HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Guest Access | Sign In via User Name/Password

This Article Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Szefler, S. J. Search for Related Content PubMed PubMed Citation Articles by Szefler, S. J.

Pediatric Asthma^*

An Approach to Pharmacogenetics Analysis

^* From the Divisions of Clinical Pharmacology and Allergy and Immunology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO.

Correspondence to: Stanley J. Szefler, MD, National Jewish Medical and Research Center, 1400 Jackson St, Room B121, Denver, CO 80206; e-mail: szeflers{at}njc.org

	Introduction

TOP Introduction Is There Evidence of... Does the Response to... Are There Ways That... Can This Information Be... Prospectus References

 
Numerous studies have clearly demonstrated that inhaled glucocorticoids alleviate clinical symptoms, improve pulmonary function, and reduce airway inflammation; there is some evidence that they may alter disease progression. Current guidelines identify inhaled glucocorticoids as the "preferred" long-term controller asthma medication, especially for moderate and severe persistent asthma.^{1 2} Clinical observations suggest that the response to inhaled glucocorticoids is highly dependent on the time of intervention: the earlier used, the more efficacious³ ; however, it is also clear that the response to inhaled glucocorticoids can vary among patients with some patients being considered "steroid resistant."⁴

Persistent asthma is currently considered a disease with a base of chronic inflammation. This chronic inflammation may contribute to declining pulmonary function over time and possibly to altered lung growth in children.^{5 6} Some feel that early intervention and continuous therapy will alter the course of the disease. A budesonide nebulizing suspension is now approved for use in children 1 year old.⁷

There are multiple indicators of asthma control, as summarized in Table 1 , that can be divided into four categories: symptoms, pulmonary function changes, measures of inflammation, and measures of disease progression.^{8 9} There is no single short-term surrogate marker for either the best asthma outcome (for example, control of disease progression) or for the most significant adverse effects (growth retardation, osteoporosis). Evaluating available markers for asthma progression, such as a decline in FEV₁, and for adverse effects on linear growth and bone development takes a long period of time (ie, years) to measure changes of statistical and clinical significance.

	Is There Evidence of Progression in Childhood Asthma?

TOP Introduction Is There Evidence of... Does the Response to... Are There Ways That... Can This Information Be... Prospectus References

 
One of the most difficult decisions in the management of childhood asthma is determining the appropriate time to begin intervention with long-term control therapy. Several studies have provided new insights into some of the unique aspects of childhood asthma. The Melbourne Asthma Study represents the longest period of follow-up for patients with varying levels of asthma severity.¹⁰ This study cohort is now approaching 40 years of evaluation. Of interest is the group of patients with severe asthma. It appears that this group already had low pulmonary function, approximately 70% predicted for FEV₁ at the age of 10 years when they began monitoring. Of interest is that the severe asthmatic group did not have further decline in pulmonary function over the remaining time period; therefore, questions are raised whether the reduced pulmonary function in the patients with severe asthma represents a low level at birth or a decline in the time period between disease onset and age of 10 years. If so, the question would be whether it occurs rapidly or gradually after disease onset.

The continuing follow-up of the cohort established in the Tucson Respiratory Study is another resource for understanding the natural history of persistent asthma.¹¹ This study suggests that patients who go on to acquire persistent asthma with onset before the age of 3 years have normal pulmonary function at the age of 1 year, and then have low pulmonary function at the age of 6 years and a smaller proportion of loss by the age of 11 years. Unfortunately, measurements have only been obtained every 5 to 6 years; therefore, the precise rate of loss between the age of 1 year and 6 years could not be ascertained. Another unique contribution of this study was the identification of features that were related to high risk of acquiring persistent asthma. Participants who had frequent episodes of wheezing prior to the age of 3 years and had one major criteria (family history of asthma or physician-diagnosed atopic dermatitis) or two minor criteria (eosinophilia, allergic rhinitis, or wheezing without the presence of respiratory infection) had a high likelihood of going on to acquire persistent asthma.¹²

