The Journal of Allergy and Clinical Immunology
Volume 123, Issue 1 , Pages 28-34, January 2009

Advances in pediatric asthma in 2008: Where do we go now?

  • Stanley J. Szefler, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Stanley J. Szefler, MD, National Jewish Health, 1400 Jackson Street, Room J304 Molly Blank Building, Denver, CO 80206.

Received 12 November 2008; accepted 14 November 2008.

Article Outline

This year's summary focuses on recent advances in pediatric asthma as reported in Journal publications in 2008. New National Asthma Education and Prevention Program asthma guidelines were released in 2007 with a special emphasis on asthma control. Attention was redirected to methods that could reduce impairment, specifically symptom control, and minimize risk, including exacerbations. Journal theme issues in 2008 focused on several relevant asthma topics including asthma exacerbations, exercise-induced bronchospasm, asthma and obesity, and occupational asthma. This review highlights Journal articles and related articles that reinforce principles of the guidelines and also direct us to new information that will advance asthma care for children. A major step forward will be finding ways to implement the asthma guidelines.

Key words: Asthma, asthma control, asthma impairment, asthma risk, asthma severity, early intervention in asthma, biomarkers, genetics, therapeutics

Abbreviations used: AHR, Airway hyperresponsiveness, EIB, Exercise-induced bronchoconstriction, FeNO, Fraction of exhaled nitric oxide (ppb), ICS, Inhaled corticosteroid, LABA, Long-acting β-adrenergic agonist

 

Last year, this Advances in Pediatric Asthma review included a summary of key features in the updated asthma guidelines and discussed new findings related to pediatric asthma.1 The asthma guidelines emphasized the importance of asthma control, a stepwise approach to asthma management, and the importance of early diagnosis and intervention.2, 3 This review highlights 2008 Journal publications that reinforce principles in the current guidelines and add new information to consider for future guidelines and observations that advance our ability to adapt personalized medicine to the management of childhood asthma (Table I).

Table I. Key advances in pediatric asthma in 2008
1. For asthma guidelines to be effective, clinicians must incorporate key messages into practice, specifically application of spirometry and appropriate use of long-term controller therapy.
2. Careful identification of asthma phenotypes combined with biomarkers and genetics will lead to new insights into the mechanisms of this complex, heterogeneous disease.
3. Attention must now be directed to reducing health disparities with better understanding of methods that lead to poor asthma control in susceptible populations.
4. Risk profiles are developing that will lead to early identification of children susceptible to persistent asthma and prompt early intervention strategies.
5. Asthma and obesity represent growing epidemics that often coexist with beginnings in early childhood.

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Implementing the asthma guidelines 

Several key terms were introduced with the new National Asthma Education and Prevention Program asthma guidelines, including severity, control, responsiveness, impairment, and risk.2, 3 Severity is defined as the intrinsic intensity of the disease process and can be measured most readily and directly in patients who are not receiving long-term controller therapy. Control is the degree to which the manifestations of asthma (symptoms, functional impairment, and risks of untoward events) are minimized and the goals of therapy are achieved. Responsiveness is the ease with which control is achieved by therapy.

Asthma severity and asthma control are both divided into 2 domains: impairment and risk. Impairment is the assessment of the frequency and intensity of symptoms, as well as the functional limitations that the patient is experiencing now or in the past because of asthma. Risk is the estimate of the likelihood of an asthma exacerbation, progressive loss of pulmonary function over time caused by asthma, or an adverse event from medication or even death. The assessment of severity and control provides guidance for the direction to take in stepping up or stepping down medications. In a recent theme issue on asthma in The Lancet, McIvor and Chapman4 provide an overview of the past 20 years of asthma guidelines by pointing out some of the challenges in addressing the appropriate target audience and assuring application of these principles to improve outcomes. They point to the many ways that clinicians have ignored key messages in these reports and support the new direction in making guidelines practical and implementable. There are ways to do this, but it will require cooperation from all stakeholders including patients, health care providers, and clinicians, to name a few.

Asthma control 

Now that attention is redirected to achieving well controlled asthma, we must carefully monitor asthma control to evaluate the benefits and risks of interventions. Asthma is a complex disease, and key to understanding individual patients is the careful assessment of control to guide treatment and help anticipate and thus prevent exacerbations and progression of the disease.5, 6 Careful identification of asthma phenotypes will lead to new insights into the mechanisms of this complex, heterogeneous disease.7

Holt et al8 applied factor analysis to explore the relationships between measures of asthma morbidity and to identify heterogeneous components of asthma health status in children age 5 to 12 years. They identified 5 factors—(1) inflammatory markers, (2) symptom/medication use, (3) asthma exacerbations, measures of lung function based on (4) FEV1 and forced vital capacity, and (5) bronchodilator response and FEV1/forced vital capacity—that appear to provide independent information in the assessment of asthma. Bender and Zhang9 examined adherence and asthma control and concluded that although negative affect and adherence were predictive of asthma control, the relationship of each to asthma control was distinctly different. They observed that the accuracy of symptom perception may be influenced by patient and parent affect characteristics.

Management 

Asthma management in children carries with it concern for adverse effects of commonly used medications. A brief report by Pelkonen et al10 provided reassuring information that short courses of high-dose inhaled corticosteroid (ICS) and long-term use of low-dose to medium-dose ICS, specifically budesonide, was not associated with the development of lens opacities or clinically important increases in intraocular pressure.

