Asthma in African Americans: What can we do about the higher rates of disease?

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Asthma in African Americans: What can we do about the higher rates of disease?
Author(s)
Stacy K. Silvers, MD
David M. Lang, MD

The last several decades have seen a dramatic surge in the prevalence of asthma. In 2009, there were an estimated 17.5 million adults and almost 7.1 million children with asthma in the United States,1 up from 9.5 million adults and slightly more than 5 million children in 1995.2

Figure 1.
While better management has reduced the rates of asthma morbidity and death in recent years, specific groups remain at higher risk of poor outcomes. Compared with whites, African Americans are not only more likely to have asthma, but they often also have more severe disease. For example, in a study in Philadelphia, PA, at all levels of poverty, asthma hospitalization rates for African Americans were substantially higher than for whites.3 African Americans with asthma are also more likely to die of asthma (Figure 1).

Multiple factors contribute to these disparities, including genetics, socioeconomic factors, cultural factors, health maintenance behaviors, provider-patient communication, air quality, and obesity.

This article is based on a literature review with PubMed conducted in November 2010 using combinations of the following search terms: African American, asthma, epidemiology, genetics, obesity, and environment. Below, we review the evidence regarding a number of these factors (Table 1) and their association with the higher asthma prevalence, morbidity, and mortality rates in African Americans.

GENETICS: 70% OF DESTINY?

The trend towards personalized medicine has spurred extensive research into the genetics of asthma. Studies in twins and familial aggregation studies suggest genetics plays a significant role, with estimates of the heritability of asthma as high as 70%.4,5 More than 100 candidate genes have been shown to be associated with asthma and atopy, 30 of them in five or more independent studies.6

Researchers face many challenges when investigating the genetics involved in asthma for a particular race. Race is both a biologic and a social construct and, as such, is a poor substitute for genetics. Race constitutes not only genetic differences in individuals, but also the behaviors, beliefs, and experiences that vary among races.

The clinical disease—the phenotype—is the product of the interaction of genes and these differing behaviors and exposures. Genetics can affect how environmental factors found in association with socioeconomic factors relate to asthma morbidity and mortality.

For example, as we will discuss below, African Americans are more likely than whites to be sensitized to cockroach allergen, even after controlling for socioeconomic variables that may be associated with greater exposure.7 High-level exposure to cockroach allergen in sensitized children has been associated with poor asthma outcomes.8 This suggests that a genetic difference may exist between African Americans and whites with respect to the potential to develop cockroach sensitization, and this difference may be of particular importance for those African Americans living in areas with higher levels of cockroach exposure.

Two polymorphisms

Two polymorphisms have garnered attention for their influence on African Americans with asthma:

TheADRB2gene. This gene codes for the beta-2 adrenergic receptor and resides at chromosome 5q13.9 The receptor is found on several types of cells in the lung, including airway smooth muscle and epithelial cells, and is responsible for the salutary effects of inhaled beta-2 agonists such as albuterol (eg, Proventil).

Allelic polymorphisms of this gene are clinically relevant. The substitution of arginine (Arg) for glycine (Gly) at codon 16 of this gene is responsible for differences in response to short-acting beta-2 agonists. The allelic frequency of Arg16 is lower in white Americans (39.3%) than in African Americans (49.2%), and thus African Americans are more likely to be homozygous for Arg16 (ie, to have the Arg/Arg genotype).10

People who are homozygous for Arg16 who use albuterol on a regular basis are at higher risk of untoward asthma outcomes.11 This is important, for several reasons. In general, adherence to inhaled corticosteroids is poor (not only in African Americans),12 and patients who do not take their inhaled corticosteroids as they should may rely on short-acting beta-2 agonists more frequently. Furthermore, African Americans may have a poorer response to the repeated doses of albuterol that are typically given in the emergency department and in the hospital for severe asthma exacerbations.13 Additionally, data suggest that Arg/Arg individuals have more frequent exacerbations independent of beta-agonist use,14 although curiously, patients who are homozygous for Arg16 have a greater benefit from single doses of short-acting beta-2 agonists than those who are Gly16 homozygous.15

TheCD14gene. An interesting relationship between innate immunity and asthma has recently been described. Polymorphisms of CD14, which codes for a receptor for endotoxin, have been uncovered. The single-nucleotide polymorphism variant thymine (T) at position −260 has been found in greater frequency in whites than in African Americans, who are more likely to have the cytosine (C) allele.16 An association between the CC genotype and atopy has been reported,16 although this has not been consistent.17

A possible explanation for these inconsistencies may lie in complex gene-environment interactions. The amount of endotoxin exposure may play a role in phenotypic expression. Individuals with the CC genotype were at lower risk of developing atopy when exposed to high levels of endotoxin; however, when exposed to lower levels of endotoxin, the CC genotype was associated with a higher risk of atopy.18 Nonfarm homes in westernized countries tend to have lower levels of endotoxin than farm homes, even in low-income urban areas.19 This implies that individuals with the CC allele, who are more likely to be African American, would be at greater risk for atopy in the United States. Greater knowledge of these types of gene-environment interactions may lead to improved understanding of the observations that have generated controversy concerning the “hygiene hypothesis.”

The details of how microbial exposure can influence the human immune response to antigen exposure are still being elucidated.20

These examples highlight not only the importance of genetics in the development of asthma, but also the role genes play in variation of treatment response and subsequent risk of morbidity and death. An understanding of these genetic differences among patients is clearly important for moving towards personalized treatment strategies for asthma.

 

 

Ancestry-informative markers

A developing strategy to assess the differences in asthma prevalence, severity, and response to treatment between racial groups is the use of ancestry-informative markers (AIMs).

AIMs are single-nucleotide polymorphisms that occur in varying allelic frequencies between ancestral groups, eg, continental Africans or European whites.21 AIMs provide an estimate of an individual’s proportion of ancestry—ie, of how “African” an African American is genetically.

African ancestry, determined using AIMs, was found to be associated with asthma in people living on the Caribbean coast of Colombia.22 However, one study found that AIMs could not predict an individual’s response to inhaled corticosteroids.23

Further research is necessary to find a technique to determine how groups of individuals can be characterized more precisely and managed more appropriately.

SOCIOECONOMIC FACTORS

African Americans living in low-income urban areas have an even greater prevalence of asthma and a greater risk of asthma-related morbidity and death than African Americans overall.3,24,25 Urban areas typically have a high proportion of residents living at or below the poverty level, and minorities often constitute a substantial proportion of the population in these areas. Evidence suggests that both African American race and lower socioeconomic status are independent risk factors for asthma prevalence, morbidity, and death.3,25

To provide better care for African Americans living in low-income urban areas, it is important to understand the factors that may be contributing to the higher morbidity and mortality rates in low-income urban areas.

Inadequate follow-up

Proper and routine follow-up for evaluation of asthma symptoms is essential for appropriate management. The Expert Panel Report 3 (EPR-3) of the National Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma,26 published in 2007, recommends that patients be seen at least every 6 months if they have been experiencing good control. While gaining control, patients should be seen every 2 to 6 weeks.26

Despite these recommendations, numerous studies have suggested that African Americans do not receive adequate follow-up. Children who are poor, are nonwhite or Hispanic, or are underinsured are more likely to lack routine health care27 and, more specifically, routine asthma care.28 Low-income patients are also more likely to receive care in a large hospital-run clinic or neighborhood clinic,27,28 where continuity of care may be less than ideal.29 Even among patients enrolled in Medicaid or Medicare, African American children with a primary care provider have fewer asthma visits compared with white Medicaid-insured children.30

Insufficient follow-up care contributes to greater asthma morbidity, resulting in, for example, more emergency department visits for asthma in African Americans.27,31,32

Suboptimal care

Data also suggest that the quality of care that residents of low-income urban areas receive is often suboptimal. Many people living in low-income urban areas are not provided with the knowledge and tools to treat asthma exacerbations at home.33 African Americans are also less likely to be seen by an asthma specialist31,34 as recommended for those with moderate or severe asthma.26

The EPR-3 guidelines also stress the importance of inhaled corticosteroids as the preferred therapy for all patients with persistent asthma. Even after controlling for the number of primary care visits, insurance status, and disease severity, African Americans are less likely to receive a prescription for inhaled corticosteroids, or they receive the same dosage of inhaled corticosteroids in the face of more severe disease.31,33,35,36

The reasons for these differences in treatment are not fully understood but are likely multiple. Lack of access to an asthma specialist and financial or formulary constraints are some of the potential barriers to optimal asthma care outcomes.

Misdiagnosis in the acute setting may also be a source of less-than-ideal care, as patients seen in emergency departments may be misdiagnosed with viral infection or bronchitis.

African Americans may report different symptoms than whites

Intriguing studies suggest that African Americans report different symptoms while describing asthma exacerbations.

In one study, compared with whites, African Americans were less likely to report nocturnal symptoms, dyspnea, or chest pain during exacerbations.37 In another study, when given a methacholine challenge that induced a significant drop in forced expiratory volume in 1 second (FEV1), African Americans with asthma were more likely to complain of upper airway symptoms as opposed to lower airway symptoms, compared with white patients.38

The symptoms that African Americans describe, such as having a tight throat or voice, are not typically regarded as related to asthma; for this reason, such descriptions may be an obstacle to correct diagnosis, management, and follow-up.