The National Heart, Lung, and Blood Institute (NHLBI) Childhood Asthma Management Program is a third long-term study that provides insight into the natural history of asthma.¹³ This group of > 1,000 children enrolled at 5 to 12 years of age represents a cohort of children with mild-to-moderate persistent asthma who were treated for 4 to 6 years with either inhaled budesonide, inhaled nedocromil, or placebo. The best asthma control was achieved for the group who received the inhaled steroid. This group had the lowest hospitalization rate, lowest urgent care visit rate, and the lowest number of prednisone courses. Also, they had lower symptoms and reduced need for exercise pretreatment. Of interest, there was no significant effect of treatment on postbronchodilator FEV₁ percentage of predicted, the selected marker of lung growth, although there was a marginal effect on prebronchodilator FEV₁ percentage of predicted. A decline in FEV₁ percentage of predicted was not observed in the placebo group, suggesting that this loss does not occur in children within this age group, perhaps related to the mean duration of disease of 5 years. The study population will now be examined for those who may have lost pulmonary function over time and to understand the clinical features of this population.

This observation prompts questions whether earlier intervention could alter the natural history of asthma by preventing a decline in pulmonary function that is projected to occur within the first several years of disease onset. The NHLBI Childhood Asthma Research and Education Network is currently conducting a study to examine the effect of inhaled steroids on altering the course of asthma in children. The study enrolled > 250 children aged 2 to 4 years at study entry who fulfilled criteria for high risk of acquiring persistent asthma. The children will be treated for 2 years with either inhaled steroid or placebo and then followed up for a third year in the absence of study medication. The primary outcome variable is asthma-free days, but pulmonary function will also be measured. This study will provide a base for determining the course of asthma in children treated within the first 3 years of disease onset.

Preliminary data from a cross-sectional study of severe asthmatics who had either childhood-onset or adult-onset asthma suggest that in children who go on to acquire severe asthma, pulmonary function is relatively normal during childhood but appears to decline with duration of disease.¹⁴ These data substantiate the concern regarding the potential deterioration in pulmonary function that occurs in a subset of children with asthma. It will be important to define the unique risk factors that predispose patients to the decline in pulmonary function, and to define the natural history of this phenomenon and the role it plays in the natural history of severe asthma.

	Does the Response to Inhaled Steroids Vary Significantly Among Patients?

TOP Introduction Is There Evidence of... Does the Response to... Are There Ways That... Can This Information Be... Prospectus References

 
The preferred long-term control therapy for persistent asthma is an inhaled glucocorticoid; however, it is not clear whether one steroid is superior to the others in achieving maximal beneficial effect. Despite widespread clinical use for > 2 decades, few studies have attempted to investigate the comparative efficacy of the available inhaled steroid preparations. A series of studies conducted by the NHLBI Asthma Clinical Research Network has provided insight regarding the comparison of beneficial and adverse effects of inhaled glucocorticoids as well as the variability in response. The first studies defined levels of cortisol suppression for six different inhaled steroid-delivery device combinations.¹⁵ Of interest, was the observation of a significant degree of variability in overnight plasma cortisol suppression among the inhaled steroid-delivery device combinations. The studies permitted the evaluation of doses of inhaled steroid that would result in equisystemic levels of cortisol suppression. One of the most interesting observations in this study was the marked difference in cortisol suppression that occurred between fluticasone propionate delivered via the metered-dose inhaler as compared to the dry powder inhaler device. While significant cortisol suppression was noted with the metered-dose inhaler preparation, equivalent doses of fluticasone propionate via the dry powder inhaler resulted in minimal cortisol suppression.¹⁵ The devices differ in the particle size delivered; therefore, the systemic effect may be related to pulmonary distribution and subsequent absorption.