The recent report of an adolescent suicide attributed to initiation of montelukast has raised concern regarding psychological adverse effects associated with leukotriene modifiers. Holbrook and Harik-Khan11 examined data from 3 controlled trials conducted within the American Lung Association Asthma Clinical Research Centers and did not find evidence of a negative effect of montelukast on emotional well being, but additional studies will be needed to examine the potential for idiosyncratic reactions.

Questions continue to be raised regarding the benefits of early intervention with ICS. Based on analysis from an early intervention study with budesonide (Inhaled Steroid Treatment As Regular Therapy in Early Asthma study) conducted in 7241 patients age 5 to 66 years with recent-onset, mild persistent asthma, Busse et al12 concluded that this form of early intervention improved asthma control including significantly lower risk of severe asthma-related events with less additional medication use.

Managed care 

Now that revised guidelines are available, it will be important to assess ways to integrate these principles into managed care systems. These systems can be used to examine the efficacy of treatment strategies. For example, Zeiger et al13 examined the effect of single controller ICS compared with other drug regimens and concluded that total direct costs and asthma-related utilizations were meaningfully less in the year after being dispensed single controller ICS compared with single controller leukotriene modifiers or most combination controllers.

Despite significant advances in care that have seen the reduction in asthma mortality over the last 10 years, certain patient populations still experience greater morbidity, and this disparity must be addressed. Stingone and Claudio14 examined allergy care in urban children and found that many children do not receive comprehensive asthma treatment that includes management of allergies and education on avoidance of household allergens. This might indicate lower access to medical care among families ineligible for public programs. Alternatively, perhaps unique programs will have to be applied to reduce health disparities. Canino et al15 evaluated the effectiveness of a culturally adapted family asthma management intervention and found that this home-based program tailored to cultural needs of low-income Puerto Rican families resulted in a number of improved asthma control measures and improved parents' confidence in managing their child's asthma.

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New insights that could affect future asthma management 

Although the asthma guidelines summarize a significant amount of information about asthma, there is much that we do not know about the susceptibility, variability, recovery, and mechanisms of the disease.16 This section highlights new findings that should receive attention in revising future asthma guidelines.

Early indicators associated with asthma 

Our ability to prevent the development of asthma is strongly linked to our ability to identify characteristics that are associated with a high likelihood of developing the disease. Some studies have pointed to prenatal indicators, and others have examined postnatal factors. In regard to prenatal factors, Pistiner et al17 reported that cesarean delivery was not associated with the development of asthma but was associated with allergic rhinitis and atopy among children with a parental history of asthma or allergies. On the other hand, Kumar et al18 reported a relationship of prematurity and chorioamnionitis on early childhood wheezing, an effect that was stronger in African Americans. These observations require confirmation to set up risk profiles for features that signal a child at risk for persistent asthma.

Several studies reported on features associated with developing asthma in children. McDonald et al,19 in a longitudinal study in Manitoba, found a negative association between delay in administration of the first dose of whole-cell diphtheria-tetanus-pertussis immunization in childhood and the development of asthma, with the association greater with delays in all of the first 3 doses.

Kim et al20 sought to describe patterns of sensitization and allergic disease in an unselected agricultural Chinese population. They noted that although atopic sensitization was common in this rural farming population, particularly to shellfish, peanut, dust mite, and cockroach, the prevalence of allergic disease was quite low. However, Donohue et al21 observed in an inner-city population that children age 2 to 3 years who develop anticockroach, mouse IgE are at increased risk of wheeze and atopy with a dose-response relationship between higher IgE class and prevalence of wheeze, rhinitis, or atopic dermatitis. Thus, the pattern of specific sensitization could be important in determining the disease course.

Interesting observations in select populations can also help our understanding of pathways to asthma. Foster et al22 noted an increased incidence of asthma in HIV+ children treated with highly active antiretroviral therapy (HAART) than HIV+ children not receiving HAART and hypothesized that this might be driven by immunoreconstitution of CD4+ T cells. Burgess et al23 examined the association between childhood eczema and asthma and concluded that childhood eczema increased the likelihood of childhood asthma, of new-onset asthma in later life, and of asthma persisting into middle age; however, this finding was no longer evident when adjusted for allergic rhinitis. Shaaban et al24 using the European Community Respiratory Health Survey investigated the onset of asthma in patients with allergic and nonallergic rhinitis in an adult population. They noted a relationship of allergic rhinitis, especially with sensitization to mite, was associated with increased risk of asthma independently of other allergens. These observations prompt studies of early intervention for allergic rhinitis or eczema either directly for these allergic disorders or as indicators for initiating treatment of asthma to determine their effect on altering the course of asthma. Lowe et al25 also studied the relationship of eczema to asthma and reported that eczema in the first 2 years of life is associated with an increased risk of childhood asthma in boys, but there was no evidence of this relationship in girls. Beasley et al,26 based on observations in the International Study of Asthma and Allergies in Childhood program, reported that use of paracetamol (acetaminophen) in the first year of life and in later childhood is associated with risk of asthma at age 6 to 7 years and might be a risk factor or signal for the development of asthma in childhood.

