The Journal of Allergy and Clinical Immunology
Volume 119, Issue 5 , Pages 1156-1163, May 2007

Demographic and clinical characteristics of children and adolescents with severe or difficult-to-treat asthma

  • Bradley E. Chipps, MD

      Affiliations

    • From the Capital Allergy and Respiratory Disease Center, Sacramento
    • Corresponding Author InformationReprint requests: Bradley E. Chipps, MD, Capital Allergy and Respiratory Disease Center, 5609 J Street, Suite C, Sacramento, CA 95819.
    • ,
  • Stanley J. Szefler, MD

      Affiliations

    • National Jewish Medical and Research Center, Denver
    • ,
  • F. Estelle R. Simons, MD

      Affiliations

    • University of Manitoba, Winnipeg
    • ,
  • Tmirah Haselkorn, PhD

      Affiliations

    • Genentech, Inc., South San Francisco
    • ,
  • David R. Mink, MS

      Affiliations

    • Ovation Research Group, San Francisco
    • ,
  • Yamo Deniz, MD

      Affiliations

    • Genentech, Inc., South San Francisco
    • ,
  • June H. Lee, MD

      Affiliations

    • Genentech, Inc., South San Francisco
    • ,
  • for the TENOR Study Group

      Affiliations

    • For a complete list of TENOR Study Group members, please contact Genentech, Inc.

Received 20 December 2005; received in revised form 22 November 2006; accepted 1 December 2006. published online 31 March 2007.

Sacramento and South San Francisco, Calif, Denver, Colo, and Winnipeg, Manitoba, Canada

Article Outline

Background

Young patients with severe or difficult-to-treat asthma are an understudied population.

Objective

To assess age-associated and gender-associated differences in children and adolescents in the observational study, The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens.

Methods

Cross-sectional baseline data for patients greater than or equal to 6 years and less than or equal to 17 years (n = 1261) were stratified by age group (6-8, 9-11, 12-14, and 15-17 years). The χ2 test for categorical variables and analysis of variance for continuous variables were used to identify differences among age groups, stratified by gender.

Results

Most patients had moderate (55%) or severe (41%) asthma by physician assessment. Of those using greater than or equal to 3 long-term controllers (62%), 53% of children (6-11 years) and 44% of adolescents (12-17 years) reported an oral corticosteroid burst and 25% and 19%, respectively, had an emergency department visit in the previous 3 months; 10% and 15%, respectively, reported past intubation. In females, weight for age ranged between the 67th and 70th percentiles; height for age was between the 42nd and 54th percentiles (P < .01 among age groups). Lung function was lower in adolescents than children: prebronchodilator percent predicted forced expiratory volume in 1 second (FEV1)/forced vital capacity was 0.92 (6-8 years) and 0.83 (15-17 years), P less than .05, in males; and 0.94 (6-8 years) and 0.87 (15-17 years), P less than .05, in females.

Conclusions

Children and adolescents demonstrated high rates of health care use and loss of lung function, despite using multiple long-term controllers.

Clinical implications

Asthma treatments that prevent loss of lung function and reduce health care resource use are needed in young patients with severe or difficult-to-treat asthma.

Key words: Asthma, health care use, long-term controllers, lung function, observational, pediatric

Abbreviations used: BMI, Body mass index, CAMP, Childhood Asthma Management Program, ED, Emergency department, FVC, Forced vital capacity, HCU, Health care use, IRB, Institutional review board, NHANES, National Health and Nutrition Examination Survey, TENOR, The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens

 

Asthma is one of the most common chronic childhood medical disorders in the United States, which affects more than 9 million children under 18 years of age.1 The prevalence of asthma symptoms and asthma diagnosis in US children is among the highest in the world.2 In children aged 5-14 years, the prevalence of self-reported asthma increased from 1.5 million cases in 1980 to 2.3 million cases in 1999.3 Along with increasing prevalence, asthma severity seems to be on the rise in pediatric and adolescent patients, based on increases in the rates of office visits, hospital admissions, and emergency department (ED) visits. Moreover, the increasing burden of asthma is consistently focused on children and young adolescents. Asthma-attributable mortality nearly doubled between 1980 and 1999 in children aged 5 to 14 years, which was a substantially greater increase than that observed in older adolescents and adults.3

Children and adolescents with severe or difficult-to-treat asthma are an understudied population. Most of the economic burden of asthma is related to severe disease,2 and severe disease is associated with more symptoms, more limitations in daily activities, greater medical resource use, and higher health care costs.4 Additional information is needed about these patients and the treatment patterns and outcomes related to their asthma.