Asthma care providers should be aware of these observations to ensure that their patients are managed appropriately.

Lack of social support

Living in a low-income urban area presents many challenges that can interfere with proper asthma control.

Asthma diagnosis, management, and morbidity are affected by family support.39 Patients with asthma who lack sufficient financial support for treatment, who lack adequate psychological support, and who have more major life stressors are at higher risk of untoward outcomes. Disruption and dysfunction of the family and the supports available have been associated with greater asthma morbidity.40–42 Unfortunately, these types of stressors are all too common in families living in low-income urban areas.43–45

Multiple stressors that can occur more often in low-income urban areas, including exposure to violent crime, have also been linked to greater asthma morbidity.45–47

POOR PHYSICIAN-PATIENT COMMUNICATION

A consistent theme in focus groups of African Americans living in inner-city areas is the perception that health care providers are not effectively communicating and taking the time to listen to their concerns.48,49 Respondents believed they had better insight into their illness than their providers, and for this reason were better able to manage their disease.

The importance of an optimal provider-patient relationship was highlighted by a prospective cohort study in which Medicaid children receiving care at physician’s offices with the highest cultural competency scores were more adherent with their asthma controller medications.50

 

 

MEDICATION ADHERENCE RATES ARE DISTURBINGLY LOW

Rates of medication adherence for chronic diseases is disturbingly low, and may be even worse for pulmonary diseases.51 Reported rates of adherence to asthma medications among all patients range from 50% to 60%.52,53 Several studies showed that African Americans have a lower rate of adherence than do whites,53–55 even after adjusting for multiple socioeconomic variables.56

Many explanations have been proposed for this discrepancy, and all likely play a role in particular environments. For example, the incidence of crime in the surrounding area was inversely related to medication adherence after adjusting for socioeconomic factors.57 African Americans may have more concern about side effects associated with inhaled corticosteroid use and may be less likely to understand how these drugs work.52,53 A poor provider-patient relationship has also been cited as a barrier to adherence.55,57 Finally, physicians are more likely to underestimate asthma severity in an African American patient than in a white patient.58

Taking the time to ensure that patients truly understand all aspects of their disease and establishing a health care environment that is culturally appropriate may have a significant impact in patients with asthma.

ENVIRONMENTAL EXPOSURES

Air quality contributes to the greater asthma morbidity observed in urban residents, including African Americans. While poor outdoor air quality has not been clearly linked to a higher incidence of asthma, it has been associated with greater asthma morbidity. Poor air quality may affect individuals of all races, but with respect to ambient pollutants such as particulate matter and diesel exhaust, outdoor air quality is worse in urban environments where greater proportions of people of low socioeconomic status reside.59,60

The most extensively studied components of air pollution are ozone, sulfur dioxide, and particulate matter. These pollutants have been associated with a higher rate of emergency department visits,61,62 worse asthma symptoms,63,64 and higher exhaled nitric oxide levels.65

Tobacco smoke

Despite the substantial success of smoking cessation efforts nationwide, exposure to tobacco smoke continues to be common and is a significant risk factor for poor asthma control. Recent data suggest that African Americans and whites have a similar prevalence of smoking,66 but a study found a very high prevalence in low-income African Americans.67

Active smoking has been associated with worse asthma control and a higher risk of death.68 People with asthma who smoke are less likely to improve in their lung function and symptom scores when treated with short courses of oral glucocorticoids compared with both nonsmokers and former smokers.69

Secondhand smoke hurts too. Many children living in low-income urban areas are exposed to secondhand smoke or environmental tobacco smoke.70,71 Passive exposure in children has been associated with worse asthma outcomes, and data suggest such exposure may be a cause of asthma.68,72–74

Environmental tobacco smoke has also been implicated in gene-environment interactions. Patients who are either homozygous or heterozygous for the Arg allele at codon 16 of the ADRB2 gene (discussed above) had significantly lower FEV1 and forced vital capacity (FVC) values when exposed to passive tobacco smoke. This difference was not seen in people who were not exposed.75

Cockroach allergen

The type and condition of a person’s housing also plays a role in asthma-related morbidity and death. Across several socioeconomic levels, it has been suggested that African Americans have poorer-quality housing compared with whites.76 Some of the conditions found in low-quality houses, such as interruptions in heat, plumbing leaks, and the presence of rodents, have been associated with a higher prevalence of asthma in the household.77

Cockroach allergen exposure and sensitization is a major contributor to asthma morbidity in African Americans, particularly those living in poorer urban areas where cockroach allergen may be the most common indoor allergen.8 Living in older housing in urban areas is associated with higher exposure to cockroach allergen, and with subsequent sensitization.78,79 Exposure to high levels of the major cockroach allergen, Bla g 1, in sensitized individuals has been linked to a greater risk of hospitalization and unscheduled medical visits for asthma. This was not found to be the case for other common indoor allergens, such as dust mite and cat dander.8

However, it is not only exposure to high cockroach allergen levels that puts African Americans at risk. African Americans living in low-income urban areas may also be more likely than whites living in low-income urban areas to become sensitized to cockroach allergen.7,80 This suggests a gene-environment interaction that may be unique to African Americans. Moreover, cockroach sensitization may occur early in life.81,82

While successful cockroach avoidance measures and environmental control may be challenging, such measures have been shown to decrease rates of asthma morbidity.83

OBESITY

Obesity has been linked to an ever-growing list of diseases, one of which is asthma. Obesity is not a unique challenge for African Americans, but recent data from the US Centers for Disease Control and Prevention show that African Americans have a 51% higher prevalence of obesity compared with whites.84

Obesity is a risk factor for greater asthma morbidity and is a significant challenge in the African American community. The rise in obesity rates has paralleled the rise in asthma in recent decades. The higher one’s body mass index, the higher one’s risk of asthma.85 This association appears to be stronger in people without concurrent atopic disease.86 Obesity has also been associated with a poorer response to inhaled corticosteroids and a higher risk of asthma exacerbations.87 Interestingly, significant weight loss has been associated with improvements in both asthma control and lung function.88,89

 

 

What is the mechanism?

The underlying pathogenic mechanisms have not been completely elucidated, and they are likely multiple.

Adipokines (cytokines secreted by adipocytes) have been implicated. Two of the most extensively studied adipokines are leptin and adiponectin. Leptin production is increased in obesity, and it has inflammatory effects on both the innate and adaptive immune systems.90 The opposite is true for adiponectin, which may have anti-inflammatory properties and which decreases as the body mass index increases.90 The precise role these molecules may have in lung disease is undergoing further investigation.

Mechanical alterations in lung function may also contribute. Obese people have a lower functional residual capacity and expiratory reserve volume. Breathing with a lower-volume functional residual capacity results in decreased airway diameter and contributes to increased airway resistance.90 The decreased airway diameter may alter the contractile properties of airway smooth muscle and lead to increased airway responsiveness.90 These differences are in addition to the lower mean values of common spirometry indices such as the FEV1 and FVC, found in nonasthmatic African Americans compared with whites.91

Data suggest these differences are primarily due to anthropometric factors, with nutritional and environmental factors playing a less significant role.92 On this basis, the American Thoracic Society recommends applying race-specific reference standards for use with spirometry in order to accurately gauge lung function in African Americans.

APPROPRIATE CARE AND EDUCATION

The cause of greater asthma prevalence and severity among African Americans is multifactorial. It is likely that a number of factors work together, rather than separately, in influencing the development of asthma and its course.

Some risk factors are avoidable, and it is important to identify and ameliorate them. Others are not preventable, but knowledge of them may provide more specific management strategies and may lead to new therapies in the future.

While more work is needed to further unravel the complex risk factors associated with asthma, ensuring that higher-risk patients are provided the appropriate care and the knowledge to help control their disease is a necessary step in improving the disparities in asthma care outcomes.