Tepper et al27 reported that atopic characteristics of the infant could be important determinants of airway physiology based on observations that infants sensitized to egg or milk compared with infants sensitized to neither egg or milk had lower flows and greater airway reactivity but no difference in exhaled nitric oxide. However, infants with total serum IgE levels >20 IU/mL had higher exhaled nitric oxide levels compared with infants with IgE levels ≤20 IU/mL but no difference in forced flows or airway reactivity.

Elliott et al28 examined the relationship between breast-feeding and later asthma and allergy outcomes using a large birth cohort in the United Kingdom and did not find a relationship. This is consistent with other reports that suggest breast-feeding may be helpful in reducing the likelihood of wheezing in young children but does not affect the course of later outcomes.29 Finally, Stern et al30 examined the contribution of sex and early life factors to asthma diagnosed in young adults. They concluded that asthma with onset in early adulthood has its origins in childhood. Factors associated with chronic asthma at 22 years of age included onset at 6 years of age and persistent wheezing in early life, sensitization to Alternaria alternata, low airway function at age 6 years, and bronchial hyperresponsiveness at 6 years. In a comprehensive review of the literature, Sly et al31 concluded that objective assessment of atopy by quantitating allergen-specific IgE in serum against common food allergens and local aeroallergens by 2 years of age in conjunction with the presence of other atopic manifestations can help identify the wheezing children at high risk of developing persistent asthma. Nicolaou et al32 noted that day care attendance was associated with a reduced risk of current wheezing in 5-year-old children. The protective effect appeared strongest for children who entered day care between the ages of 6 and 12 months.

This information helps set the stage for early identification of children at risk for developing asthma and for designing trials to develop methods to modify the course of asthma. Indeed, some of these risk factors have already been used to design trials for intervention in young children at high risk for developing asthma.33

Asthma and obesity 

National attention has been directed to the growing epidemic of obesity. The May 2008 theme issue was devoted to asthma and obesity. Litonjua and Gold34 comment that the prevalence of both asthma and obesity has increased, and both have their beginnings in early childhood. Therefore, common exposures that predispose individuals to both conditions may explain the association. They discuss some common factors, such as common genetic predictors, prenatal exposure to specific nutrients and overall maternal nutrition, patterns of colonization of the neonatal and infant gut, birth weight and infant weight gain, sedentary behaviors, and levels of adipokines in early life, as features to explore.

Shore35 extends this discussion by presenting several mechanisms associated with obesity that contribute to asthma, including reduced lung volume and tidal volume in obesity that promote airway narrowing; low-grade inflammation that may act on the lungs to exacerbate asthma; obesity-related changes in adipose-derived hormones including leptin and adiponectin; and comorbidities of obesity, such as dyslipidemia, gastroesophageal reflux, sleep-disordered breathing, type 2 diabetes, or hypertension that may provoke or worsen asthma. Therefore, novel therapeutic strategies for treatment of the obese patient with asthma may result from a better understanding of the mechanisms that contribute to both disorders.

Mehra and Redline36 identified a coaggregated relationship between obesity and sleep apnea that may affect asthma control through augmented inflammation and oxidative stress affecting cardiopulmonary disease. Mosen et al37 demonstrate that obesity is associated with worse asthma outcomes, especially an increased risk of asthma-related hospitalization. Although this relationship between asthma and worse outcomes has not been clearly demonstrated in children, the pattern is set because infants with higher weight-for-length scores at 6 months of age have a greater risk of recurrent wheezing by age 3 years.38 Therefore, early interventions to prevent excess infant adiposity might help reduce children's risk of asthma-related symptoms.

Asthma exacerbations 

The revised asthma guidelines also redirect attention to assessing and preventing asthma exacerbations. The October 2008 theme issue was focused on asthma exacerbations.39 Sears40 provides an excellent review on the epidemiology of asthma exacerbations, indicating that exacerbations are often, but not always, associated with viral infection, especially rhinovirus, with significant interaction with allergen sensitization and exposure. Seasonal patterns of exacerbations are seen especially in children, and may be aggravated by lack of adequate maintenance anti-inflammatory treatment during the high-risk viral season, especially that reflected in the Northern Hemisphere in the month of September after returning to school. Therefore, recognizing these risk factors can be used to design prevention measures to reduce morbidity and mortality associated with asthma exacerbations. Sykes and Johnston41 and Kelly and Busse42 provide detailed discussions on the mechanisms of asthma exacerbations, especially related to rhinovirus infection. Most important for therapeutic advances will be the evaluation of the possibility of defective epithelial antiviral response to rhinovirus in asthma.42

Covar et al from the National Heart, Lung, and Blood Institute Childhood Asthma Research and Education Network,43 based on evaluation of the previously reported Pediatric Asthma Controller Trial study,44 noted that children with mild-to-moderate persistent asthma with previous exacerbations are more likely to have a repeat exacerbation despite controller treatment. They also noted that ICSs are superior to montelukast at modifying the exacerbation risk. Of interest, they also noted that available physiologic measures, biomarkers, and diary cards are not reliable predictors of asthma exacerbations. Sorkness et al45 reported on the asthma index, a continuous variable to characterize exacerbations of asthma, and proposed it as a tool for quantitative comparisons among groups and for exploring time-linked associations between asthma control and other viral and biologic variables of interest.