The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) is an observational study of a large cohort of patients with severe or difficult-to-treat asthma. This TENOR analysis focuses on cross-sectional baseline data from the children and adolescents enrolled in the study. It provides the opportunity to characterize and better understand the natural history of asthma in these patients in terms of disease severity, lung function, medication use, and health care use (HCU). We hypothesized that children and adolescents with severe or difficult-to-treat asthma would have high rates of HCU and loss of lung function despite being on currently accepted guideline-directed therapy.

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Methods 

Study design and participants 

The TENOR study was a prospective, observational, 3-year study (2001-2004) conducted in the United States in patients with severe or difficult-to-treat asthma who received care from either an allergist or a pulmonologist. No experimental intervention was involved; participants continued to receive medications and treatments for their asthma as directed by their asthma specialist. The design and protocol of TENOR were approved by a central institutional review board (IRB) and, when necessary, by the IRB at each site; Genentech, Inc, contracted with an independent, external IRB to review and approve the protocol for sites without an IRB. All patients or their parents/guardians supplied written informed consent.

The TENOR study included patients greater than or equal to 6 years of age with severe or difficult-to-treat asthma; patients with mild or moderate asthma were eligible for enrollment if their physician considered their asthma difficult-to-treat and if they met the additional inclusion and exclusion criteria.5 Patients had to have evidence of either high HCU (2 or more unscheduled care visits for asthma or 2 or more oral corticosteroid bursts) or high medication use (currently requiring ≥3 medications to control asthma or long-term daily high doses of inhaled corticosteroids or use of 5 mg/day or more of oral prednisone), or both, in the past year.5 Patients were excluded if they were heavy smokers (≥30 pack-years) or if they had a diagnosis of cystic fibrosis. Few current or former smokers were included in this cohort; therefore, smoking data were not included in this analysis. Additional detail regarding inclusion/exclusion criteria has been described previously5 and can be found in this article's Online Repository at www.jacionline.org.

Demographic, clinical, and laboratory assessments 

Data presented in this analysis were obtained at study entry and are cross-sectional. In addition to assessing the asthma severity of each participant, physicians reported whether their patient's asthma was considered difficult-to-treat based on specified parameters (that is, complex treatment regimen, multiple drugs required, unable to avoid triggers, frequent exacerbations, severe exacerbations, and/or unresponsive to therapy).5

For participants less than 12 years of age, the parent or guardian was present to help answer interview questions and complete questionnaires fully and accurately; if needed, adolescents were permitted to obtain assistance from a parent (or other adult if a parent was not available). Demographic (age, gender, race, height, and weight), clinical data (including HCU and medication use), and laboratory data (total serum IgE, spirometry) were collected by study coordinator interview and evaluation. Overweight was defined as weight-for-age greater than or equal to the 95th percentile based on the US growth charts developed by the Centers for Disease Control.6

HCU 

Data on asthma-related HCU were based on data collected at study entry by study coordinator interview5 and included ED visits, overnight hospitalizations, corticosteroid bursts, and unscheduled office visits/contacts with physician during the previous 3 months. Baseline data on intubation was obtained in answer to the question “have you ever been intubated?”

Asthma medications 

Information about all current asthma medications, including long-term controller and quick-relief medications, was collected by the study coordinator during an interview in which patients and parents actually brought in their medications for review.

IgE data 

Total serum IgE levels (IU/mL) were measured at baseline by each study site using any commercially available assay. All total serum IgE assay tests used in TENOR received 510 (k) Food and Drug Administration approval and were considered substantially equivalent in accuracy and precision.7 In addition, all total serum IgE assays were calibrated to the World Health Organization's second International Reference Preparation for Human Serum IgE, World Health Organization IRP 75/502.

Spirometry 

Spirometry measurements in TENOR were performed according to American Thoracic Society guidelines.8 All sites were required to have a certified device that was calibrated daily for performing flow spirometry. For this analysis, predicted values for spirometry measures were race-adjusted. Formulas of Wang et al9 were applied for the predicted values of white and black patients. Because these formulas do not address Hispanics, the formulas of Hsu et al10 were used for Hispanic patients. About 5% of patients self-described as “other” did not have predicted spirometry values calculated but were included in the overall study.