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  70. Wilson SE, Kahn RS, Khoury J, Lanphear BP. Racial differences in exposure to environmental tobacco smoke among children. Environ Health Perspect 2005; 113:362–367.
  71. Huss K, Rand CS, Butz AM, et al. Home environmental risk factors in urban minority asthmatic children. Ann Allergy 1994; 72:173–177.
  72. Samir S, Colin Y, Thomas S. Impact of environmental tobacco smoke on children admitted with status asthmaticus in the pediatric intensive care unit. Pediatr Pulmonol 2010. [Epub ahead of print]
  73. Lannerö E, Wickman M, Pershagen G, Nordvall L. Maternal smoking during pregnancy increases the risk of recurrent wheezing during the first years of life (BAMSE). Respir Res 2006; 7:3.
  74. Hedman L, Bjerg A, Sundberg S, Forsberg B, Rönmark E. Both environmental tobacco smoke and personal smoking is related to asthma and wheeze in teenagers. Thorax 2011; 66:20–25.
  75. Zhang G, Hayden CM, Khoo SK, et al. Beta2-adrenoceptor polymorphisms and asthma phenotypes: interactions with passive smoking. Eur Respir J 2007; 30:48–55.
  76. Rosenbaum E, Friedman S. The Housing Divide: How Generations of Immigrants Fare in New York’s Housing Market. New York, NY: New York University Press; 2007.
  77. Rosenbaum E. Racial/ethnic differences in asthma prevalence: the role of housing and neighborhood environments. J Health Soc Behav 2008; 49:131–145.
  78. Rauh VA, Chew GR, Garfinkel RS. Deteriorated housing contributes to high cockroach allergen levels in inner-city households. Environ Health Perspect 2002; 110( suppl 2):323–327.
  79. Eggleston PA, Rosenstreich D, Lynn H, et al. Relationship of indoor allergen exposure to skin test sensitivity in inner-city children with asthma. J Allergy Clin Immunol 1998; 102:563–570.
  80. Togias A, Horowitz E, Joyner D, Guydon L, Malveaux F. Evaluating the factors that relate to asthma severity in adolescents. Int Arch Allergy Immunol 1997; 113:87–95.
  81. Alp H, Yu BH, Grant EN, Rao V, Moy JN. Cockroach allergy appears early in life in inner-city children with recurrent wheezing. Ann Allergy Asthma Immunol 2001; 86:51–54.
  82. Miller RL, Chew GL, Bell CA, et al. Prenatal exposure, maternal sensitization, and sensitization in utero to indoor allergens in an inner-city cohort. Am J Respir Crit Care Med 2001; 164:995–1001.
  83. Morgan WJ, Crain EF, Gruchalla RS, et al; Inner-City Asthma Study Group. Results of a home-based environmental intervention among urban children with asthma. N Engl J Med 2004; 351:1068–1080.
  84. Centers for Disease Control and Prevention (CDC). Overweight and Obesity. US Obesity Trends. http://templatelab.com/us-obesity-trends/. Accessed February 1, 2012.
  85. Beuther DA, Sutherland ER. Overweight, obesity, and incident asthma: a meta-analysis of prospective epidemiologic studies. Am J Respir Crit Care Med 2007; 175:661–666.
  86. Visness CM, London SJ, Daniels JL, et al. Association of childhood obesity with atopic and nonatopic asthma: results from the National Health and Nutrition Examination Survey 1999–2006. J Asthma 2010; 47:822–829.
  87. Camargo CA, Sutherland ER, Bailey W, et al. Effect of increased body mass index on asthma risk, impairment and response to asthma controller therapy in African Americans. Curr Med Res Opin 2010; 26:1629–1635.
  88. Hakala K, Stenius-Aarniala B, Sovijärvi A. Effects of weight loss on peak flow variability, airways obstruction, and lung volumes in obese patients with asthma. Chest 2000; 118:1315–1321.
  89. Stenius-Aarniala B, Poussa T, Kvarnström J, Grönlund EL, Ylikahri M, Mustajoki P. Immediate and long term effects of weight reduction in obese people with asthma: randomised controlled study. BMJ 2000; 320:827–832.
  90. Dixon AE, Holguin F, Sood A, et al; American Thoracic Society Ad Hoc Subcommittee on Obesity and Lung Disease. An official American Thoracic Society Workshop report: obesity and asthma. Proc Am Thorac Soc 2010; 7:325–335.
  91. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med 1999; 159:179–187.
  92. Harik-Khan RI, Muller DC, Wise RA. Racial difference in lung function in African-American and white children: effect of anthropometric, socioeconomic, nutritional, and environmental factors. Am J Epidemiol 2004; 160:893–900.
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Section of Allergy/Immunology, Respiratory Institute, Cleveland Clinic

David M. Lang, MD
Co-Director, Asthma Center, and Head, Section of Allergy/Immunology, Respiratory Institute, Cleveland Clinic

Address: David M. Lang, MD, Respiratory Institute, A90, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail langd@ccf.org

Dr. Lang has disclosed teaching and speaking for Genentech/Novartis, Glaxo SmithKline, Merck, and Teva.

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Section of Allergy/Immunology, Respiratory Institute, Cleveland Clinic

David M. Lang, MD
Co-Director, Asthma Center, and Head, Section of Allergy/Immunology, Respiratory Institute, Cleveland Clinic

Address: David M. Lang, MD, Respiratory Institute, A90, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail langd@ccf.org

Dr. Lang has disclosed teaching and speaking for Genentech/Novartis, Glaxo SmithKline, Merck, and Teva.

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Section of Allergy/Immunology, Respiratory Institute, Cleveland Clinic

David M. Lang, MD
Co-Director, Asthma Center, and Head, Section of Allergy/Immunology, Respiratory Institute, Cleveland Clinic

Address: David M. Lang, MD, Respiratory Institute, A90, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail langd@ccf.org

Dr. Lang has disclosed teaching and speaking for Genentech/Novartis, Glaxo SmithKline, Merck, and Teva.

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The last several decades have seen a dramatic surge in the prevalence of asthma. In 2009, there were an estimated 17.5 million adults and almost 7.1 million children with asthma in the United States,1 up from 9.5 million adults and slightly more than 5 million children in 1995.2

Figure 1.
While better management has reduced the rates of asthma morbidity and death in recent years, specific groups remain at higher risk of poor outcomes. Compared with whites, African Americans are not only more likely to have asthma, but they often also have more severe disease. For example, in a study in Philadelphia, PA, at all levels of poverty, asthma hospitalization rates for African Americans were substantially higher than for whites.3 African Americans with asthma are also more likely to die of asthma (Figure 1).

Multiple factors contribute to these disparities, including genetics, socioeconomic factors, cultural factors, health maintenance behaviors, provider-patient communication, air quality, and obesity.

This article is based on a literature review with PubMed conducted in November 2010 using combinations of the following search terms: African American, asthma, epidemiology, genetics, obesity, and environment. Below, we review the evidence regarding a number of these factors (Table 1) and their association with the higher asthma prevalence, morbidity, and mortality rates in African Americans.

GENETICS: 70% OF DESTINY?

The trend towards personalized medicine has spurred extensive research into the genetics of asthma. Studies in twins and familial aggregation studies suggest genetics plays a significant role, with estimates of the heritability of asthma as high as 70%.4,5 More than 100 candidate genes have been shown to be associated with asthma and atopy, 30 of them in five or more independent studies.6

Researchers face many challenges when investigating the genetics involved in asthma for a particular race. Race is both a biologic and a social construct and, as such, is a poor substitute for genetics. Race constitutes not only genetic differences in individuals, but also the behaviors, beliefs, and experiences that vary among races.

The clinical disease—the phenotype—is the product of the interaction of genes and these differing behaviors and exposures. Genetics can affect how environmental factors found in association with socioeconomic factors relate to asthma morbidity and mortality.

For example, as we will discuss below, African Americans are more likely than whites to be sensitized to cockroach allergen, even after controlling for socioeconomic variables that may be associated with greater exposure.7 High-level exposure to cockroach allergen in sensitized children has been associated with poor asthma outcomes.8 This suggests that a genetic difference may exist between African Americans and whites with respect to the potential to develop cockroach sensitization, and this difference may be of particular importance for those African Americans living in areas with higher levels of cockroach exposure.

Two polymorphisms

Two polymorphisms have garnered attention for their influence on African Americans with asthma:

TheADRB2gene. This gene codes for the beta-2 adrenergic receptor and resides at chromosome 5q13.9 The receptor is found on several types of cells in the lung, including airway smooth muscle and epithelial cells, and is responsible for the salutary effects of inhaled beta-2 agonists such as albuterol (eg, Proventil).

Allelic polymorphisms of this gene are clinically relevant. The substitution of arginine (Arg) for glycine (Gly) at codon 16 of this gene is responsible for differences in response to short-acting beta-2 agonists. The allelic frequency of Arg16 is lower in white Americans (39.3%) than in African Americans (49.2%), and thus African Americans are more likely to be homozygous for Arg16 (ie, to have the Arg/Arg genotype).10

People who are homozygous for Arg16 who use albuterol on a regular basis are at higher risk of untoward asthma outcomes.11 This is important, for several reasons. In general, adherence to inhaled corticosteroids is poor (not only in African Americans),12 and patients who do not take their inhaled corticosteroids as they should may rely on short-acting beta-2 agonists more frequently. Furthermore, African Americans may have a poorer response to the repeated doses of albuterol that are typically given in the emergency department and in the hospital for severe asthma exacerbations.13 Additionally, data suggest that Arg/Arg individuals have more frequent exacerbations independent of beta-agonist use,14 although curiously, patients who are homozygous for Arg16 have a greater benefit from single doses of short-acting beta-2 agonists than those who are Gly16 homozygous.15

TheCD14gene. An interesting relationship between innate immunity and asthma has recently been described. Polymorphisms of CD14, which codes for a receptor for endotoxin, have been uncovered. The single-nucleotide polymorphism variant thymine (T) at position −260 has been found in greater frequency in whites than in African Americans, who are more likely to have the cytosine (C) allele.16 An association between the CC genotype and atopy has been reported,16 although this has not been consistent.17

A possible explanation for these inconsistencies may lie in complex gene-environment interactions. The amount of endotoxin exposure may play a role in phenotypic expression. Individuals with the CC genotype were at lower risk of developing atopy when exposed to high levels of endotoxin; however, when exposed to lower levels of endotoxin, the CC genotype was associated with a higher risk of atopy.18 Nonfarm homes in westernized countries tend to have lower levels of endotoxin than farm homes, even in low-income urban areas.19 This implies that individuals with the CC allele, who are more likely to be African American, would be at greater risk for atopy in the United States. Greater knowledge of these types of gene-environment interactions may lead to improved understanding of the observations that have generated controversy concerning the “hygiene hypothesis.”

