The Journal of Allergy and Clinical Immunology
Volume 125, Issue 1 , Pages 79-84, January 2010

Advances in adult asthma diagnosis and treatment in 2009

  • Andrea J. Apter, MD, MSc

      Affiliations

    • Corresponding Author InformationReprint requests: Andrea J. Apter, MD, MSc, 829 Gates Bldg, Hospital of the University of Pennsylvania, 3600 Spruce St, Philadelphia, PA 19104.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, Pa

Received 17 November 2009; accepted 19 November 2009.

Article Outline

There is a growing need to standardize and validate outcomes for asthma research. In this review of asthma-related publications from the Journal in 2009, efforts to standardize methodology and reporting of translational research, the influence of the environment, therapeutics, and management of asthma are highlighted.

Key words: Asthma, adults, genetics, inhaled corticosteroids, nitric oxide, health disparities, biomarker, leukotriene modifier, obesity

Abbreviations used: BF, Budesonide/formoterol, BMI, Body mass index, ED, Emergency department, Feno, Fraction of exhaled nitric oxide, GSTM1, Glutathione-S-transferase M1 gene, HEDIS, Healthcare Effectiveness Data and Information Set, ICS, Inhaled corticosteroid, MBT, Mannitol bronchoprovocation test, PLAUR, Urokinase plasminogen activator receptor gene, TSLP, Thymic stromal lymphopoietin, UK, United Kingdom

 

As in past Advances articles,1, 2, 3, 4, 5, 6, 7 our review examines research on management, therapeutics, and the role of environmental exposures on asthma. During the past year, substantial efforts were initiated to promote standardization and validation of outcomes used in asthma–related research. In July 2009, a joint task force of the European Respiratory Society and the American Thoracic Society published recommendations providing the foundation for standardization of end points for both clinical trials and practice.8 Specifically, the task force sought to define asthma control, which they considered a “summary term”8; exacerbations; and severity. Their recommendations included a multicomponent assessment of control. A consortium of several National Institutes of Health institutes, the Agency for Healthcare Research and Quality, and the Merck Childhood Asthma Network will hold an Asthma Outcomes Workshop in March 2010 to further refine standard definitions and data collection methodologies and identify promising new outcome measures. The workshop's goals are to enable comparisons across studies and clinical trials and to enhance the level of confidence in research findings. This consortium will consider endorsing a selective set of “core” outcomes to be identified as required outcome measures in National Institutes of Health–initiated asthma clinical research programs. Also over the past year, the National Committee for Quality Assurance and the American Medical Association Physician Consortium for Performance Improvement have proposed asthma measures to be used in assessing quality improvement.9

Outcomes, whether used for research, patient care decisions, or quality improvement, must be valid, easily obtainable, and reproducible. Some, such as self-report measures (eg, questionnaires and unobserved effort-dependent peak flow records), are easy to obtain but might not be valid or reproducible. Nevertheless, they could add another dimension when combined in a multicomponent assessment.8 As we review this year's research, we invite the reader to consider the study populations, their applicability to their own patients, and the measures used for outcomes.

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Genetics: From bench to bedside 

Several genetic studies suggest possible future therapeutic applications. Thymic stromal lymphopoietin (TSLP) is an IL-7–like cytokine that induces myeloid dendritic cells to stimulate naive T cells to differentiate into TH2 cells.10 TSLP is located on chromosome 5q22 near genes for IL-4, IL-5, IL-9, and IL-13. He et al,11 using DNA from 5565 subjects from 4 asthma studies, identified TSLP variants associated with asthma, mostly defined as a self-reported doctor's diagnosis.

Barton et al12 studied the urokinase plasminogen activator receptor gene (PLAUR) as an asthma susceptibility gene in United Kingdom (UK) and Dutch families by combining several studies with slightly different inclusion criteria. Using linkage and association analyses, they found PLAUR to be associated with a decrease in FEV1 and bronchial hyperresponsiveness to methacholine or histamine.

