can also trigger asthma attacks, which can sometimes be fatal. The symptoms of asthma include wheezing (a high-pitched whistling sound during breathing), coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
What Did the Researchers Do and Find?
The researchers identified 30 studies undertaken between 1995 and the present (a time span chosen to allow for recent changes in the management of prematurity) that investigated the association between preterm birth and asthma/wheezing disorders in more than 1.5 million children. Across the studies, 13.7% of preterm babies developed asthma/wheezing disorders during childhood, compared to only 8.3% of babies born at term. Thus, the risk of preterm babies developing asthma or a wheezing disorder during childhood was 1.71 times higher than the risk of term babies developing these conditions (an unadjusted odds ratio [OR] of 1.71). In analyses that allowed for confounding factors—other factors that affect the risk of developing asthma/wheezing disorders such as maternal smoking—the risk of preterm babies developing asthma or a wheezing disorder during childhood was 1.46 times higher than that of babies born at term (an adjusted OR of 1.46). Notably, compared to children born at term, children born very early (before 32 weeks of gestation) had about three times the risk of developing asthma/wheezing disorders in unadjusted and adjusted analyses. Finally, the population-attributable risk of preterm birth for childhood wheezing disorders was more than 3.1%. That is, if no preterm births had occurred, there would have been more than a 3.1% reduction in childhood wheezing disorders.
What Do These Findings Mean?
These findings strongly suggest that preterm birth increases the risk of asthma and wheezing disorders during childhood and that the risk of asthma/wheezing disorders increases as the degree of prematurity increases. The accuracy of these findings may be affected, however, by residual confounding. That is, preterm children may share other, unknown characteristics that increase their risk of developing asthma/wheezing disorders. Moreover, the generalizability of these findings is limited by the lack of data from low- and middle-income countries. However, given the projected global increases in children surviving preterm births, these findings highlight the need to undertake research into the mechanisms underlying the association between preterm birth and asthma/wheezing disorders and the need to develop appropriate preventative and therapeutic measures.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001596.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
Nemours, another nonprofit organization for child health, also provides information (in English and Spanish) on premature babies and on asthma (including personal stories)
The UK National Health Service Choices website provides information about premature labor and birth and a real story about having a preterm baby; it provides information about asthma in children (including real stories)
The MedlinePlus Encyclopedia has pages on preterm birth, asthma, asthma in children, and wheezing (in English and Spanish); MedlinePlus provides links to further information on premature birth, asthma, and asthma in children (in English and Spanish)
doi:10.1371/journal.pmed.1001596
PMCID: PMC3904844  PMID: 24492409
23.  Severe Asthma in Childhood: Recent Advances in Phenotyping and Pathogenesis 
Purpose of the review
Children with severe asthma have a high degree of respiratory morbidity despite treatment with high doses of inhaled corticosteroids and are therefore very difficult to treat. This review will discuss phenotypic and pathogenic aspects of severe asthma in childhood, as well as remaining knowledge gaps.
Recent findings
As a group, children with severe asthma have a number of distinct phenotypic features compared to children with mild-to-moderate asthma. Clinically, children with severe asthma are differentiated by greater allergic sensitization, increased exhaled nitric oxide, and significant airflow limitation and air trapping that worsens as a function of age. These findings are accompanied by structural airway changes and increased and dysregulated airway inflammation and oxidant stress which may explain the differential nature of corticosteroid responsiveness in this population. Because children with severe asthma themselves are a heterogeneous group, current efforts are focused on improved definition and sub-phenotyping of the disorder. While the clinical relevance of phenotyping approaches in severe asthma is not yet clear, they may provide important insight into the mechanisms underlying the disorder.