The details of how microbial exposure can influence the human immune response to antigen exposure are still being elucidated.20

These examples highlight not only the importance of genetics in the development of asthma, but also the role genes play in variation of treatment response and subsequent risk of morbidity and death. An understanding of these genetic differences among patients is clearly important for moving towards personalized treatment strategies for asthma.

 

 

Ancestry-informative markers

A developing strategy to assess the differences in asthma prevalence, severity, and response to treatment between racial groups is the use of ancestry-informative markers (AIMs).

AIMs are single-nucleotide polymorphisms that occur in varying allelic frequencies between ancestral groups, eg, continental Africans or European whites.21 AIMs provide an estimate of an individual’s proportion of ancestry—ie, of how “African” an African American is genetically.

African ancestry, determined using AIMs, was found to be associated with asthma in people living on the Caribbean coast of Colombia.22 However, one study found that AIMs could not predict an individual’s response to inhaled corticosteroids.23

Further research is necessary to find a technique to determine how groups of individuals can be characterized more precisely and managed more appropriately.

SOCIOECONOMIC FACTORS

African Americans living in low-income urban areas have an even greater prevalence of asthma and a greater risk of asthma-related morbidity and death than African Americans overall.3,24,25 Urban areas typically have a high proportion of residents living at or below the poverty level, and minorities often constitute a substantial proportion of the population in these areas. Evidence suggests that both African American race and lower socioeconomic status are independent risk factors for asthma prevalence, morbidity, and death.3,25

To provide better care for African Americans living in low-income urban areas, it is important to understand the factors that may be contributing to the higher morbidity and mortality rates in low-income urban areas.

Inadequate follow-up

Proper and routine follow-up for evaluation of asthma symptoms is essential for appropriate management. The Expert Panel Report 3 (EPR-3) of the National Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma,26 published in 2007, recommends that patients be seen at least every 6 months if they have been experiencing good control. While gaining control, patients should be seen every 2 to 6 weeks.26

Despite these recommendations, numerous studies have suggested that African Americans do not receive adequate follow-up. Children who are poor, are nonwhite or Hispanic, or are underinsured are more likely to lack routine health care27 and, more specifically, routine asthma care.28 Low-income patients are also more likely to receive care in a large hospital-run clinic or neighborhood clinic,27,28 where continuity of care may be less than ideal.29 Even among patients enrolled in Medicaid or Medicare, African American children with a primary care provider have fewer asthma visits compared with white Medicaid-insured children.30

Insufficient follow-up care contributes to greater asthma morbidity, resulting in, for example, more emergency department visits for asthma in African Americans.27,31,32

Suboptimal care

Data also suggest that the quality of care that residents of low-income urban areas receive is often suboptimal. Many people living in low-income urban areas are not provided with the knowledge and tools to treat asthma exacerbations at home.33 African Americans are also less likely to be seen by an asthma specialist31,34 as recommended for those with moderate or severe asthma.26

The EPR-3 guidelines also stress the importance of inhaled corticosteroids as the preferred therapy for all patients with persistent asthma. Even after controlling for the number of primary care visits, insurance status, and disease severity, African Americans are less likely to receive a prescription for inhaled corticosteroids, or they receive the same dosage of inhaled corticosteroids in the face of more severe disease.31,33,35,36

The reasons for these differences in treatment are not fully understood but are likely multiple. Lack of access to an asthma specialist and financial or formulary constraints are some of the potential barriers to optimal asthma care outcomes.

Misdiagnosis in the acute setting may also be a source of less-than-ideal care, as patients seen in emergency departments may be misdiagnosed with viral infection or bronchitis.

African Americans may report different symptoms than whites

Intriguing studies suggest that African Americans report different symptoms while describing asthma exacerbations.

In one study, compared with whites, African Americans were less likely to report nocturnal symptoms, dyspnea, or chest pain during exacerbations.37 In another study, when given a methacholine challenge that induced a significant drop in forced expiratory volume in 1 second (FEV1), African Americans with asthma were more likely to complain of upper airway symptoms as opposed to lower airway symptoms, compared with white patients.38

The symptoms that African Americans describe, such as having a tight throat or voice, are not typically regarded as related to asthma; for this reason, such descriptions may be an obstacle to correct diagnosis, management, and follow-up.

Asthma care providers should be aware of these observations to ensure that their patients are managed appropriately.

Lack of social support

Living in a low-income urban area presents many challenges that can interfere with proper asthma control.

Asthma diagnosis, management, and morbidity are affected by family support.39 Patients with asthma who lack sufficient financial support for treatment, who lack adequate psychological support, and who have more major life stressors are at higher risk of untoward outcomes. Disruption and dysfunction of the family and the supports available have been associated with greater asthma morbidity.40–42 Unfortunately, these types of stressors are all too common in families living in low-income urban areas.43–45

Multiple stressors that can occur more often in low-income urban areas, including exposure to violent crime, have also been linked to greater asthma morbidity.45–47

POOR PHYSICIAN-PATIENT COMMUNICATION

A consistent theme in focus groups of African Americans living in inner-city areas is the perception that health care providers are not effectively communicating and taking the time to listen to their concerns.48,49 Respondents believed they had better insight into their illness than their providers, and for this reason were better able to manage their disease.

The importance of an optimal provider-patient relationship was highlighted by a prospective cohort study in which Medicaid children receiving care at physician’s offices with the highest cultural competency scores were more adherent with their asthma controller medications.50

 

 

MEDICATION ADHERENCE RATES ARE DISTURBINGLY LOW

Rates of medication adherence for chronic diseases is disturbingly low, and may be even worse for pulmonary diseases.51 Reported rates of adherence to asthma medications among all patients range from 50% to 60%.52,53 Several studies showed that African Americans have a lower rate of adherence than do whites,53–55 even after adjusting for multiple socioeconomic variables.56

Many explanations have been proposed for this discrepancy, and all likely play a role in particular environments. For example, the incidence of crime in the surrounding area was inversely related to medication adherence after adjusting for socioeconomic factors.57 African Americans may have more concern about side effects associated with inhaled corticosteroid use and may be less likely to understand how these drugs work.52,53 A poor provider-patient relationship has also been cited as a barrier to adherence.55,57 Finally, physicians are more likely to underestimate asthma severity in an African American patient than in a white patient.58

Taking the time to ensure that patients truly understand all aspects of their disease and establishing a health care environment that is culturally appropriate may have a significant impact in patients with asthma.

ENVIRONMENTAL EXPOSURES

Air quality contributes to the greater asthma morbidity observed in urban residents, including African Americans. While poor outdoor air quality has not been clearly linked to a higher incidence of asthma, it has been associated with greater asthma morbidity. Poor air quality may affect individuals of all races, but with respect to ambient pollutants such as particulate matter and diesel exhaust, outdoor air quality is worse in urban environments where greater proportions of people of low socioeconomic status reside.59,60

The most extensively studied components of air pollution are ozone, sulfur dioxide, and particulate matter. These pollutants have been associated with a higher rate of emergency department visits,61,62 worse asthma symptoms,63,64 and higher exhaled nitric oxide levels.65

Tobacco smoke

Despite the substantial success of smoking cessation efforts nationwide, exposure to tobacco smoke continues to be common and is a significant risk factor for poor asthma control. Recent data suggest that African Americans and whites have a similar prevalence of smoking,66 but a study found a very high prevalence in low-income African Americans.67

Active smoking has been associated with worse asthma control and a higher risk of death.68 People with asthma who smoke are less likely to improve in their lung function and symptom scores when treated with short courses of oral glucocorticoids compared with both nonsmokers and former smokers.69

Secondhand smoke hurts too. Many children living in low-income urban areas are exposed to secondhand smoke or environmental tobacco smoke.70,71 Passive exposure in children has been associated with worse asthma outcomes, and data suggest such exposure may be a cause of asthma.68,72–74

Environmental tobacco smoke has also been implicated in gene-environment interactions. Patients who are either homozygous or heterozygous for the Arg allele at codon 16 of the ADRB2 gene (discussed above) had significantly lower FEV1 and forced vital capacity (FVC) values when exposed to passive tobacco smoke. This difference was not seen in people who were not exposed.75

Cockroach allergen

The type and condition of a person’s housing also plays a role in asthma-related morbidity and death. Across several socioeconomic levels, it has been suggested that African Americans have poorer-quality housing compared with whites.76 Some of the conditions found in low-quality houses, such as interruptions in heat, plumbing leaks, and the presence of rodents, have been associated with a higher prevalence of asthma in the household.77