Haller et al13 compared rare variants of the IL4 gene in subjects of African descent. They hypothesized that because populations of African descent have increased genetic variation, rare variants of a gene important in atopic disease, such as IL4, might play a role in asthma susceptibility. African Americans with doctor-diagnosed asthma and demonstrated bronchial hyperresponsiveness to methacholine or reversibility of obstruction with albuterol were compared with African Americans without asthma. They identified 26 private single nucleotide polymorphisms in the IL4 region: 18 present only in cases and 8 present only in control subjects. The investigators concluded that these rare variants, most not included in common genotyping platforms, might contribute to asthma susceptibility in African American subjects.

Basu et al14 found the Arg16 genotype of the adrenergic β2-receptor agonist gene (ADRB2) increased the risk of asthma exacerbations among young patients using daily β2-agonists. By recruiting additional subjects to those enrolled in an earlier study, they doubled the study population from 546 to 1190. These studies of genetic risk factors demonstrate tradeoffs of increasing sample size by combining patient populations with potential changes to generalizability and potential limitations to the measures that can be used to characterize asthma and study outcomes.

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Measuring outcomes and quality of care 

Clinical measures 

The effort to standardize outcomes has led to examination of self-report questionnaires and biomarkers. Schatz et al15 determined the minimal clinically important difference on the Asthma Control Test.16 Four large samples were recruited: (1) subjects from an Internet comparison study of modes of administration of surveys, (2) patients from 6 asthma specialty practices, (3) asthmatic subjects recruited from local media advertising or by consulting one of these advertising practices, and (4) subjects from the Kaiser Permanente asthma database. When applying Asthma Control Test results, users must consider how representative these patients are to theirs.

Yong and Werner17 identified Medicaid beneficiaries from the Healthcare Effectiveness Data and Information Set (HEDIS) to evaluate the HEDIS quality measure for asthma care used by health plans. Subjects satisfied at least 1 asthma-related category in both 2001 and 2002: emergency department (ED) visit, hospitalization, at least 4 outpatient visits and at least 2 asthma-medication dispensing events, or at least 4 asthma medication-dispensing events. The investigators compared (1) the current HEDIS criterion of at least 1 controller-medication filling, (2) at least 4 controller-medications fillings yearly, and (3) a controller/total asthma medication ratio of at least 0.5. Filling 1 or 4 asthma controller prescriptions was associated with higher likelihood of exacerbations (ED visit, hospitalization, or dispensing of an oral steroid for asthma), but those with a controller/total asthma medication ratio of at least 50% were 23% less likely to have such an exacerbation. The authors concluded that the controller/total asthma medication ratio is more sensitive to unmeasured disease severity. These findings are particularly pertinent because HEDIS criteria are now under revision.

Biomarkers 

Biomarkers potentially can noninvasively assess airway inflammation, complementing clinical measures. Feno, described in last year's Advances article as an indicator of eosinophilic inflammation,4 can be influenced by nonpathologic factors, such as genetic and environmental variation.18 Information on its limitations grows. Smith et al19 found reductions in fraction of exhaled nitric oxide (Feno) levels when prednisone was administered to adults with mild-to-moderate asthma, but the levels did not always agree with values predicted by published references nor did they predict good control with inhaled corticosteroids (ICSs). The authors found “personal best” Feno values might be a better marker than absolute levels, but whether Feno is more feasible and cost-effective than patient history or spirometry is doubtful.20 Gruchalla et al21 examined inner-city asthmatic adolescents for biomarkers and other predictors of exacerbations. Feno values were not predictive of maximum symptom days recalled over a 2-week period and only weakly correlated with exacerbations. Additionally, all the baseline subjects' characteristics accounted for only about 12% of the variance for future maximum symptom days. The authors concluded that the usual predictors of disease activity have little predictive power in a population already receiving guidelines-based care. This underlines the importance of investigation of the outcomes presented above.8

Gergen et al22 examined total IgE level as a potential biomarker of cumulative sensitivity to all allergens. Using National Health and Nutrition Examination Survey data, they found IgE levels varied with age, sex, race/ethnicity, serum cotinine levels, body size, and socioeconomic status and were associated only with self-reported asthma among persons with positive allergen-specific IgE. Thus measurement of total IgE was not recommended. Kaminska et al23 searched for biomarkers that distinguish reversible from irreversible obstruction in patients with severe asthma. None of the biomarkers of inflammation or remodeling (eg, eosinophil cationic protein, myeloperoxidase, matrix metalloproteinase analyses, cytokines, and cell counts) separated these 2 groups. Wu et al24 examined the repeatability of various biomarkers over 4 years in the Childhood Asthma Management Program. They found FEV1 and PC20 values, but not bronchodilator response, had high repeatability.