Exercise-induced asthma exacerbations 

In association with the 2008 Summer Olympics, the August 2008 theme issue was devoted to a discussion of exercise and asthma. Fitch et al46 provided a workshop summary on asthma and the elite athlete. They indicate that long-term intense endurance training, particularly in unfavorable environmental conditions, appears to be associated with an increased risk of developing asthma and airway hyperresponsiveness (AHR) in elite athletes. They reinforced the policy requiring Olympic athletes to demonstrate the presence of asthma, exercise-induced bronchoconstriction (EIB), or AHR to be approved to use inhaled ß2-agonists. Anderson and Kippelen47 discuss airway injury as a mechanism for EIB in elite athletes. They propose that the pathogenesis of EIB relates to epithelial injury arising from breathing poorly conditioned air at high flow rates for long periods or high volumes of irritant particles or gases. Furthermore, this repeated injury-repair process over time can lead to an alteration in the contractile properties of the smooth muscle, making it more sensitive to mediators of bronchoconstriction. Pedersen et al48 suggest that elite swimmers do not have susceptible airways but develop respiratory symptoms, airway inflammation, and AHR during their swimming careers. Rundell and Slee49 provide a detailed discussion of the advantages and disadvantages of each diagnostic procedure for EIB. Weinberger50 reviewed the use of long-acting ß-adrenergic agonists (LABAs) in asthma management. Although the benefits of LABA have been demonstrated to be useful for many patients whose symptoms are not adequately controlled with conventional doses of ICS alone, there appears to be considerable individual variability. He indicates that some patients may show loss of bronchoprotective effect for EIB that will occur with regular use of LABA and may be clinically important. Until a predictive marker is available to recognize these patients, clinicians would be wise to add LABAs selectively rather than using combinations as initial therapy.

Poorly controlled asthma 

It is important to understand the phenotype of difficult-to-control asthma to identify mechanisms and potential therapeutic interventions. Sharma et al,51 using the database developed in the National Heart, Lung, and Blood Institute Childhood Asthma Management Program, evaluated the subgroup with consistent bronchodilator response over time and noted that this phenotype is associated with poor clinical outcomes. Therefore, the clinician should recognize this pattern, and it should prompt a re-evaluation of the patient's asthma medication regimen. Patients with difficult-to-control asthma are often resistant to steroid therapy; however, the cause is unknown. Goleva et al52 noted that the classic macrophage activation and induction of LPS signaling pathways along with high endotoxin levels detected in bronchoalveolar lavage in subjects with corticosteroid-resistant asthma suggest that LPS exposure might contribute to corticosteroid-resistant asthma, prompting an evaluation of conditions that lead to the presence of LPS in the airways.

Monitoring progression 

Our March 2008 theme issue was devoted to asthma progression.53 Several key articles in that issue addressed topics such as the natural history of asthma,54 immunologic and inflammatory mechanisms that drive asthma progression to remodeling,55 interpatient variability in rates of asthma progression,56 and methods to assess progression in the clinic setting.6 Clearly, this is an area of current interest, and we have much to learn about the integration of clinical symptoms, environmental exposures, pulmonary physiology, biomarkers, and genetics to monitor disease progression, as well as interventions that will successfully alter the course of the disease.

Several new reports helped provide some insight into asthma progression. Leigh et al57 studied human rhinovirus infection on airway epithelial cells and reported that rhinovirus upregulates growth factors involved in airway remodeling, specifically amphiregulin, activin A, and vascular endothelial growth factor. Sackesen et al58 reported that childhood asthma is associated with significant decreases in various components of both enzymatic and nonenzymatic antioxidant defenses. Also of interest, Fitzpatrick et al59 described compromised alveolar macrophage phagocytosis in children with poorly controlled asthma. These are all factors that could contribute to asthma progression.

Epidemiology of asthma and environmental impact 

Our knowledge of environmental and occupational factors that contribute to respiratory disease is rapidly expanding.60 It is important not only to understand the specific impact of allergens and pollutants but also to conduct careful assessments of regional exposure. Gupta et al61 characterized the geographic variability of childhood asthma prevalence among neighborhoods of Chicago and reported wide variability by neighborhood. O'Connor et al62 noted short-term increases in air pollution were associated with adverse respiratory health effects in inner-city children with asthma.

In relation to allergen exposure, Tovey et al63 examined a birth cohort and reported a nonlinear relationship between mite exposure and clinical outcomes in a generally high mite allergen environment with lowest and highest mite exposure associated with lowest prevalence of asthma. In relation to tobacco smoke exposure, Kumar et al64 reported that caregiver smoking was strongly associated with child exposure and lower socioeconomic status, non-Hispanic ethnicity, and caregiver depression symptoms. Rabinovitch et al65 reported an interesting relationship of increased urinary cysteinyl leukotrienes, albuterol use, and montelukast responsiveness in children exposed to tobacco smoke, especially girls. They suggested that perhaps measurement of leukotriene E4 to fraction of exhaled nitric oxide (ppb; FeNO) ratios may help predict responsiveness to montelukast. Rayens et al66 reported a reduction in asthma emergency department visits among both children and adults associated with implementation of smoke-free legislation in a community setting.

Management 

Although much has been accomplished in improving asthma care, there still are higher emergency department visit rates for acute asthma observed among specific demographic groups, including women and children, and widening disparities among black subjects, which calls for further investigation and improved methods of care.67 In a study of moderate-to-severe asthma in children, Strunk et al68 found that neither azithromycin, a macrolide antibiotic, nor montelukast, a leukotriene receptor antagonist, were effective ICS-sparing alternatives. In a study of young children with moderate to severe intermittent wheezing, Bacharier et al69 reported that episodic use of either budesonide or montelukast early in respiratory tract illnesses, when added to albuterol, did not increase the proportion of episode free days or decrease oral corticosteroid use, but did reduce the severity of acute illnesses, especially in those considered at risk for developing asthma.