An evaluation was made of the efficacy of two inhaled steroids, beclomethasone dipropionate and fluticasone propionate administered via metered-dose inhaler and spacer, and administered at doses that were projected to result in equisystemic effect based on overnight plasma cortisol suppression.¹⁶ Several interesting observations were derived from this study. First, it was observed that for both inhaled steroids, maximum improvement in FEV₁ and reduction in methacholine reactivity occurred with doses that are considered low to medium in the national guidelines; second, increasing the dose beyond that needed to attain maximal effect on these parameters only increased systemic effect; and third, there was marked variability in the magnitude of response for these two efficacy parameters among individual patients for both inhaled steroids. Approximately one third of the patients failed to achieve an improvement in FEV₁ despite high-dose inhaled glucocorticoid therapy. Similarly, approximately one third of the participants failed to reduce airway hyperresponsiveness even in the presence of high-dose inhaled glucocorticoid therapy. Since the improvement in FEV₁ did not correlate to reduction in airway responsiveness this prompted an evaluation of patient characteristics associated with failure to respond in one or both response parameters. This will be discussed further in the next section.

It has not been determined whether this same variability of response to inhaled glucocorticoids occurs in children with asthma. The NHLBI Childhood Asthma Research and Education Network is currently conducting a study to evaluate pulmonary response to two classes of medications, an inhaled glucocorticoid and a leukotriene antagonist, in a cross-over study. This study will also attempt to define parameters associated with the level of response and to define an asthma phenotype and genotype.

	Are There Ways That We Can Predict the Response to Inhaled Glucocorticoids?

TOP Introduction Is There Evidence of... Does the Response to... Are There Ways That... Can This Information Be... Prospectus References

 
The NHLBI Asthma Clinical Research Network study on the efficacy of inhaled glucocorticoids also provided preliminary information on asthma characteristics associated with a favorable FEV₁ and provocative concentration of methacholine causing a 20% fall in FEV₁ (PC₂₀) response.¹⁶ The features differed for the two parameters. For FEV₁ response, a good response was associated with a high level of exhaled nitric oxide, increased bronchodilator reversibility, and lower FEV₁/FVC at the time of starting treatment as compared to those who did not respond. A good response in reducing airway responsiveness with inhaled glucocorticoid was seen in the group with lower PC₂₀, higher sputum eosinophils, and shorter duration of asthma, as compared to those who did not change PC₂₀ despite 18 weeks of treatment. Exhaled nitric oxide also tended to be higher in those who demonstrated a good response as compared to the poor responders for this parameter. As noted, the features of response varied based on the parameter selected.

The NHLBI Asthma Clinical Research Network is now conducting a study to validate this preliminary data to determine whether these features can be used to predict response to inhaled glucocorticoids in a larger patient population. In addition, this study will also seek to define the mechanisms for poor response to inhaled glucocorticoids.

	Can This Information Be Used To Explore the Pharmacogenetics of Response to Inhaled Glucocorticoids?

TOP Introduction Is There Evidence of... Does the Response to... Are There Ways That... Can This Information Be... Prospectus References

 
The severity of asthma and failure to respond to medications could be related to the predisposition for persistent inflammation or the failure to control the disease with standard doses of available medications. Genetic analysis can be directed to gene polymorphisms directly related to the response of the selected asthma medications evaluated, such as a leukotriene antagonist, an inhaled corticosteroid, or a ß-adrenergic agonist. The response to these medications could be related to genetic polymorphisms altering the site of action (for example, the drug receptor), or the availability of the drug at the site of action (for example, cytochrome P₄₅₀ pathways).

In addition, genes related to asthma-associated disease features could affect the response to these medications. For example, one feature of asthma is allergy, an IgE-mediated response. IgE synthesis is mediated through IL-4 stimulation of B lymphocytes; therefore, interleukin (IL)-4 serves a disease-modifying role. Genetic features of IL-4–mediated IgE synthesis could be related to at least two polymorphisms, increased IL-4 synthesis (C589T) or increased sensitivity to IL-4 at the IL-4 receptor level (R576 IL-4 receptor).^{17 18 19 20 21 22} An association of a sequence variant in the IL-4 gene promoter region at the C589T locus has been made to asthma severity, as indicated by the level of FEV₁.¹⁸ The R576 IL-4 receptor polymorphism has also been associated with asthma severity.²² Since IL-13 shares a receptor subunit with IL4 (IL-4R), and it contributes to corticosteroid resistance in monocytes, polymorphisms at the IL-13 level are also of interest.^{23 24} Therefore, benefit of a medication could be tied to an active disease pathway influenced by the specific drug, for example, leukotriene synthesis and leukotriene antagonists, as well as cytokine synthesis and glucocorticoids. Failure to respond to treatment could be due to excessive activity of this pathway or possibly alternative pathways involved in the disease. There is sufficient interaction between the two mediator pathways, ie, cytokines and leukotrienes, to merit evaluation of genetic polymorphisms for both mediator pathways in relation to response to the two study medications.