The mannitol bronchoprovocation test (MBT) is an indirect test, acting on smooth muscle by stimulating mediator release, whereas methacholine and histamine directly cause muscle contraction. Sverrild et al25 determined the sensitivity and specificity of the MBT in young adults independently classified as asthmatic as 58.8% and 98.4%, respectively. Thus the MBT might have greater specificity but less sensitivity than bronchoprovocation with methacholine or histamine. There is a tradeoff between sensitivity and specificity.26 Sensitive tests are more likely to generate false-positive results and fewer false-negative results, whereas specific tests are more likely to have false-negative results and fewer false-positive results. Specific tests, like the MBT, are best used to diagnose asthma, whereas methacholine and histamine bronchoprovocations are best used to rule out asthma.

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Environment 

Pollution, viral infection, and social stress are some environmental risk factors studied in 2009. Traffic exposure has been associated with adverse outcomes in asthmatic children.27, 28 In adults Balmes et al29 found FEV1 to be positively associated with distance from the nearest roadways. Controlling for income, itself related to distance from major roadways, did not substantively change this association. The study was a secondary analysis and limited by nonuniform inclusion criteria because some subjects had rhinitis rather than asthma.

Ozone increases the risk of asthma in part by exposing lung tissue to higher oxidative stress. Glutathione-S-transferase is an antioxidant. Deletion of an allele of the glutathione-S-transferase M1 gene (GSTM1) produces a nonfunctioning product associated with asthma and poorer lung function. Alexis et al30 compared the effects of ozone exposure in healthy volunteers with the wild-type and null GSTM1 genotypes. GSTM1-null volunteers had increased neutrophil and activated macrophage counts in induced sputum 24 hours after ozone exposure, which is consistent with the lag time to symptoms previously observed with ambient ozone exposure. There was no difference in FEV1 and forced vital capacity between groups, although values decreased in both groups after ozone exposure.

Respiratory tract viral infections also increase the risk of asthma exacerbations. DeMore et al31 hypothesized that host defense against viruses is defective in asthmatic subjects. Young adults with or without mild allergic asthma were inoculated nasally with rhinovirus. No difference was observed in cold symptoms or viral shedding in nasal lavage and sputum samples. With the exception of sputum eosinophil counts, which were higher at baseline in allergic asthmatic subjects, there were no differences in cytokine or cellular composition of the samples. The study hypothesis was not supported, although the sample size was small.

Sternthal et al32 probed the effect of maternal lifetime interpersonal trauma on the fetal TH2 cytokine/chemokine milieu in a cohort of Boston-area inner-city women during and after pregnancy. Their secondary analysis assessed and correlated stress at successive life stages (childhood, adolescence, and adulthood before and during the current pregnancy) and found an association of chronic maternal interpersonal trauma with higher cord blood IgE levels. Although preliminary, the study emphasizes the need for better understanding of lifetime maternal stress on asthma outcomes in infants.

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Practice or management 

Therapeutics 

Leukotriene modifiers 

The possible association of montelukast with depression was raised by the US Food and Drug Administration in 2007. In 2008, Holbrook and Harik-Khan33 combined data from 3 studies and found no association. In 2009, responding to US Food and Drug Administration requests, the manufacturers performed secondary analyses of studies comparing montelukast with placebo or comparison drug.34, 35 Few behavior-related adverse events (eg, depressive symptoms, anxiety, agitation, and aggression)34 and no reports of completed suicide were found.35 Although reassuring, as Kelsay36 notes in an accompanying editorial, patients with significant mental health disorders are frequently excluded from clinical trials.

Hope et al37 studied oral aspirin challenges in patients with aspirin-exacerbated respiratory disease to better understand risk factors for challenge-induced adverse events. Moderate-to-severe bronchial reactions were more likely when the baseline FEV1 was less than 80%, leukotriene modifier premedication was not used, and there was a history of asthma-related ED visits. Most reactions occurred in the 45- to 100-mg dose range.