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Moving toward personalized medicine 

Application of biomarkers and genetics along with defined therapeutic targets offer the hope of individualizing our approach to asthma care. Exhaled nitric oxide is a biomarker of allergic airway inflammation that has received the most attention to date. Moeller et al70 provided evidence that high FeNO levels were associated with young children with recurrent episodes of wheezing and at high risk for developing asthma compared with those with recurrent cough and children less likely to develop asthma. Szefler et al and the National Institute of Allergy and Infectious Diseases Inner City Asthma Consortium71 studied the benefits of adding FeNO measurements to a guidelines-based approach to asthma care and concluded that FeNO resulted in higher doses of ICS without clinically important improvements in symptomatic control. Exhaled breath condensates offer the potential to measure biomarkers affected by allergen and air pollution in an easily accessible manner,72, 73 but the role of mediators measured from this source for clinical management remains to be defined.

Knowledge regarding genetics and the resultant complex disease of asthma continues to develop with information related to the effect of the environment on gene-environment interactions, the contribution of TH2 immunity gene variants to allergic inflammation, and the role of filaggrin mutations in atopic dermatitis.56, 74, 75 To date, 6 genes have been identified by means of positional cloning as linking with asthma: ADAM33, GRPA, PHF11, DPP1V, HLA-G, and CYF1P2.74 However, application of this information to clinical practice awaits confirmation through validation and replication studies. In addition, the following observations were reported: genetic association of acidic mammalian chitinase, CHIA, with atopic asthma and serum total IgE levels in an Indian population76; increased susceptibility to asthma and poor asthma control in children and young adults with genetic variation at a locus controlling ORMDL3 expression77; increased serum TGF-ß1 levels and airflow obstruction with C-509T polymorphism78; and functional relevant Toll-like receptors 1 and 6 and a potential protective role in childhood asthma.79 In addition, Hunninghake et al80 observed that dust mite allergen levels modified the effect of IL10 single nucleotide polymorphisms on allergy and asthma exacerbations, and Weidinger et al81 observed that filaggrin mutations affect the development of eczema and confer significant risks of asthma in the context of eczema. Bouzigon et al82 reported an increased risk of asthma associated with 17q21 genetic variants related to early-onset asthma with increased risk through early-life exposure to environmental tobacco smoke.

With the increased understanding of biologic mechanisms and gene-environment interactions, the hope is that this information will help identify therapeutic targets, such as transcription factors, that could lead to new treatment strategies.83, 84, 85, 86, 87

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I thank Gretchen Hugen for assistance with manuscript preparation.