Cockroach allergen exposure and sensitization is a major contributor to asthma morbidity in African Americans, particularly those living in poorer urban areas where cockroach allergen may be the most common indoor allergen.8 Living in older housing in urban areas is associated with higher exposure to cockroach allergen, and with subsequent sensitization.78,79 Exposure to high levels of the major cockroach allergen, Bla g 1, in sensitized individuals has been linked to a greater risk of hospitalization and unscheduled medical visits for asthma. This was not found to be the case for other common indoor allergens, such as dust mite and cat dander.8

However, it is not only exposure to high cockroach allergen levels that puts African Americans at risk. African Americans living in low-income urban areas may also be more likely than whites living in low-income urban areas to become sensitized to cockroach allergen.7,80 This suggests a gene-environment interaction that may be unique to African Americans. Moreover, cockroach sensitization may occur early in life.81,82

While successful cockroach avoidance measures and environmental control may be challenging, such measures have been shown to decrease rates of asthma morbidity.83

OBESITY

Obesity has been linked to an ever-growing list of diseases, one of which is asthma. Obesity is not a unique challenge for African Americans, but recent data from the US Centers for Disease Control and Prevention show that African Americans have a 51% higher prevalence of obesity compared with whites.84

Obesity is a risk factor for greater asthma morbidity and is a significant challenge in the African American community. The rise in obesity rates has paralleled the rise in asthma in recent decades. The higher one’s body mass index, the higher one’s risk of asthma.85 This association appears to be stronger in people without concurrent atopic disease.86 Obesity has also been associated with a poorer response to inhaled corticosteroids and a higher risk of asthma exacerbations.87 Interestingly, significant weight loss has been associated with improvements in both asthma control and lung function.88,89

 

 

What is the mechanism?

The underlying pathogenic mechanisms have not been completely elucidated, and they are likely multiple.

Adipokines (cytokines secreted by adipocytes) have been implicated. Two of the most extensively studied adipokines are leptin and adiponectin. Leptin production is increased in obesity, and it has inflammatory effects on both the innate and adaptive immune systems.90 The opposite is true for adiponectin, which may have anti-inflammatory properties and which decreases as the body mass index increases.90 The precise role these molecules may have in lung disease is undergoing further investigation.

Mechanical alterations in lung function may also contribute. Obese people have a lower functional residual capacity and expiratory reserve volume. Breathing with a lower-volume functional residual capacity results in decreased airway diameter and contributes to increased airway resistance.90 The decreased airway diameter may alter the contractile properties of airway smooth muscle and lead to increased airway responsiveness.90 These differences are in addition to the lower mean values of common spirometry indices such as the FEV1 and FVC, found in nonasthmatic African Americans compared with whites.91

Data suggest these differences are primarily due to anthropometric factors, with nutritional and environmental factors playing a less significant role.92 On this basis, the American Thoracic Society recommends applying race-specific reference standards for use with spirometry in order to accurately gauge lung function in African Americans.

APPROPRIATE CARE AND EDUCATION

The cause of greater asthma prevalence and severity among African Americans is multifactorial. It is likely that a number of factors work together, rather than separately, in influencing the development of asthma and its course.

Some risk factors are avoidable, and it is important to identify and ameliorate them. Others are not preventable, but knowledge of them may provide more specific management strategies and may lead to new therapies in the future.

While more work is needed to further unravel the complex risk factors associated with asthma, ensuring that higher-risk patients are provided the appropriate care and the knowledge to help control their disease is a necessary step in improving the disparities in asthma care outcomes.

The last several decades have seen a dramatic surge in the prevalence of asthma. In 2009, there were an estimated 17.5 million adults and almost 7.1 million children with asthma in the United States,1 up from 9.5 million adults and slightly more than 5 million children in 1995.2

Figure 1.
While better management has reduced the rates of asthma morbidity and death in recent years, specific groups remain at higher risk of poor outcomes. Compared with whites, African Americans are not only more likely to have asthma, but they often also have more severe disease. For example, in a study in Philadelphia, PA, at all levels of poverty, asthma hospitalization rates for African Americans were substantially higher than for whites.3 African Americans with asthma are also more likely to die of asthma (Figure 1).

Multiple factors contribute to these disparities, including genetics, socioeconomic factors, cultural factors, health maintenance behaviors, provider-patient communication, air quality, and obesity.

This article is based on a literature review with PubMed conducted in November 2010 using combinations of the following search terms: African American, asthma, epidemiology, genetics, obesity, and environment. Below, we review the evidence regarding a number of these factors (Table 1) and their association with the higher asthma prevalence, morbidity, and mortality rates in African Americans.

GENETICS: 70% OF DESTINY?

The trend towards personalized medicine has spurred extensive research into the genetics of asthma. Studies in twins and familial aggregation studies suggest genetics plays a significant role, with estimates of the heritability of asthma as high as 70%.4,5 More than 100 candidate genes have been shown to be associated with asthma and atopy, 30 of them in five or more independent studies.6

Researchers face many challenges when investigating the genetics involved in asthma for a particular race. Race is both a biologic and a social construct and, as such, is a poor substitute for genetics. Race constitutes not only genetic differences in individuals, but also the behaviors, beliefs, and experiences that vary among races.

The clinical disease—the phenotype—is the product of the interaction of genes and these differing behaviors and exposures. Genetics can affect how environmental factors found in association with socioeconomic factors relate to asthma morbidity and mortality.

For example, as we will discuss below, African Americans are more likely than whites to be sensitized to cockroach allergen, even after controlling for socioeconomic variables that may be associated with greater exposure.7 High-level exposure to cockroach allergen in sensitized children has been associated with poor asthma outcomes.8 This suggests that a genetic difference may exist between African Americans and whites with respect to the potential to develop cockroach sensitization, and this difference may be of particular importance for those African Americans living in areas with higher levels of cockroach exposure.

Two polymorphisms

Two polymorphisms have garnered attention for their influence on African Americans with asthma:

TheADRB2gene. This gene codes for the beta-2 adrenergic receptor and resides at chromosome 5q13.9 The receptor is found on several types of cells in the lung, including airway smooth muscle and epithelial cells, and is responsible for the salutary effects of inhaled beta-2 agonists such as albuterol (eg, Proventil).

Allelic polymorphisms of this gene are clinically relevant. The substitution of arginine (Arg) for glycine (Gly) at codon 16 of this gene is responsible for differences in response to short-acting beta-2 agonists. The allelic frequency of Arg16 is lower in white Americans (39.3%) than in African Americans (49.2%), and thus African Americans are more likely to be homozygous for Arg16 (ie, to have the Arg/Arg genotype).10

People who are homozygous for Arg16 who use albuterol on a regular basis are at higher risk of untoward asthma outcomes.11 This is important, for several reasons. In general, adherence to inhaled corticosteroids is poor (not only in African Americans),12 and patients who do not take their inhaled corticosteroids as they should may rely on short-acting beta-2 agonists more frequently. Furthermore, African Americans may have a poorer response to the repeated doses of albuterol that are typically given in the emergency department and in the hospital for severe asthma exacerbations.13 Additionally, data suggest that Arg/Arg individuals have more frequent exacerbations independent of beta-agonist use,14 although curiously, patients who are homozygous for Arg16 have a greater benefit from single doses of short-acting beta-2 agonists than those who are Gly16 homozygous.15

TheCD14gene. An interesting relationship between innate immunity and asthma has recently been described. Polymorphisms of CD14, which codes for a receptor for endotoxin, have been uncovered. The single-nucleotide polymorphism variant thymine (T) at position −260 has been found in greater frequency in whites than in African Americans, who are more likely to have the cytosine (C) allele.16 An association between the CC genotype and atopy has been reported,16 although this has not been consistent.17

A possible explanation for these inconsistencies may lie in complex gene-environment interactions. The amount of endotoxin exposure may play a role in phenotypic expression. Individuals with the CC genotype were at lower risk of developing atopy when exposed to high levels of endotoxin; however, when exposed to lower levels of endotoxin, the CC genotype was associated with a higher risk of atopy.18 Nonfarm homes in westernized countries tend to have lower levels of endotoxin than farm homes, even in low-income urban areas.19 This implies that individuals with the CC allele, who are more likely to be African American, would be at greater risk for atopy in the United States. Greater knowledge of these types of gene-environment interactions may lead to improved understanding of the observations that have generated controversy concerning the “hygiene hypothesis.”

The details of how microbial exposure can influence the human immune response to antigen exposure are still being elucidated.20

These examples highlight not only the importance of genetics in the development of asthma, but also the role genes play in variation of treatment response and subsequent risk of morbidity and death. An understanding of these genetic differences among patients is clearly important for moving towards personalized treatment strategies for asthma.

 

 

Ancestry-informative markers

A developing strategy to assess the differences in asthma prevalence, severity, and response to treatment between racial groups is the use of ancestry-informative markers (AIMs).

AIMs are single-nucleotide polymorphisms that occur in varying allelic frequencies between ancestral groups, eg, continental Africans or European whites.21 AIMs provide an estimate of an individual’s proportion of ancestry—ie, of how “African” an African American is genetically.

African ancestry, determined using AIMs, was found to be associated with asthma in people living on the Caribbean coast of Colombia.22 However, one study found that AIMs could not predict an individual’s response to inhaled corticosteroids.23

Further research is necessary to find a technique to determine how groups of individuals can be characterized more precisely and managed more appropriately.