	Prospectus

TOP Introduction Is There Evidence of... Does the Response to... Are There Ways That... Can This Information Be... Prospectus References

 
The future is bright for exciting new developments in understanding the natural history of asthma in children. We can now begin to address the questions raised at the onset of this discussion. Is there a marker that can be used to define the best overall asthma control? It appears that the response to treatment is parameter specific. We now need to change our treatment approach to look at success or failure with each response parameter in the individual patient including disease progression.

Two easily obtained measures of disease progression include the escalation of therapy over time and the decline of FEV₁ percentage of predicted over time. With these two parameters in hand, the patient's risk for disease progression and response to treatment can be monitored. Can pharmacogenetics be a useful tool for identifying the patient at risk for progression and for selecting medications? This will require an organized approach to define relevant genetic polymorphisms. First of all, it will be important to evaluate each level of response to treatment and to examine patients in a parameter specific manner. It will also be important to identify predictors related to failure to respond. This could lead to insight regarding polymorphisms that could be related to inflammatory pathways associated with a failure to respond. Since asthma is a complex disease with multiple phenotypes, ie, nocturnal asthma, exercise-induced asthma, allergen-induced asthma, etc., this will require a large database, multiple measures of response, and a broad array of genetic markers for drug response and disease. However, gaining this information will help to reorganize our approach to medication selection for specific types of asthma.

	Footnotes

 
Abbreviations: IL = interleukin; NHLBI = National Heart, Lung, and Blood Institute; PC₂₀ = provocative concentration of methacholine causing a 20% fall in FEV₁

Supported in part by Public Health Services research grants 1NO1-HR-16048, HL36577, HL 51834, General Clinical Research Center grant 5 MO1 RR00051 from the Division of Research Resources, and NICHHD Pediatric Pharmacology Research Unit Network grant 1-U01-HD37237.

	References

TOP Introduction Is There Evidence of... Does the Response to... Are There Ways That... Can This Information Be... Prospectus References

 