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References 

  1. Szefler SJ. Advances in pediatric asthma in 2007. J Allergy Clin Immunol. 2008;121:614–619
  2. National Institutes of Health. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and management of asthma. August 2007. NIH publication no. 07-4051. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/index.htm. Accessed November, 10, 2008.
  3. Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma—summary report 2007. J Allergy Clin Immunol. 2007;120:S94–S138
  4. McIvor RA, Chapman KR. The coming of age of asthma guidelines. Lancet. 2008;372:1021–1022
  5. Frey U, Suki B. Complexity of chronic asthma and chronic obstructive pulmonary disease: implications for risk assessment and disease progression and control. Lancet. 2008;372:1088–1099
  6. Spahn JD, Covar RA. Clinical assessment of asthma progression in children and adults. J Allergy Clin Immunol. 2008;121:548–557
  7. Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008;372:1107–1119
  8. Holt EW, Cook EF, Covar RA, Spahn JD, Fuhlbrigge AL. Identifying the components of asthma health status in children with mild to moderate asthma. J Allergy Clin Immunol. 2008;121:1175–1180
  9. Bender B, Zhang L. Negative affect, medication adherence, and asthma control in children. J Allergy Clin Immunol. 2008;122:490–495
  10. Pelkonen A, Kari O, Selroos O, Nikander K, Haahtela T, Turpeinen M. Ophthalmologic findings in children with asthma receiving inhaled budesonide. J Allergy Clin Immunol. 2008;122:832–834
  11. Holbrook JT, Harik-Khan R. Montelukast and emotional well-being as a marker for depression: results from three randomized double-masked clinical trials. J Allergy Clin Immunol. 2008;122:828–829
  12. Busse WW, Pedersen S, Pauwels RA, Tan WC, Chen YZ, Lamm CJ, et al. START Investigators Group. The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early intervention with budesonide in mild persistent asthma. J Allergy Clin Immunol. 2008;121:1167–1174
  13. Zeiger RS, Hay JW, Contreras R, Chen W, Quinn VP, Seal B, et al. Asthma costs and utilization in a managed care organization. J Allergy Clin Immunol. 2008;121:885–892
  14. Stingone JA, Claudio L. Disparities in allergy testing and health outcomes among urban children with asthma. J Allergy Clin Immunol. 2008;122:748–753
  15. Canino G, Vila D, Normand ST, Acosta-Pérez E, Ramírez R, García P, et al. Reducing asthma health disparities in poor Puerto Rican children: the effectiveness of a culturally tailored family intervention. J Allergy Clin Immunol. 2008;121:665–670
  16. Reed CE. What the 21st century does not know about asthma—yet. J Allergy Clin Immunol. 2008;121:601–602
  17. Pistiner M, Gold DR, Abdulkerim H, Hoffman E, Celedón JC. Birth by cesarean section, allergic rhinitis, and allergic sensitization among children with a parental history of atopy. J Allergy Clin Immunol. 2008;122:274–279
  18. Kumar R, Yu Y, Story RE, Pongracic JA, Gupta R, Pearson C, et al. Prematurity, chorioamnionitis, and the development of recurrent wheezing: A prospective birth cohort study. J Allergy Clin Immunol. 2008;121:878–884
  19. McDonald KL, Huq SI, Lix LM, Becker AB, Kozyrskyj AL. Delay in diphtheria, pertussis, tetanus vaccination is associated with a reduced risk of childhood asthma. J Allergy Clin Immunol. 2008;121:626–631
  20. Kim JS, Ouyang F, Pongracic JA, Fang Y, Wang B, Liu X, et al. Dissociation between the prevalence of atopy and allergic disease in rural China among children and adults. J Allergy Clin Immunol. 2008;122:929–935
  21. Donohue KM, Al-alem U, Perzanowski MS, Chew GL, Johnson A, Divjan A, et al. Anti-cockroach, mouse IgE is associated with early wheeze and atopy in an inner-city birth cohort. J Allergy Clin Immunol. 2008;122:914–920
  22. Foster SB, McIntosh K, Thompson B, Lu M, Yin W, Rich KC, et al. Increased incidence of asthma in HIV-infected children treated with highly active antiretroviral therapy in the National Institutes of Health Women and Infants Transmission Study. J Allergy Clin Immunol. 2008;122:159–165
  23. Burgess JA, Dharmage SC, Byrnes GB, Matheson MC, Gurrin LC, Wharton CL, et al. Childhood eczema and asthma incidence and persistence: a cohort study from childhood to middle age. J Allergy Clin Immunol. 2008;122:280–285
  24. Shaaban R, Zureik M, Soussan D, Neukirch C, Heinrich J, Sunyer J, et al. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet. 2008;372:1049–1057
  25. Lowe AJ, Carlin JB, Bennett CM, Hosking CS, Abramson MJ, Hill DJ, et al. Do boys do the atopic march while girls dawdle?. J Allergy Clin Immunol. 2008;121:1190–1195
  26. Beasley R, Clayton T, Crane J, von Mutius E, Lai CKW, Montefort S, et al. ISAAC Phase Three Study Group Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6-7 years: Analysis from Phase Three of the ISAAC programme. Lancet. 2008;372:1039–1048
  27. Tepper RS, Llapur CJ, Jones MH, Tiller C, Coates C, Kimmel R, et al. Expired nitric oxide and airway reactivity in infants at risk for asthma. J Allergy Clin Immunol. 2008;122:760–765
  28. Elliott L, Henderson J, Northstone K, Chiu GY, Dunson D, London SJ. Prospective study of breast-feeding in relation to wheeze, atopy, and bronchial responsiveness in the Avon Longitudinal Study of Parents and Children (ASPAC). J Allergy Clin Immunol. 2008;122:49–54
  29. Sicherer SH, Burks AW. Maternal and infant diets for prevention of allergic diseases: understanding menu changes in 2008. J Allergy Clin Immunol. 2008;122:29–33
  30. Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet. 2008;372:1058–1064