SOCIOECONOMIC FACTORS

African Americans living in low-income urban areas have an even greater prevalence of asthma and a greater risk of asthma-related morbidity and death than African Americans overall.3,24,25 Urban areas typically have a high proportion of residents living at or below the poverty level, and minorities often constitute a substantial proportion of the population in these areas. Evidence suggests that both African American race and lower socioeconomic status are independent risk factors for asthma prevalence, morbidity, and death.3,25

To provide better care for African Americans living in low-income urban areas, it is important to understand the factors that may be contributing to the higher morbidity and mortality rates in low-income urban areas.

Inadequate follow-up

Proper and routine follow-up for evaluation of asthma symptoms is essential for appropriate management. The Expert Panel Report 3 (EPR-3) of the National Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma,26 published in 2007, recommends that patients be seen at least every 6 months if they have been experiencing good control. While gaining control, patients should be seen every 2 to 6 weeks.26

Despite these recommendations, numerous studies have suggested that African Americans do not receive adequate follow-up. Children who are poor, are nonwhite or Hispanic, or are underinsured are more likely to lack routine health care27 and, more specifically, routine asthma care.28 Low-income patients are also more likely to receive care in a large hospital-run clinic or neighborhood clinic,27,28 where continuity of care may be less than ideal.29 Even among patients enrolled in Medicaid or Medicare, African American children with a primary care provider have fewer asthma visits compared with white Medicaid-insured children.30

Insufficient follow-up care contributes to greater asthma morbidity, resulting in, for example, more emergency department visits for asthma in African Americans.27,31,32

Suboptimal care

Data also suggest that the quality of care that residents of low-income urban areas receive is often suboptimal. Many people living in low-income urban areas are not provided with the knowledge and tools to treat asthma exacerbations at home.33 African Americans are also less likely to be seen by an asthma specialist31,34 as recommended for those with moderate or severe asthma.26

The EPR-3 guidelines also stress the importance of inhaled corticosteroids as the preferred therapy for all patients with persistent asthma. Even after controlling for the number of primary care visits, insurance status, and disease severity, African Americans are less likely to receive a prescription for inhaled corticosteroids, or they receive the same dosage of inhaled corticosteroids in the face of more severe disease.31,33,35,36

The reasons for these differences in treatment are not fully understood but are likely multiple. Lack of access to an asthma specialist and financial or formulary constraints are some of the potential barriers to optimal asthma care outcomes.

Misdiagnosis in the acute setting may also be a source of less-than-ideal care, as patients seen in emergency departments may be misdiagnosed with viral infection or bronchitis.

African Americans may report different symptoms than whites

Intriguing studies suggest that African Americans report different symptoms while describing asthma exacerbations.

In one study, compared with whites, African Americans were less likely to report nocturnal symptoms, dyspnea, or chest pain during exacerbations.37 In another study, when given a methacholine challenge that induced a significant drop in forced expiratory volume in 1 second (FEV1), African Americans with asthma were more likely to complain of upper airway symptoms as opposed to lower airway symptoms, compared with white patients.38

The symptoms that African Americans describe, such as having a tight throat or voice, are not typically regarded as related to asthma; for this reason, such descriptions may be an obstacle to correct diagnosis, management, and follow-up.

Asthma care providers should be aware of these observations to ensure that their patients are managed appropriately.

Lack of social support

Living in a low-income urban area presents many challenges that can interfere with proper asthma control.

Asthma diagnosis, management, and morbidity are affected by family support.39 Patients with asthma who lack sufficient financial support for treatment, who lack adequate psychological support, and who have more major life stressors are at higher risk of untoward outcomes. Disruption and dysfunction of the family and the supports available have been associated with greater asthma morbidity.40–42 Unfortunately, these types of stressors are all too common in families living in low-income urban areas.43–45

Multiple stressors that can occur more often in low-income urban areas, including exposure to violent crime, have also been linked to greater asthma morbidity.45–47

POOR PHYSICIAN-PATIENT COMMUNICATION

A consistent theme in focus groups of African Americans living in inner-city areas is the perception that health care providers are not effectively communicating and taking the time to listen to their concerns.48,49 Respondents believed they had better insight into their illness than their providers, and for this reason were better able to manage their disease.

The importance of an optimal provider-patient relationship was highlighted by a prospective cohort study in which Medicaid children receiving care at physician’s offices with the highest cultural competency scores were more adherent with their asthma controller medications.50

 

 

MEDICATION ADHERENCE RATES ARE DISTURBINGLY LOW

Rates of medication adherence for chronic diseases is disturbingly low, and may be even worse for pulmonary diseases.51 Reported rates of adherence to asthma medications among all patients range from 50% to 60%.52,53 Several studies showed that African Americans have a lower rate of adherence than do whites,53–55 even after adjusting for multiple socioeconomic variables.56

Many explanations have been proposed for this discrepancy, and all likely play a role in particular environments. For example, the incidence of crime in the surrounding area was inversely related to medication adherence after adjusting for socioeconomic factors.57 African Americans may have more concern about side effects associated with inhaled corticosteroid use and may be less likely to understand how these drugs work.52,53 A poor provider-patient relationship has also been cited as a barrier to adherence.55,57 Finally, physicians are more likely to underestimate asthma severity in an African American patient than in a white patient.58

Taking the time to ensure that patients truly understand all aspects of their disease and establishing a health care environment that is culturally appropriate may have a significant impact in patients with asthma.

ENVIRONMENTAL EXPOSURES

Air quality contributes to the greater asthma morbidity observed in urban residents, including African Americans. While poor outdoor air quality has not been clearly linked to a higher incidence of asthma, it has been associated with greater asthma morbidity. Poor air quality may affect individuals of all races, but with respect to ambient pollutants such as particulate matter and diesel exhaust, outdoor air quality is worse in urban environments where greater proportions of people of low socioeconomic status reside.59,60

The most extensively studied components of air pollution are ozone, sulfur dioxide, and particulate matter. These pollutants have been associated with a higher rate of emergency department visits,61,62 worse asthma symptoms,63,64 and higher exhaled nitric oxide levels.65

Tobacco smoke

Despite the substantial success of smoking cessation efforts nationwide, exposure to tobacco smoke continues to be common and is a significant risk factor for poor asthma control. Recent data suggest that African Americans and whites have a similar prevalence of smoking,66 but a study found a very high prevalence in low-income African Americans.67

Active smoking has been associated with worse asthma control and a higher risk of death.68 People with asthma who smoke are less likely to improve in their lung function and symptom scores when treated with short courses of oral glucocorticoids compared with both nonsmokers and former smokers.69

Secondhand smoke hurts too. Many children living in low-income urban areas are exposed to secondhand smoke or environmental tobacco smoke.70,71 Passive exposure in children has been associated with worse asthma outcomes, and data suggest such exposure may be a cause of asthma.68,72–74

Environmental tobacco smoke has also been implicated in gene-environment interactions. Patients who are either homozygous or heterozygous for the Arg allele at codon 16 of the ADRB2 gene (discussed above) had significantly lower FEV1 and forced vital capacity (FVC) values when exposed to passive tobacco smoke. This difference was not seen in people who were not exposed.75

Cockroach allergen

The type and condition of a person’s housing also plays a role in asthma-related morbidity and death. Across several socioeconomic levels, it has been suggested that African Americans have poorer-quality housing compared with whites.76 Some of the conditions found in low-quality houses, such as interruptions in heat, plumbing leaks, and the presence of rodents, have been associated with a higher prevalence of asthma in the household.77

Cockroach allergen exposure and sensitization is a major contributor to asthma morbidity in African Americans, particularly those living in poorer urban areas where cockroach allergen may be the most common indoor allergen.8 Living in older housing in urban areas is associated with higher exposure to cockroach allergen, and with subsequent sensitization.78,79 Exposure to high levels of the major cockroach allergen, Bla g 1, in sensitized individuals has been linked to a greater risk of hospitalization and unscheduled medical visits for asthma. This was not found to be the case for other common indoor allergens, such as dust mite and cat dander.8

However, it is not only exposure to high cockroach allergen levels that puts African Americans at risk. African Americans living in low-income urban areas may also be more likely than whites living in low-income urban areas to become sensitized to cockroach allergen.7,80 This suggests a gene-environment interaction that may be unique to African Americans. Moreover, cockroach sensitization may occur early in life.81,82

While successful cockroach avoidance measures and environmental control may be challenging, such measures have been shown to decrease rates of asthma morbidity.83

OBESITY

Obesity has been linked to an ever-growing list of diseases, one of which is asthma. Obesity is not a unique challenge for African Americans, but recent data from the US Centers for Disease Control and Prevention show that African Americans have a 51% higher prevalence of obesity compared with whites.84

Obesity is a risk factor for greater asthma morbidity and is a significant challenge in the African American community. The rise in obesity rates has paralleled the rise in asthma in recent decades. The higher one’s body mass index, the higher one’s risk of asthma.85 This association appears to be stronger in people without concurrent atopic disease.86 Obesity has also been associated with a poorer response to inhaled corticosteroids and a higher risk of asthma exacerbations.87 Interestingly, significant weight loss has been associated with improvements in both asthma control and lung function.88,89

 

 

What is the mechanism?