Data retrieval and monitoring 

The TENOR study used a Web-based system for data collection (developed using Quintiles WebCollect services and PhaseForward's InForm application; Quintiles Transnational Corp, Research Triangle Park, NC). Data were entered directly on electronic case report forms and transferred in encrypted form onto a secure server at the data coordinating center. All study coordinators received website and study protocol training.

Statistical methods 

The χ2 test for categorical variables and analysis of variance for continuous variables were used to identify significant differences among age groups (6-8, 9-11, 12-14, and 15-17 years), stratified by gender. All analyses were performed using SAS Version 9.1 for Windows (SAS Institute, Cary, NC).

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Results 

Demographic, clinical, and laboratory assessments 

A total of 4756 patients were enrolled by 283 US study sites between January and October 2001. Of these, 1261 patients were greater than or equal to 6 years and less than or equal to 17 years at baseline. Demographic and clinical characteristics stratified by gender and baseline age group are shown in Table I. The proportion of white males was consistent among age groups (58% to 61%), whereas the proportion of white females ranged from 54% (9-11 years) to 80% (15-17 years). A significant difference was found among age groups in the proportion of female patients that were white versus nonwhite (P = .0008).

Table I. Demographic and clinical characteristics of female and male pediatric and adolescent patients at baseline∗
Male Female
Age group (y) Age group (y)
6-89-1112-1415-17P value6-89-1112-1415-17P value
All patients, n145282240124 8812017191
Race/ethnicity, n (%)
White87 (60)165 (58)141 (59)76 (61)NS†62 (70)65 (54)115 (67)73 (80).0008†
Black38 (26)70 (25)69 (29)31 (25) 17 (19)33 (27)39 (23)11 (12)
Hispanic9 (6)31 (11)16 (7)11 (9) 7 (8)17 (14)12 (7)3 (3)
Asian/PI3 (2)3 (1)3 (1)1 (1) 1 (1)1 (1)3 (2)0 (0)
Other8 (5)13 (5)11 (5)5 (4) 1 (1)4 (3)2 (1)4 (4)
Height for age, mean ± SD (percentile)48.8 ± 30.551.0 ± 29.347.2 ± 28.745.0 ± 31.0NS54.2 ± 30.454.3 ± 31.246.8 ± 29.041.6 ± 32.1<.01
Weight for age, mean ± SD (percentile)64.8 ± 29.564.8 ± 30.767.9 ± 29.966.9 ± 34.0NS66.9 ± 30.968.8 ± 29.770.4 ± 27.768.9 ± 27.4NS
Weight for age percentile, n (%)
≤85th102 (70)174 (62)138 (56)69 (56)<.0152 (60)70 (58)101 (59)54 (59)NS
85th to ≤95th10 (7)54 (19)41 (17)18 (14) 16 (18)17 (14)32 (19)15 (16)
95th+33 (23)54 (19)61 (25)37 (30) 19 (22)33 (27)37 (22)22 (24)
Body mass index, mean ± SD (kg/m2)18.9 ± 7.420.6 ± 5.423.6 ± 6.425.6 ± 7.1<.000119.2 ± 5.221.9 ± 5.824.5 ± 7.126.4 ± 7.6<.0001
Total serum IgE (IU/mL), geometric mean (95% CI)145.7 (106.0-200.0)232.9 (190.5-284.8)260.2 (219.5-308.4)253.9 (199.5-323.1)<.01112.0 (75.7-165.6)144.2‡ (102.3-203.2)215.6 (169.3-274.6)145.4‡ (98.7-214.2)<.05
Physician-assessed asthma severity, n (%)
Mild8 (5)17 (6)8 (3)6 (5)<.0014 (5)4 (3)9 (5)2 (2)NS
Moderate88 (61)164 (58)133 (55)45 (36) 55 (63)71 (59)90 (53)42 (46)
Severe49 (34)101 (36)99 (41)73 (59) 29 (33)45 (37)72 (42)47 (52)
Treating physician specialty, n (%)
Pulmonology82 (57)158 (58)134 (57)58 (47)NS51 (60)80 (68)109 (64)45 (51)NS
Allergy58 (41)115 (42)100 (44)65 (53) 34 (40)37 (32)60 (35)44 (49)

NS, Not significant; PI, Pacific Islander.