  31. Sly PD, Boner AL, Bjorksten B, Bush A, Custovic A, Eigenmann PA, et al. Early identification of atopy in the prediction of persistent asthma in children. Lancet. 2008;372:1100–1106
  32. Nicolaou NC, Simpson A, Lowe LA, Murray CS, Woodcock A, Custovic A. Day-care attendance, position in sibship, and early childhood wheezing: a population-based birth cohort study. J Allergy Clin Immunol. 2008;122:500–506
  33. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Two year inhaled corticosteroid treatment on subsequent asthma in high-risk toddlers. N Engl J Med. 2006;354:1985–1997
  34. Litonjua AA, Gold DR. Asthma and obesity: common early-life influences in the inception of disease. J Allergy Clin Immunol. 2008;121:1075–1084
  35. Shore SA. Obesity and asthma: possible mechanisms. J Allergy Clin Immunol. 2008;121:1087–1093
  36. Mehra R, Redline S. Sleep apnea: a proinflammatory disorder that coaggregates with obesity. J Allergy Clin Immunol. 2008;121:1096–1102
  37. Mosen DM, Schatz M, Magid DJ, Camargo CA. The relationship between obesity and asthma severity and control in adults. J Allergy Clin Immunol. 2008;122:507–511
  38. Taveras EM, Rifas-Shiman SL, Camargo CA, Gold DR, Litonjua AA, Oken E, et al. Higher adiposity in infancy associated with recurrent wheeze in a prospective cohort of children. J Allergy Clin Immunol. 2008;121:1161–1166
  39. Szefler SJ. Asthma exacerbations: putting a lid on the volcano. J Allergy Clin Immunol. 2008;122:697–699
  40. Sears MR. Epidemiology of asthma exacerbations. J Allergy Clin Immunol. 2008;122:662–668
  41. Sykes A, Johnston SL. Etiology of asthma exacerbations. J Allergy Clin Immunol. 2008;122:685–688
  42. Kelly JT, Busse WW. Host immune responses to rhinovirus: mechanisms in asthma. J Allergy Clin Immunol. 2008;122:671–682
  43. Covar RA, Szefler SJ, Zeiger RS, Sorkness CA, Moss M, Mauger DT, et al. Childhood Asthma Research and Education Network Factors associated with asthma exacerbations during a long-term clinical trial of controller medications in children. J Allergy Clin Immunol. 2008;122:741–747
  44. Sorkness CA, Lemanske RF, Mauger DT, Boehmer SJ, Chinchilli VM, Martinez FD, et al. Childhood Asthma Research and Education Network of the National Heart, Lung, and Blood Institute Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial. J Allergy Clin Immunol. 2007;119:64–72
  45. Sorkness RL, Gonzalez-Fernandez G, Billmeyer EE, Evans MD, Gern JE, Jarjour NN. The asthma index: a continuous variable to characterize exacerbations of asthma. J Allergy Clin Immunol. 2008;122:838–840
  46. Fitch KD, Sue-Chu M, Anderson SD, Boulet LP, Hancox RJ, McKenzie DC, et al. Asthma and the elite athlete: summary of the International Olympic Committee's Consensus Conference, Lausanne, Switzerland, January 22-24, 2008. J Allergy Clin Immunol. 2008;122:254–260
  47. Anderson SD, Kippelen P. Airway injury as a mechanism for exercise-induced bronchoconstriction in elite athletes. J Allergy Clin Immunol. 2008;122:225–235
  48. Pedersen L, Lund TK, Barnes PJ, Kharitonov SA, Backer V. Airway responsiveness and inflammation in adolescent elite swimmers. J Allergy Clin Immunol. 2008;122:322–327
  49. Rundell KW, Slee JB. Exercise and other indirect challenges to demonstrate asthma or exercise-induced bronchoconstriction in athletes. J Allergy Clin Immunol. 2008;122:238–246
  50. Weinberger M. Long-acting β-agonists and exercise. J Allergy Clin Immunol. 2008;122:251–253
  51. Sharma S, Litonjua AA, Tantisira KG, Fuhlbrigge AL, Szefler SJ, Strunk RC, et al. CAMP Research Group Clinical predictors and outcomes of consistent bronchodilator response in the Childhood Asthma Management Program. J Allergy Clin Immunol. 2008;122:921–928
  52. Goleva E, Hauk PJ, Hall CF, Liu AH, Riches DWH, Martin RJ, et al. Corticosteroid-resistant asthma is associated with classic antimicrobial activation of airway macrophages. J Allergy Clin Immunol. 2008;122:550–559
  53. Szefler SJ. Asthma progression: can we and should we measure it?. J Allergy Clin Immunol. 2008;121:598–600
  54. Panettieri RA, Covar RA, Grant E, Hillyer EV, Bacharier L. Natural history of asthma: persistence versus progression—does the beginning predict the end?. J Allergy Clin Immunol. 2008;121:607–613
  55. Broide DH. Immunologic and inflammatory mechanisms that drive asthma progression to remodeling. J Allergy Clin Immunol. 2008;121:560–570
  56. Holloway JW, Yang IA, Holgate ST. Interpatient variability in rates of asthma progression: can genetics provide an answer?. J Allergy Clin Immunol. 2008;121:573–579
  57. Leigh R, Oyelusi W, Wiehler S, Koetzler R, Zaheer RS, Newton R, et al. Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in airway remodeling. J Allergy Clin Immunol. 2008;121:1238–1245
  58. Sackesen C, Ercan H, Dizdar E, Soyer O, Gumus P, Nursal Tosun B, et al. A comprehensive evaluation of the enzymatic and nonenzymatic antioxidant systems in childhood asthma. J Allergy Clin Immunol. 2008;122:78–85
  59. Fitzpatrick AM, Holguin F, Teague WG, Brown LAS. Alveolar macrophage phagocytosis is impaired in children with poorly controlled asthma. J Allergy Clin Immunol. 2008;121:1372–1378
  60. Bush RK, Peden D. Advances in environmental and occupational respiratory disease in 2007. J Allergy Clin Immunol. 2008;121:1359–1362
  61. Gupta RS, Zhang X, Sharp LK, Shannon JJ, Weiss KB. Geographic variability in childhood asthma prevalence in Chicago. J Allergy Clin Immunol. 2008;121:639–645