Wise et al38, 39, 40 and the American Lung Association Asthma Clinical Research Centers examined the effect of drug presentation on asthma outcomes in adults with poorly controlled physician-diagnosed asthma. The study used a factorial design and randomized subjects to montelukast or placebo and a neutral or optimistic (“enhanced”) message about the benefit of treatment. Asthma control improved in the placebo-treated, but not montelukast-treated, recipients of enhanced messaging. Peak flow and other lung function measures were not associated with message assignment, emphasizing that reported symptoms and lung function measurement do not always coincide; both should be included in reports of clinical research.

ICSs 

Thomas et al41 examined whether the first increase in medication for patients already prescribed a low-dose ICS should be an increased ICS dose or the addition of a long-acting β-agonist. Patient cohorts were selected from the General Practitioners Research Database, a large UK electronic medical record database. Symptom control with high-dose ICSs was not as effective as adding a long-acting β-agonist, but a higher-dose ICS alone was associated with a lower risk of severe exacerbations and hospitalizations. However, the baseline characteristics of the 2 groups were dissimilar in several important parameters; for example, the ICS cohort was younger with lower body mass index (BMI), fewer had required oral steroids in the previous year, but more had respiratory hospitalizations during the year before enrollment.

Pavord et al42 conducted a 52-week parallel-group, randomized, double-blind study comparing high-dose budesonide/formoterol (BF) (800/12 μg) twice daily plus as-needed BF with low-dose BF (200/6 μg) twice daily plus as-needed inhaled terbutaline. Eosinophil counts from sputum and bronchial biopsy specimens (weeks 0 and 52) were lower in the higher-dose BF group, but there was no difference in other inflammatory biomarkers (Feno, mast cell numbers, eosinophil cationic protein, or lymphocytes), clinical exacerbations, or FEV1. At entry, subjects were using an ICS, approximately 800 μg/d. Although control was not measured, the findings suggest ICS doses can be reduced in comparable patients.

Haahtela et al43 studied whether early ICS therapy had lasting benefit, re-examining 90 of 103 patients who 13 years earlier experienced new-onset mild asthma and were randomized to the immediate start of ICSs versus a 1-year delay.44 At year 3, patients immediately treated with the ICS had better asthma outcomes, but in the current re-analysis all subjects had normal lung function and there were no differences in clinical or functional variables. Thus it remains unclear whether early ICS therapy makes a long-term difference.

Folate 

Because folic acid has been associated with inflammatory diseases, Matsui and Matsui45 examined a potential role for folate in either mitigating or promoting allergic diseases. Using National Health and Nutrition Examination Survey data, they found folate levels were inversely associated with total IgE levels, atopy, and wheeze, but further interpretation was precluded by the study design.

Practice 

Within the ED 

Tsai et al46 conducted a retrospective chart review of quality of care of acute asthma in 63 EDs using National Emergency Department Safety Study data. They found the overall concordance of treatment with National Asthma Education and Prevention Program Guidelines47, 48, 49 was moderate and associated with a reduced risk of hospitalization, although there was geographic variation.

Women's health 

Whether sex hormones affect asthma risk is unknown. Macsali et al50 used postcards to survey Northern European women for report of doctor-diagnosed asthma and the use of oral contraceptives. Among responders, asthma was associated with oral contraceptive use by normal-weight and overweight but not lean women. The cross-sectional study design did not permit analysis of temporal associations and explanatory relationships, and selection bias might have influenced the results.

Several studies found poorer asthma outcomes in women. Temprano and Mannino51 analyzed data from the National Asthma Survey, Four State Sample (Alabama, California, Illinois, and Texas). Women were more likely to have poorer asthma control, as reflected by several self-reported short-term and long-term variables, including asthma hospitalization, which is consistent with other national survey data.52 Interestingly, twice as many women as men responded to the Survey. Appleton et al53 followed a large Australian cohort for a mean of 3.5 years and found that the incidence of self-reported cardiovascular disease is associated with asthma, particularly in female subjects (odds ratio, 3.24; 95% CI, 1.55-6.78).