∗All data are from baseline visit. Overweight was defined based on the US growth charts developed by the Centers for Disease Control.9

†White versus nonwhite.

‡Statistically significantly (P < .05) different compared with boys of the same age.

Most patients had moderate (55%) or severe (41%) asthma by physician assessment. The proportion of patients with severe asthma increased significantly across age groups in males (P < .001) but not females (Table I). No differences were found across age groups by treating physician specialist; more of the children and adolescents in TENOR were under the care of a pulmonologist than an allergist.

HCU by number of long-term controllers 

Overall, 62% of patients were using 3 or more long-term controllers. Across all measures of HCU in the 12-17–year age group, patients using 3 or more long-term controllers had greater HCU compared with those requiring 1 or 2 long-term controllers (Fig 1), although differences were not statistically significant. Of those using 3 or more long-term controllers, 53% of children and 44% of adolescents reported a corticosteroid burst and 25% of the children and 19% of adolescents had an ED visit in the 3 months before the baseline visit. A history of intubation was reported in 10% to 15% of children and adolescents using 3 or more long-term controllers.

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  • Fig 1. 

    HCU by number of long-term controller medications in patients aged 6-11 years (left panel) and 12-17 years (right panel). Long-term controllers included inhaled corticosteroids, long-acting β-agonists, leukotriene modifiers, methylxanthines, and cromolyn sodium or nedocromil. No statistically significant differences were found in rates of HCU by number of long-term controllers.

Medication use 

Overall, 96% of children and adolescents were using short-acting β-agonists, 95% inhaled corticosteroids, 74% long-acting β-agonists, 73% leukotriene modifiers, 15% systemic corticosteroids, 10% anticholinergics, 8% methylxanthines, and 9% cromolyn or nedocromil. For the combined gender groups, rates of use of inhaled corticosteroids (94% to 96%) and short-acting β-agonists (96% to 97%) were relatively consistent among age groups (Fig 2). Use of long-acting β-agonists and methylxanthines significantly increased across age groups (P < .05).

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  • Fig 2. 

    Medication use by age category. ∗Based on test for linear trend, a statistically significant age trend (P < .05) was observed for methylxanthines and long-acting β-agonists.

Height and weight 

For males, the mean weight for age ranged between the 65th and the 68th percentiles and the mean height for age ranged between the 45th and the 51st percentiles. For females, the mean weight for age ranged between the 67th and the 70th percentile and the mean height for age ranged between the 42nd and the 54th percentile; mean height for age was significantly different among age groups in females (P < .01) (Fig 3). Approximately 25% of children and adolescents in TENOR were considered overweight (weight for age ≥ 95th percentile) and a larger proportion of females (14% to 19%) than males (7% to 19%) were at risk for becoming overweight (weight for age >85th to <95th percentile).

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  • Fig 3. 

    Height and weight for age in male (left panel) and female (right panel) pediatric and adolescent patients in TENOR. ∗Differences across height for age categories in females are statistically significant, P = .0062.

Serum IgE levels 

Geometric means for total serum IgE levels were generally higher in males than in females across age groups; the differences between males and females were statistically significant for the 9-11–year and 15-17–year age groups (P < .05) (Table I). Mean total serum IgE was significantly different among age groups in males (P < .01) and females (P < .05).

Spirometry 

Lung function was lower in adolescents than in children, and spirometric measures were lower in males than females (Fig 4). Prebronchodilator percent predicted FEV1/forced vital capacity (FVC) was 0.92 in males 6-8 years at baseline and 0.83 in males 15-17 years at baseline (P < .05); and was 0.94 in females 6-8 years at baseline and 0.87 in females 15-17 years at baseline (P < .05). Prebronchodilator percent predicted FEV1 was 0.91 in males 6-8 years at baseline and 0.82 in males 15-17 years at baseline (P < .05); and was 0.94 in females 6-8 years at baseline and 0.84 in females 15-17 years at baseline (P < .05). Additional spirometry results are presented in Fig E1 in this article's Online Repository at www.jacionline.org.

  • View full-size image.
  • Fig 4. 