  62. O'Connor GT, Neas L, Vaughn B, Kattan M, Mitchell H, Crain EF, et al. Acute respiratory health effects of air pollution on children with asthma in US inner cities. J Allergy Clin Immunol. 2008;121:1133–1139
  63. Tovey ER, Almqvist C, Li Q, Crisafulli D, Marks GB. Nonlinear relationship of mite allergen exposure to mite sensitization and asthma in a birth cohort. J Allergy Clin Immunol. 2008;122:114–118
  64. Kumar R, Curtis LM, Khiani S, Moy J, Shalowitz MU, Sharp L, et al. A community-based study of tobacco smoke exposure among inner city children with asthma in Chicago. J Allergy Clin Immunol. 2008;122:754–759
  65. Rabinovitch N, Strand M, Stuhlman K, Gelfand EG. Exposure to tobacco smoke increases leukotriene E4–related albuterol usage and response to montelukast. J Allergy Clin Immunol. 2008;121:1365–1371
  66. Rayens MK, Burkhart PV, Zhang M, Lee S, Moser DK, Mannino D, et al. Reduction in asthma-related emergency department visits after implementation of a smoke-free law. J Allergy Clin Immunol. 2008;122:537–541
  67. Ginde AA, Espinola JA, Camargo CA. Improved overall trends but persistent racial disparities in emergency department visits for acute asthma, 1993-2005. J Allergy Clin Immunol. 2008;122:313–318
  68. Strunk RC, Bacharier LB, Phillips BR, Szefler SJ, Zeiger RS, Chinchilli VM, et al. Childhood Asthma Research and Education Network of the National Heart, Lung and Blood Institute Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate to severe childhood asthma study. J Allergy Clin Immunol. 2008;122:1138–1144
  69. Bacharier LB, Phillips BR, Zeiger RS, Szefler SJ, Martinez FD, Lemanske RF, et al. Childhood Asthma Research and Education Network of the National Heart, Lung and Blood Institute Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127–1135
  70. Moeller A, Diefenbacher C, Lehmann A, Rochat M, Brooks-Wildhaber J, Hall GL, et al. Exhaled nitric oxide distinguishes between subgroups of preschool children with respiratory symptoms. J Allergy Clin Immunol. 2008;121:705–709
  71. Szefler SJ, Mitchell H, Sorkness CA, Gergen PJ, O'Connor GT, Morgan WJ, et al. Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomized controlled trial. Lancet. 2008;372:1065–1072
  72. Ono E, Mita H, Taniguchi M, Higashi N, Tsuburai T, Hasegawa M, et al. Increase in inflammatory mediator concentrations in exhaled breath condensate after allergen inhalation. J Allergy Clin Immunol. 2008;122:768–773
  73. Romieu I, Barraza-Villarreal A, Escamilla-Nuñez C, Almstrand AC, Diaz-Sanchez D, Sly PD, et al. Exhaled breath malondialdehyde as a marker of effect of exposure to air pollution in children with asthma. J Allergy Clin Immunol. 2008;121:903–909
  74. Steinke JW, Rich SS, Borish L. Genetics of allergic disease. J Allergy Clin Immunol. 2008;121:S384–S387
  75. Vercelli D. Advances in asthma and allergy genetics in 2007. J Allergy Clin Immunol. 2008;122:267–271
  76. Chatterjee R, Batra J, Das S, Kumar Sharma S, Ghosh B. Genetic association of acidic mammalian chitinase with atopic asthma and serum total IgE levels. J Allergy Clin Immunol. 2008;122:202–208
  77. Tavendale R, Macgregor DF, Mukhopadhyay S, Palmer CNA. A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications. J Allergy Clin Immunol. 2008;121:860–863
  78. Ueda T, Niimi A, Matsumoto H, Takemura M, Yamaguchi M, Matsuoka H, et al. TGFB1 promoter polymorphism C-509T and pathophysiology of asthma. J Allergy Clin Immunol. 2008;121:659–664
  79. Kormann MSD, Depner M, Hartl D, Klopp N, Illig T, Adamski J, et al. Toll-like receptor heterodimer variants protect from childhood asthma. J Allergy Clin Immunol. 2008;122:86–92
  80. Hunninghake GM, Soto-Quirós ME, Lasky-Su J, Avila L, Ly NP, Liang C, et al. Dust mite exposure modifies the effect of functional IL10 polymorphisms on allergy and asthma exacerbations. J Allergy Clin Immunol. 2008;122:93–98
  81. Weidinger S, O'Sullivan M, Illig T, Baurecht H, Depner M, Rodriguez E, et al. Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J Allergy Clin Immunol. 2008;121:1203–1209
  82. Bouzigon E, Corda E, Aschard H, Dizier M-H, Boland A, Bousquet J, et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med. 2008;359:1985–1994
  83. Adcock IM, Caramori G, Chung KF. New targets for drug development in asthma. Lancet. 2008;372:1073–1087
  84. Casale TB, Stokes JR. Immunomodulators for allergic respiratory disorders. J Allergy Clin Immunol. 2008;121:288–296
  85. Cousins DJ, McDonald J, Lee TH. Therapeutic approaches for control of transcription factors in allergic disease. J Allergy Clin Immunol. 2008;121:803–809
  86. Bhavsar P, Ahmad T, Adcock IM. The role of histone deacetylases in asthma and allergic diseases. J Allergy Clin Immunol. 2008;121:580–584
  87. Chatila TA, Li N, Garcia-Lloret M, Kim HJ, Nel AE. T-cell effector pathways in allergic diseases: transcriptional mechanisms and therapeutic targets. J Allergy Clin Immunol. 2008;121:812–823

 Supported in part by Public Health Services Research Grants HR-16048, HL64288, HL51834, AI-25496, HL081335, and HL075416; General Clinical Research Center Grant 5 MO1 RR00051; and the Colorado Cancer, Cardiovascular and Pulmonary Disease Program.

 Disclosure of potential conflict of interest: S. J. Szefler has served as a consultant for GlaxoSmithKline, Genentech, and Merck and has received research support from the National Institutes of Health, the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, Ross Pharmaceuticals, and GlaxoSmithKline.

PII: S0091-6749(08)02185-4

doi:10.1016/j.jaci.2008.11.002

The Journal of Allergy and Clinical Immunology
Volume 123, Issue 1 , Pages 28-34, January 2009