Summary
Improved classification of severe asthma through unified definitions, careful phenotypic analyses, and mechanism-focused endotyping approaches may ultimately advance knowledge and personalized treatment.
doi:10.1097/ACI.0b013e32835090ac
PMCID: PMC3310912  PMID: 22249197
Severe asthma; difficult asthma; children; phenotype; endotype
24.  Asthma and the risk of type 2 diabetes in the Singapore Chinese Health Study 
Aim
Asthma is believed to increase the risk for several proinflammatory diseases, yet epidemiologic studies on asthma in relation to risk of developing type 2 diabetes are sparse and have reported inconsistent results. In the present study, we investigated the hypothesis that asthma is associated with an increased risk of incident type 2 diabetes in Chinese adults.
Methods
We used data from the Singapore Chinese Health Study, including Chinese men and women aged 45–74 years, free of cancer, heart disease, stroke, and diabetes at baseline (1993–1998) and followed through 2004 for incident physician-diagnosed diabetes. Cox regression models were used to examine the associations between self-reported history of physician-diagnosed asthma and risk of diabetes.
Results
During an average follow-up of 5.7 years per person, 2,234 of the 42,842 participants included in the current analyses reported diagnoses of type 2 diabetes. After adjustment for potential confounders, not including body mass index (BMI), asthma was associated with a 31% increased risk of incident diabetes (HR = 1.31; 95% CI: 1.00–1.72). The association was attenuated after adjustment for adult BMI (HR = 1.25 95% CI: 0.95–1.64). The asthma-diabetes association appeared stronger for adult- versus child-diagnosed asthma cases, and for participants who were obese compared to non-obese.
Conclusions
In Singaporean Chinese adults we observed a positive association between self-reported, physician-diagnosed asthma and risk of developing type 2 diabetes that was modestly attenuated upon adjustment for BMI.
doi:10.1016/j.diabres.2012.11.019
PMCID: PMC3615124  PMID: 23260853
Asthma; Type 2 diabetes; Obesity
25.  Skin Exposure to Isocyanates: Reasons for Concern 
Environmental Health Perspectives  2006;115(3):328-335.
Objective
Isocyanates (di- and poly-), important chemicals used worldwide to produce polyurethane products, are a leading cause of occupational asthma. Respiratory exposures have been reduced through improved hygiene controls and the use of less-volatile isocyanates. Yet isocyanate asthma continues to occur, not uncommonly in settings with minimal inhalation exposure but opportunity for skin exposure. In this review we evaluate the potential role of skin exposure in the development of isocyanate asthma.
Data sources
We reviewed the published animal and human literature on isocyanate skin-exposure methods, workplace skin exposure, skin absorption, and the role of skin exposure in isocyanate sensitization and asthma.
Data extraction
We selected relevant articles from computerized searches on Medline, U.S. Environmental Protection Agency, Occupational Safety and Health Administration, National Institute for Occupational Safety and Health, and Google databases using the keywords “isocyanate,” “asthma,” “skin,” “sensitization,” and other synonymous terms, and our own extensive collection of isocyanate publications.
Data synthesis
Isocyanate production and use continues to increase as the polyurethane industry expands. There is substantial opportunity for isocyanate skin exposure in many work settings, but such exposure is challenging to quantify and continues to be underappreciated. Isocyanate skin exposure can occur at work, even with the use of personal protective equipment, and may also occur with consumer use of certain isocyanate products. In animals, isocyanate skin exposure is an efficient route to induce sensitization, with subsequent inhalation challenge resulting in asthma-like responses. Several lines of evidence support a similar role for human isocyanate skin exposure, namely, that such exposure occurs and can contribute to the development of isocyanate asthma in certain settings, presumably by inducing systemic sensitization.
Conclusions
Integrated animal and human research is needed to better understand the role of skin exposure in human isocyanate asthma and to improve diagnosis and prevention. In spite of substantial research needs, sufficient evidence already exists to justify greater emphasis on the potential risks of isocyanate skin exposure and the importance of preventing such exposures at work and during consumer use of certain isocyanate products.
doi:10.1289/ehp.9557
PMCID: PMC1849909  PMID: 17431479
asthma; dermal exposure; isocyanates; sensitization; skin

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