How asthma affects pregnancy remains a concern. Cookson et al54 conducted a longitudinal secondary analysis from a UK birth cohort. Higher levels of maternal anxiety during pregnancy increased the child's risk of asthma at 7.5 years. Blais et al55 merged 3 Canadian administrative databases to examine the association of congenital malformations with ICS use by asthmatic women during the first trimester of pregnancy. There was no increase in congenital malformations among the offspring of 4392 women who used an ICS of less than 1000 μg/d versus control asthmatic women who did not use an ICS during the first trimester. However, there was an increased risk of congenital malformation, although not of major malformations, in the 154 women who used more than 1000 μg/d compared with the 4392 women using less ICS (risk ratio, 1.63; 95% CI, 1.02-2.60). Residual confounding by severity of asthma was possible: women taking higher doses of ICSs had more severe asthma; their asthma severity rather than its treatment might be the primary association.

Asthma and obesity 

It remains controversial whether excess body mass and asthma are related by pathophysiology or share other environmental, behavioral, and social risk factors.56 Marcon et al57 examined the 4-year change in weight and FEV1 in European adults with asthma and found BMI gain associated with a decrease in FEV1 but only for subjects without measurable airflow obstruction at baseline, suggesting the importance of weight management early in asthma. Interestingly, in a cross-sectional study Clerisme-Beaty et al56 found no association of asthma control with obesity in US urban patients. However, in a 9-year prospective study of African American women, Coogan al58 observed higher BMI associated with increased risk of self-reported physician-diagnosed asthma in a dose-response relationship. Sutherland et al59 found that increased BMI was not associated with clinically significant worsening of asthma impairment using data from 1265 participants with mild-to-moderate asthma from Asthma Clinical Research Network studies. With differences in methodology, study populations, and study outcomes, whether asthma is physiologically associated with obesity remains unproved. As the authors admit, these studies are open to detection bias. Standardized and validated measures of asthma impairment are particularly needed here. Studies of well-characterized asthmatic patients with increased BMIs who undergo weight loss will be of great interest.

Asthma and sleep apnea 

Julien et al60 found obstructive sleep apnea was more prevalent in patients with severe asthma. The basis for this relationship is not elucidated. However, obstructive sleep apnea–hypopnea severity measures did not correlate with asthma severity or control scores, including FEV1.

Adherence 

Janson et al61 conducted a 24-week, prospective, randomized controlled trial to improve adherence to ICSs and asthma control in 95 adults with moderate or severe asthma. The intervention comprised three 30-minute sessions delivered by a certified asthma educator and included facts about asthma, medications, spirometry, peak flow, use of inhalers, and allergen skin testing tailored to the patient. Control asthmatic subjects performed self-monitoring but did not receive asthma education. Mean adherence did not significantly differ between groups, but a relative decrease in perceived symptoms and nighttime awakenings occurred in the intervention group. Morning peak flow and FEV1 improved equally in both groups. Mean adherence did not differ, but the usual decrease over time was attenuated in both groups. The cost-effectiveness of an asthma educator was not calculated. This important study shows that focusing attention on patients' asthma and not necessarily this specific intervention improves outcomes.

Naimi et al62 studied adherence to prescribed ICSs in 40 older urban adolescents. Electronic monitoring was combined with semi-structured face-to-face interviews conducted at the beginning and end of the 1-month observation period. The interviews explored teens' attitudes toward ICS treatment and their suggestions for improving adherence. Forty-three percent had an ED visit, and 20% had a hospitalization for asthma in the past year. Despite knowing that ICS use was monitored, teens took an average of 43% (range, 4% to 89%) of their prescribed doses. They disliked ICS taste, doubted the necessity of taking it regularly, and thus forgot to do so when feeling well. Although most felt well, there was significant variation in FEV1 (mean, 98% of predicted value; range, 67% to 127%). They expressed annoyance with receiving reminders from parents but saw these reminders as signs of attention and concern. Lives were busy, and schedules were complicated.