The underlying pathogenic mechanisms have not been completely elucidated, and they are likely multiple.

Adipokines (cytokines secreted by adipocytes) have been implicated. Two of the most extensively studied adipokines are leptin and adiponectin. Leptin production is increased in obesity, and it has inflammatory effects on both the innate and adaptive immune systems.90 The opposite is true for adiponectin, which may have anti-inflammatory properties and which decreases as the body mass index increases.90 The precise role these molecules may have in lung disease is undergoing further investigation.

Mechanical alterations in lung function may also contribute. Obese people have a lower functional residual capacity and expiratory reserve volume. Breathing with a lower-volume functional residual capacity results in decreased airway diameter and contributes to increased airway resistance.90 The decreased airway diameter may alter the contractile properties of airway smooth muscle and lead to increased airway responsiveness.90 These differences are in addition to the lower mean values of common spirometry indices such as the FEV1 and FVC, found in nonasthmatic African Americans compared with whites.91

Data suggest these differences are primarily due to anthropometric factors, with nutritional and environmental factors playing a less significant role.92 On this basis, the American Thoracic Society recommends applying race-specific reference standards for use with spirometry in order to accurately gauge lung function in African Americans.

APPROPRIATE CARE AND EDUCATION

The cause of greater asthma prevalence and severity among African Americans is multifactorial. It is likely that a number of factors work together, rather than separately, in influencing the development of asthma and its course.

Some risk factors are avoidable, and it is important to identify and ameliorate them. Others are not preventable, but knowledge of them may provide more specific management strategies and may lead to new therapies in the future.

While more work is needed to further unravel the complex risk factors associated with asthma, ensuring that higher-risk patients are provided the appropriate care and the knowledge to help control their disease is a necessary step in improving the disparities in asthma care outcomes.

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References
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  2. National Institutes of Health. National Heart, Lung, and Blood Institute. Data Fact Sheet. Asthma statistics. January 1999. http://www.nhlbi.nih.gov/health/prof/lung/asthma/asthstat.pdf. Accessed February 1, 2012.
  3. Lang DM, Polansky M, Sherman MS. Hospitalizations for asthma in an urban population: 1995–1999. Ann Allergy Asthma Immunol 2009; 103:128–133.
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  5. Koeppen-Schomerus G, Stevenson J, Plomin R. Genes and environment in asthma: a study of 4 year old twins. Arch Dis Child 2001; 85:398–400.
  6. Meng JF, Rosenwasser LJ. Unraveling the genetic basis of asthma and allergic diseases. Allergy Asthma Immunol Res 2010; 2:215–227.
  7. Stevenson LA, Gergen PJ, Hoover DR, Rosenstreich D, Mannino DM, Matte TD. Sociodemographic correlates of indoor allergen sensitivity among United States children. J Allergy Clin Immunol 2001; 108:747–752.
  8. Rosenstreich DL, Eggleston P, Kattan M, et al. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med 1997; 336:1356–1363.
  9. Kobilka BK, Dixon RA, Frielle T, et al. cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proc Natl Acad Sci U S A 1987; 84:46–50.
  10. Maxwell TJ, Ameyaw MM, Pritchard S, et al. Beta-2 adrenergic receptor genotypes and haplotypes in different ethnic groups. Int J Mol Med 2005; 16:573–580.
  11. Israel E, Chinchilli VM, Ford JG, et al; National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 2004; 364:1505–1512.
  12. Wells K, Pladevall M, Peterson EL, et al. Race-ethnic differences in factors associated with inhaled steroid adherence among adults with asthma. Am J Respir Crit Care Med 2008; 178:1194–1201.
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  59. Kinney PL, Aggarwal M, Northridge ME, Janssen NA, Shepard P. Airborne concentrations of PM(2.5) and diesel exhaust particles on Harlem sidewalks: a community-based pilot study. Environ Health Perspect 2000; 108:213–218.
  60. O’Neill MS, Jerrett M, Kawachi I, et al; Workshop on Air Pollution and Socioeconomic Conditions. Health, wealth, and air pollution: advancing theory and methods. Environ Health Perspect 2003; 111:1861–1870.
  61. Schwartz J, Slater D, Larson TV, Pierson WE, Koenig JQ. Particulate air pollution and hospital emergency room visits for asthma in Seattle. Am Rev Respir Dis 1993; 147:826–831.
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  63. Yu O, Sheppard L, Lumley T, Koenig JQ, Shapiro GG. Effects of ambient air pollution on symptoms of asthma in Seattle-area children enrolled in the CAMP study. Environ Health Perspect 2000; 108:1209–1214.
  64. Slaughter JC, Lumley T, Sheppard L, Koenig JQ, Shapiro GG. Effects of ambient air pollution on symptom severity and medication use in children with asthma. Ann Allergy Asthma Immunol 2003; 91:346–353.
  65. Koenig JQ, Jansen K, Mar TF, et al. Measurement of offline exhaled nitric oxide in a study of community exposure to air pollution. Environ Health Perspect 2003; 111:1625–1629.
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  67. Delva J, Tellez M, Finlayson TL, et al. Cigarette smoking among low-income African Americans: a serious public health problem. Am J Prev Med 2005; 29:218–220.
  68. McLeish AC, Zvolensky MJ. Asthma and cigarette smoking: a review of the empirical literature. J Asthma 2010; 47:345–361.
  69. Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med 2003; 168:1308–1311.
  70. Wilson SE, Kahn RS, Khoury J, Lanphear BP. Racial differences in exposure to environmental tobacco smoke among children. Environ Health Perspect 2005; 113:362–367.
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KEY POINTS

  • To better identify those at risk, researchers are looking at genetic markers such as polymorphisms in ADRB2 and CD14.
  • Exposure to tobacco smoke and to cockroach allergen contribute to higher rates of asthma prevalence and morbidity.
  • African Americans are more likely to receive suboptimal care, in particular to be misdiagnosed with other conditions, to not receive inhaled corticosteroids, and to not receive proper follow-up.
  • Better physician-patient communication is one of the keys to improving this problem.
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New asthma guidelines emphasize control, regular monitoring

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New asthma guidelines emphasize control, regular monitoring
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David M. Lang, MD

This review focuses on several elements in the National Asthma Education and Prevention Program’s new guidelines, the third Expert Panel Report (EPR3),1 that differ substantially from those in EPR2,2 issued in 1997 and updated in 2002.3 These differences in approach to the management of asthma described in EPR3 offer a clear potential for reducing the gap between optimal asthma care outcomes as described in guidelines and normative asthma care outcomes in the “real world.”

GREATER EMPHASIS ON CONTROL

The EPR2 guidelines2 recommended that asthma management be carried out in an algorithmic manner. Patients were classified into four severity categories: mild intermittent, mild persistent, moderate persistent, and severe persistent asthma, based on assessment of the level of symptoms (day/night), reliance on “reliever” medication, and lung function at the time of presentation. Pharmacologic management was then assigned according to each respective categorization in an evidence-based fashion.

In an ideal world, this would result in patients with asthma receiving appropriate pharmacotherapeutic agents associated with favorable asthma care outcomes, which were also advantageous from both cost- and risk-benefit standpoints. In the real world, however, this paradigm was flawed, as it relied on accurate categorization of patients in order for pharmacotherapy to be prescribed appropriately. Both providers and patients are prone to underestimate asthma severity,4,5 and for this reason many patients managed on the basis of this paradigm were undertreated.

A new paradigm, based on the assessment of asthma control, has been encouraged in the EPR3 guidelines.1

Severity and control are not synonymous

More than a decade ago, Cockroft and Swystun6 pointed out that asthma control (or lack thereof) is often used inappropriately to define asthma severity: ie, well-controlled asthma is seen as synonymous with mild asthma, and poorly controlled asthma with severe asthma.

Asthma severity can be defined as the intrinsic intensity of the disease process, while asthma control is the degree to which the manifestations of asthma are minimized. Asthma severity is clearly a determinant of asthma control, but its impact is affected by a variety of factors, including but not limited to:

  • Whether appropriate medication is prescribed
  • Patterns of therapeutic adherence
  • The degree to which recommended measures for avoiding for clinically relevant aeroallergens are pursued.

Health care utilization, including hospitalizations and emergency department visits, correlates more closely with asthma control than with asthma severity.7–9 Indeed, a patient with severe persistent asthma who is treated appropriately with multiple “controller” medications and who takes his or her medications and avoids allergens as directed can achieve well-controlled or totally controlled asthma, and is not likely to require hospitalization or emergency department management, to miss school or work, or to experience nocturnal awakening or limitation in routine activities due to asthma. This patient has severe persistent asthma that is well controlled.

In contrast, a patient with mild or moderate persistent asthma who does not receive appropriate instructions for avoiding allergens or taking controller medication regularly or who is poorly adherent will likely have poor asthma control. This patient is more likely to require hospitalization or emergency department management, to miss school or work, and to experience nocturnal awakening or limitation in routine activities due to asthma. This patient has mild persistent asthma that is poorly controlled.