1. . Global Initiative for Asthma (1995) Global strategy for asthma management and prevention: NHLBI/NIH workshop report National Institutes of Health, National Heart, Lung, and Blood Institute Bethesda, MD. publication No. 95–3659
2. National Asthma Education and Prevention Program. Expert panel report 2: Guidelines for the diagnosis and management of asthma 1997 National Institutes of Health, National Heart, Lung, and Blood Institute Bethesda, MD. publication No. 97-4051
3. Agertoft, L, Pedersen, S Effects of long term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994;88,373-381[CrossRef][ISI][Medline]
4. Leung, DYM, Spahn, JD, Szefler, SJ Steroid-resistant asthma: new insights and implications for management. Szefler, SJ Leung, DYM eds. Severe asthma: a multidisciplinary approach 2nd ed. 2001,597-619 Marcel Dekker New York, NY.
5. Peat, JK Asthma: a longitudinal perspective. J Asthma 1998;35,235-241[ISI][Medline]
6. Zeiger, RS, Dawson, C, Weiss, S, et al Relationships between duration of asthma and asthma severity among children in the Childhood Asthma Management Program (CAMP). J Allergy Clin Immunol 1999;103,376-387[CrossRef][ISI][Medline]
7. Szefler, SJ, Eigen, H Budesonide inhalation suspension: a nebulized corticosteroid for persistent asthma. J Allergy Clin Immunol 2002;109,730-742[CrossRef][ISI][Medline]
8. Szefler, SJ, Martin, RJ, the Asthma Clinical Research Network. Evaluation and comparison of inhaled steroids. Schleimer, PM O’Byrne, PM Szefler, SJet al eds. Airway activity and selectivity of inhaled steroids in asthma: mechanisms, models of evaluation, and clinical impacts. Lung biology in health and disease series 2002,389-418 Marcel Dekker New York, NY.
9. Spahn, JD, Szefler, SJ Childhood asthma: new insights into management. J Allergy Clin Immunol 2002;109,3-13[CrossRef][ISI][Medline]
10. Phelan, PD, Robertson, CF, Olinsky, A The Melbourne Asthma Study: 1964–1999. J Allergy Clin Immunol 2002;109,189-194[CrossRef][ISI][Medline]
11. Martinez, FD Development of wheezing disorders and asthma in preschool children. Pediatrics 2002;109,362-367[Abstract/Free Full Text]
12. Castro-Rodriguez, JA, Holberg, CJ, Wright, AL, et al A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000;162,1403-1406[Abstract/Free Full Text]
13. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000;343,1054-1063[Abstract/Free Full Text]
14. Jenkins, HA, Szefler, SJ, Covar, RA, et al New insight into the clinical characteristics of adults vs children with severe asthma [abstract]. J Allergy Clin Immunol 2002;109,1100A
15. Martin, RJ, Szefler, SJ, Chinchilli, VM, et al Systemic effect comparisons of six inhaled corticosteroid preparations. Am J Respir Crit Care Med. 2002;165,1377-1383[Abstract/Free Full Text]
16. Szefler, SJ, Richard, J, Martin, RJ, et al Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109,410-418[CrossRef][ISI][Medline]
17. Marsh, DG, Neely, JD, Breazeale, DR, et al Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994;264,1152-1156[Abstract/Free Full Text]
18. Borish, L, Mascali, JJ, Klinnert, M, et al SSC polymorphisms in interleukin genes. Hum Mol Genet 1994;3,1710 [erratum, Hum Mol Genet 1995; 4:974][Free Full Text]
19. Rosenwasser, LJ, Klemm, DJ, Dresback, JK, et al Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clin Exp Allergy 1995;25(Suppl 2),74-78 discussion 95–96
20. Burchard, EG, Silverman, EK, Rosenwasser, LJ, et al Association between a sequence variant in the IL-4 gene promoter and FEV₁ in asthma. Am J Respir Crit Care Med 1999;160,919-922[Abstract/Free Full Text]
21. Hershey, GK, Friedrich, MF, Esswein, LA, et al The association of atopy with a gain-of-function mutation in the subunit of the interleukin-4 receptor. N Engl J Med 1997;337,1720-1725[Abstract/Free Full Text]
22. Rosa-Rosa, L, Zimmermann, N, Bernstein, JA, et al The R576 IL-4 receptor allele correlates with asthma severity. J Allergy Clin Immunol 1999;104,1008-1014[CrossRef][ISI][Medline]
23. Martinez, FD Maturation of immune responses at the beginning of asthma. J Allergy Clin Immunol 1999;103,355-361[CrossRef][ISI][Medline]
24. Spahn, JD, Szefler, SJ, Surs, W, et al A novel action of IL-13: induction of diminished monocyte glucocorticoid receptor-binding affinity. J Immunol 1996;157,2654-2659[Abstract]

This article has been cited by other articles:

				N. Kunzli, R. McConnell, D. Bates, T. Bastain, A. Hricko, F. Lurmann, E. Avol, F. Gilliland, and J. Peters Breathless in Los Angeles: The Exhausting Search for Clean Air Am J Public Health, September 1, 2003; 93(9): 1494 - 1499. [Abstract] [Full Text] [PDF]

				J. M. Drazen Asthma and the Human Genome Project: Summary of the 45th Annual Thomas L. Petty Aspen Lung Conference Chest, March 1, 2003; 123(2007): 447S - 449S. [Full Text] [PDF]

This Article Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Szefler, S. J. Search for Related Content PubMed PubMed Citation Articles by Szefler, S. J.