Health equity 

The June 2009 issue was devoted to promoting health equity63, 64, 65, 66; disparities are pervasive in the United States and prominent in asthma. In comprehensive reviews63, 64, 65 the authors advocated interventions at many levels (eg, patient-provider interface, practice, health system, community, and nation) to improve communication with patients, remove barriers to access, and eliminate the effects of poverty, such as increased exposure to pollution29 and inadequate schools. Because low literacy is widespread, affecting half of the US population,67 provider-level attention to improving effective health literacy might be one intervention leading to better patient-provider communication, patient self-management of chronic diseases, and health outcomes.68, 69 Adams et al70 examined the association of asthma with literacy assessed from reading nutrition labels.71 Although low literacy was not more common among those with self-reported asthma, those with low literacy were more likely to report nighttime awakening or hospitalizations. In another study low literacy was not an impediment to learning skills for self-management.72

Esteban et al,73 in a cross-sectional study, compared asthma control in 7- to 15-year-old Island Puerto Ricans with Rhode Island Puerto Ricans, Dominicans, and whites. Self-reported asthma was milder among Island Puerto Ricans compared with Rhode Island Puerto Ricans, but Island Puerto Ricans had more ED visits. These differences might be related to a variety of social (poverty, acculturation, cultural differences in reporting experiences, and access to health care) and physical environmental differences, which merit further research, including intervention studies. Martin et al74 tested a community-based intervention to improve asthma control directed at improving self-efficacy for self-management. Of 107 participants with poorly controlled asthma identified from clinics serving low-income African American communities, 42 enrolled. They were randomized to 4 group educational sessions led by a community social worker and 6 home visits conducted by community health workers compared with receiving mailed asthma educational materials. Although only 20% attended all the group sessions and the mean number of home visits was 4, self-efficacy and asthma-related quality of life improved in the intervention group. However, there were no significant changes in clinical outcomes. The biggest limitation of the study was its small size, which was complicated by the fact the groups differed in educational attainment and household income. This study demonstrates how difficult it is to conduct these needed intervention studies.

Poverty, whether urban or rural, greatly affects asthma and other health outcomes.63, 64, 65, 75 In a cross-sectional analysis Gupta et al75 found positive community factors, such as greater potential for economic development; more sociodemographic diversity, voters, restaurants, and cultural/entertainment facilities have an inverse relationship with asthma prevalence. This relationship was attenuated but not eliminated when controlling for race, suggesting that race serves as a “proxy for many sociocultural and environmental risk factors for asthma.”75

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Conclusions 

Clinical research is difficult to carry out, but it is evident that such asthma research is making important contributions to patient care. Finding ways to recruit adequate and representative patient cohorts and defining outcomes that are standardized and comparable across studies is particularly difficult. We look forward to reporting the results of the current standardization efforts and the results of the Asthma Outcome Workshop along with the significant research conducted in the next year.

Key advances in the care of adults with asthma, 2009


•There is an ongoing effort to promote standardization and validation of outcomes for asthma–related research.

•The TSLP gene is associated with self-reported doctor-diagnosed asthma.11

•The current HEDIS criterion of asthma quality of care (≥1 controller-medication filling) is less predictive of a good clinical outcome than a controller/total asthma medication ratio of at least 50%.17

•Inhaled mannitol is a diagnostic test with high specificity and is best used to diagnose asthma, whereas methacholine and histamine bronchoprovocation tests are best used to rule out asthma.25

•Feno was not predictive of maximum symptom days reported by adolescents.21

•Total IgE levels were associated only with self-reported asthma among persons with positive allergen-specific IgE levels and have no role as a biomarker for asthma in the general population.22

•The placebo effect has its greatest influence on self-reported outcomes rather than measures of lung function.38

•Achieving health equity will require interventions at many levels with attention to patient and provider beliefs, patient-provider communication, social and financial barriers to access, and patient poverty.38, 63, 64, 65, 66

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I thank Anita T. Gewurz, MD, and Penny Apter for careful reviews and insightful suggestions.

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 Disclosure of potential conflict of interest: A. J. Apter receives research support from the National Heart, Lung, and Blood Institute. A. J. Apter is supported by grants HL070392, HL088469, and RC1 HL099612.

PII: S0091-6749(09)01749-7

doi:10.1016/j.jaci.2009.11.028

The Journal of Allergy and Clinical Immunology
Volume 125, Issue 1 , Pages 79-84, January 2010

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