    Prebronchodilator (left panel) and postbronchodilator (right panel) spirometry measures in male and female pediatric and adolescent patients in TENOR. Predicted values were calculated using formulas of Wang et al9 and Hsu et al.10 Based on test for linear trend, spirometry values are statistically significant (P < .05) across age categories.

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Discussion 

The TENOR study is one of the few observational studies to characterize the natural history of asthma in young patients with severe or difficult-to-treat asthma. In this cross-sectional analysis at baseline, most children and adolescents had moderate or severe asthma by physician assessment. Despite that almost two thirds of patients were using 3 or more long-term controllers, HCU in these patients was high. An increase in systemic corticosteroid use across the 3 youngest age groups was observed, and assessment of age-associated and gender-associated differences revealed that height for age decreased across age groups, especially in females. In general, the children and adolescents in TENOR were shorter and heavier compared with national averages. Lung function decreased with increasing age, and this trend seemed to be more pronounced in males than females.

Although a recent study showed that inhaled corticosteroids conferred a significant protective effect on the risk of hospitalization and ED visits in children with asthma,11 the TENOR data demonstrate that high rates of HCU are still evident, despite the use of multiple asthma medications in most children and adolescents. Although the selection criteria for TENOR included patients with high HCU, these young patients continued to demonstrate high rates of asthma-related health care utilization throughout the 3-year study (data not shown). These findings could be interpreted to mean that physicians treat patients with higher morbidity with increased numbers of controller medications, but they do certainly suggest that the prescribed medications do not prevent morbidity adequately. Nonadherence with increased numbers of prescribed medications cannot be excluded. These findings demonstrate the possibility of an unmet need in asthma care for young patients with severe or difficult-to-treat asthma. They also lend support to the conclusions reached in recent reviews by leading experts in the field, which highlighted the need for a more global assessment of asthma severity that includes asthma-related HCU and medication use.12, 13, 14 Similar conclusions were reached in a recent analysis of TENOR data in adults.15

In TENOR, height for age decreased across age groups, and this was particularly pronounced in females. We also observed an increase in systemic corticosteroid bursts across the 3 youngest age groups. Whether the decrease in height is related to the cumulative effect of systemic corticosteroid or high-dose inhaled corticosteroid use requires further study. However, concerns about the side effects associated with long-term inhaled corticosteroid therapy, especially about delays in growth in children, have often been cited as a major factor in nonadherence with asthma guidelines.16, 17 Data from several prospective, randomized, double-blind placebo-controlled studies,18, 19, 20 including the Childhood Asthma Management Program (CAMP),18 have shown that budesonide 200 μg twice daily or beclomethasone dipropionate 200 μg twice daily were associated with small reductions in growth velocity in children soon after the onset of corticosteroid treatment but did not progress during follow-up for 1 or more years. Other reports, however, based on a nonrandomized study, have indicated that children treated with long-term budesonide attain normal adult height.21, 22

Childhood obesity appears to be related to asthma, as supported by numerous publications.23, 24, 25, 26 An analysis of data from the Third National Health and Nutrition Examination Survey (NHANES III) showed that the prevalence of asthma rose significantly with increasing quartiles of body mass index (BMI) in children aged 4-17 years.24 Other analyses from NHANES showed that physician-diagnosed asthma was almost 2-fold higher in children with BMI greater than or equal to the 85th percentile compared with those with BMI below this percentile,25 and in children with BMI above the 95th percentile, the asthma risk was 3 times higher compared with those with BMI within the 25th-49th percentiles.26 Data from CAMP also showed an association between asthma severity, as measured by the FEV1/FVC ratio, and BMI in children with mild-to-moderate asthma.23 In our population of severe or difficult-to-treat asthma, approximately 25% of children and adolescents were considered overweight. In contrast, the prevalence of overweight based on BMI at or above the 95th percentile in children aged 6-17 years in the NHANES was 11%.27

Physician-assessed severe/difficult-to-treat asthma in children and adolescents in TENOR is supported by lung function data. By most measures of spirometry, worse lung function was observed in the older children and adolescents. This is consistent with data from cohorts of children with asthma followed longitudinally.18, 28, 29, 30, 31, 32 In the CAMP study, 26% of children with mild-to-moderate asthma showed a significant reduction in percent predicted postbronchodilator FEV130; among the entire cohort, a gradual decline in the ratio of FEV1/FVC was observed over 4 years despite treatment with budesonide or nedocromil.18 Data from Sears et al31 in a large cohort of children followed from age 9 years to adulthood showed that participants with persistent wheezing had consistently lower FEV1/FVC ratios than those without persistent wheezing. Because of different clinical phenotypes of the cohorts enrolled into the above studies, the direct comparison of lung function values to the TENOR data is not possible. However, cross-sectional data from this TENOR analysis and another study,33 as well as the longitudinal studies of children with asthma28, 29, 30, 31, 32 described above, consistently demonstrate that lung function is compromised at an early age. Furthermore, the persistence of abnormalities and the worsening of lung function is observed over time in children and adolescents28, 29, 30, 31 and in young adults with a history of mild-to-moderate childhood allergic asthma.34 Notably, similar to the TENOR data, Sears et al31 also demonstrated lower lung function values in males compared with females.

Of note was the higher proportion of males than females across age groups in TENOR. This finding is consistent with general epidemiologic data and other pediatric studies, which show a higher prevalence of asthma in male pediatric and adolescent patients, whereas in adulthood, the prevalence of asthma is higher in females.18, 35, 36, 37 Reasons for the gender discrepancy in asthma by age are not entirely clear but have been attributed to hormonal changes during puberty or to gender-specific differences in environmental exposures such as diet, obesity, allergen exposure, or cigarette smoking.38

Several limitations of the current analysis should be mentioned. Data are cross-sectional and, therefore, provide a description of this cohort at a single point in time. Future planned analyses of TENOR will be based on data from repeated visits over the 3 years of this observational study and will be able to provide a description of changes in medication and health care resource use that occur over time. The impact of allergic sensitization, IgE, and obesity will also be addressed in a separate analysis.

It may be more difficult to obtain accurate and consistent results, particularly spirometry measures,39 in young children than in older children and adolescents, possibly contributing to the differences observed among age groups. In addition, as they age, patients may have an increased awareness of those measures that relied partially on self-report, such as HCU, which could potentially lead to higher reporting in older age cohorts compared with younger age cohorts. Presumably, the parental assistance young children received during the baseline interview and when completing questionnaires should have mitigated this potential bias. Compliance with prescribed medications was based on patient self-report or parent report. Although patients with known cystic fibrosis were excluded, we cannot rule out the possibility that the TENOR cohort may contain some patients with other conditions misdiagnosed as asthma.

In conclusion, results of the current analysis of data from a large cohort showed that children and adolescents in TENOR demonstrated high rates of HCU, despite using multiple long-term controller medications. High proportions of these children and adolescents with severe or difficult-to-treat asthma were overweight, and most were at or below the median height for their age. Furthermore, data showed that older children and adolescents had worse lung function than younger children. The TENOR findings lend weight to the concept of asthma as a multifactorial disease with complex variations by age and gender. They also demonstrate the need for increased targeting of intervention programs and novel strategies to prevent loss of lung function and reduce health-care utilization in children with severe or difficult-to-treat asthma.

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Appendix. Supplementary data 

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 Supported by Genentech, Inc. and Novartis Pharmaceuticals Corp.Disclosure of potential conflict of interest: B. E. Chipps has consulting arrangements with Aventis, Genentech, AstraZeneca, GlaxoSmithKline, MedPoint, Novartis, Schering, Sepracor, and Merck; has received grant support from Aventis, Genentech, AstraZeneca, GlaxoSmithKline, Novartis, Schering, Sepracor, and Merck; is on the speakers' bureau for Aventis, Genentech, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, MedPoint, Novartis, Pfizer, Schering, Sepracor, and Merck; and has served as an expert witness in mold litigation. S. J. Szefler has received grant support from AstraZeneca, GlaxoSmithKline, Aventis, Genentech, and Merck and has received grant support from the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, and Ross Pharmaceuticals. T. Haselkorn has consulting arrangements with Genentech. D. R. Mink is employed by the Ovation Research Group. Y. Deniz owns stock in and is employed by Genentech. J. H. Lee owns stock in and is employed by Genentech. F. E. R. Simons has declared that she has no conflict of interest.

PII: S0091-6749(07)00236-9

doi:10.1016/j.jaci.2006.12.668

The Journal of Allergy and Clinical Immunology
Volume 119, Issue 5 , Pages 1156-1163, May 2007

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