Assess asthma severity in the first visit, and control in subsequent visits

Li JT, et al. Attaining optimal asthma control: a practice parameter J Allergy Clin Immunol 2005; 116:S3-S11.
Figure 1. The revised paradigm for asthma management recommends that asthma be categorized initially on the basis of severity, with management assigned in an evidence-based manner, but that subsequently, asthma control should be assessed at every clinical encounter, with management decisions based on the level of asthma control.
The revised algorithm for asthma management (Figure 1) recommends that asthma care providers categorize asthma severity at the initial visit (Table 1) and assess asthma control in subsequent visits (Table 2).

How to assess severity

The previous guidelines proposed that asthma severity be assessed before starting long-term therapy. However, many patients are already taking controller medications when initially seen. In the EPR3 guidelines,1 asthma severity can be inferred on the basis of response or lack of response to drug therapy. Responsiveness is defined as the ease with which asthma control can be achieved by therapy. At the initial visit, severity is assessed on the basis of impairment and risk (Table 1), whether or not the patient is regularly taking controller medication. In assessing impairment, we focus on the present, eg, ascertaining symptom frequency and intensity, functional limitation, lung function, and whether the patient follows the treatment and is satisfied with it.

In assessing risk, we focus on the future, with the aim of preventing exacerbations, minimizing the need for emergency department visits or hospitalizations, reducing the tendency for progressive decline in lung function, and providing the least amount of drug therapy required to maintain control in order to minimize risk of untoward effects. The impairment and risk domains may respond differently to treatment.

How to measure control

For all patients with asthma, regardless of severity, the goal is the same: to achieve control by reducing both impairment and risk. Asthma is classified as well controlled, not well controlled, or poorly controlled (Table 2).1

 

 

Validated tests are available to assess control

Asthma control is multidimensional9 and can be assessed by use of validated tests such as the Asthma Control Questionnaire (ACQ), Asthma Therapy Assessment Questionnaire (ATAQ), and the Asthma Control Test (ACT) (Table 3). These tests were designed to gauge asthma control over time in a user-friendly fashion. They are valid, reliable, and responsive to asthma control over time.9–13

In the case of the ACT (Table 4), the patient answers five questions (each on a scale of 1 to 5) about symptoms and the use of rescue medications in the previous 4 weeks. In general, the higher the score (range 5–25), the better the control of the asthma; a cut-point of 19 yields the best balance of sensitivity (71%) and specificity (71%) for classifying asthma as well controlled or not well controlled.13

Serial testing as a quality indicator

Serial ACT scores give an objective measure of the degree to which the goals of management1 are being achieved, and in so doing can encourage optimal outcomes.14

Another use of these tests is to document whether asthma control improves over time when patients receive care from a particular physician or group. This use may become increasingly important in view of efforts underway to implement a pay-for-performance model for asthma care, in which providers will be financially rewarded for improved patient care outcomes and adherence to standards of practice based on Health Plan Employer Data and Information Set measures.15

Figure 2. Mean scores on the Asthma Control Test (ACT) from patients seen in the Section of Allergy/Immunology at Cleveland Clinic in 2005. Among patients who accomplished initial and follow-up ACT measurements, mean scores reflecting self-reported asthma control increased from 14.54 to 19.06.

We have used the ACT in the Section of Allergy/Immunology at Cleveland Clinic for 3 years on a routine basis. All patients with asthma being seen either for the first time or as follow-up complete the ACT, which has been entered in a flow sheet in our electronic medical record, at the same time they undergo spirometry. We have shown that care in the Section of Allergy/Immunology is associated with improvement in asthma control over time, in patients who have completed serial ACT measurements at initial visits and at follow-up visits (Figure 2).

Objective measurement of lung function is also important

Serial monitoring of lung function at every patient visit with spirometry is also important, as some patients may be “poor perceivers,”16 ie, they may have little or no subjective awareness of moderate or even severe ventilatory impairment. A number of studies17,18 support the contention that symptoms and lung function are separate and independent dimensions of asthma control, and that both of them need to be assessed.

Responding to changes in control

If the disease is well controlled, the provider, in collaboration with the patient, may consider continuing the current regimen or “stepping down” to a less aggressive treatment. If the patient’s asthma is not well controlled, it is appropriate to “step up” the treatment. The EPR3 guidelines outline a stepwise approach to therapy (Table 5), from intermittent asthma (step 1) to severe persistent asthma (steps 5 and 6).9 If asthma is poorly controlled, the patient is at risk of exacerbation of asthma and on this basis is clearly a candidate for intervention.11–13,19

THE STEP 3 CONTROVERSY

Salmeterol Multicenter Asthma Research Trial

In the Salmeterol Multicenter Asthma Research Trial (SMART), patients randomized to the long-acting beta agonist (LABA) salmeterol (Serevent)—particularly African Americans—had a statistically significant increase in the risk of untoward asthma care outcomes.20

SMART was launched in 1996. Patients were randomized in a double-blind fashion to receive either salmeterol 42 μg twice a day or placebo in addition to their usual asthma therapy for 28 weeks. The rate of the primary outcome (respiratory-related deaths or life-threatening experiences) was not significantly different with salmeterol than with placebo (relative risk [RR] = 1.40, 95% confidence interval [CI] 0.91–2.14). However, in 2003, the study was halted prematurely because of difficulty enrolling the targeted number of 60,000 patients, and an interim analysis that revealed significantly higher rates of secondary outcomes in subjects randomized to salmeterol. Compared with the placebo group, the salmeterol group had significantly higher rates of respiratory-related deaths (RR 2.16, 95% CI 1.06–4.41), asthma-related deaths (RR = 4.37, 95% CI = 1.25–15.34), and combined asthma-related deaths or life-threatening experiences (RR = 1.71, 95% CI 1.01–2.89). There were 13 asthma-related deaths and 37 combined asthma-related deaths or life-threatening experiences in the salmeterol group, compared with 3 and 22, respectively, in the placebo group. Of the 16 asthma deaths in the study, 13 (81%) occurred in the initial phase of SMART, when patients were recruited via print, radio, and television advertising; afterward, patients were recruited directly by investigators.

Statistically significant differences in outcomes occurred primarily in African Americans. African Americans who received salmeterol had higher rates of respiratory death or life-threatening experiences (RR = 4.10, 95% CI 1.54–10.90), the primary end point for the study, as well as higher rates of combined asthma-related deaths or life-threatening experiences (RR = 10.46, 95% CI 1.34–81.58), a secondary end point. No statistically significant differences were observed in white patients randomized to salmeterol with respect to the primary end point (RR = 1.05, 95% = 0.62–1.76); the secondary end point of combined asthma-related deaths or life-threatening experiences (RR = 1.08, 95% CI 0.55–2.14); or other end points.

Medication exposures were not tracked during the study, and allocation to inhaled corticosteroids combined with salmeterol was not randomized, so the effect of concomitant inhaled corticosteroid use cannot be determined from these data.

As a result of SMART, medications that contain either of the two LABAs, salmeterol or formoterol (Foradil), carry a black-box warning.

 

 

LABAs: Risks and benefits

Two studies21,22 have suggested that asthmatic patients who are homozygous for Arg/Arg at codon 16 of the beta-2 adrenergic receptor are predisposed to untoward asthma outcomes with regular exposure to LABAs. However, other data23–25 do not support the contention that B16 Arg/Arg patients experience adverse asthma outcomes with LABA exposure. In two recently published studies, no difference in rates of exacerbations, severe exacerbations, lung function, frequency of reliance on SABA, or nocturnal awakenings was observed in patients receiving formoterol combined with budesonide24 or salmeterol combined with fluticasone25 according to genotype. A prospective study26 also found no statistically significant difference in exacerbation rates according to beta adrenergic receptor genotype in individuals randomized to LABA monotherapy, or LABA combined with inhaled corticosteroids.

The updated EPR2 asthma guidelines,3 published in November 2002, stipulated that LABAs were the preferred controller agent to “add on” to low-dose inhaled corticosteroids for patients with moderate persistent asthma, and that the combination of low-dose inhaled corticosteroids and LABA was associated with superior outcomes: reduction of symptoms, including nocturnal awakening, increase in lung function, improvement in health-related quality of life, decreased use of “rescue” medication, and reduced rate of exacerbations and severe exacerbations, compared with higher-dose inhaled corticosteroid monotherapy. This management recommendation was categorized as level A, on the basis of data from multiple randomized, controlled, double-blinded trials.27–29 Additional evidence14,30 and data from two meta-analyses31,32 have provided further support for this recommendation, while no evidence linking LABA exposure to risk for fatal or near-fatal asthma has been found in cohort or case-control studies.33–38

Based on safety concerns, the EPR3 guidelines1 recommend that medium-dose inhaled corticosteroids be regarded as equivalent to adding LABAs to low-dose inhaled corticosteroids, and state: “the established, beneficial effects of LABA for the great majority of patients whose asthma is not well controlled with [inhaled corticosteroids] alone should be weighed against the increased risk for severe exacerbations, although uncommon, associated with daily use of LABA.”1

There is currently an honest difference of opinion39,40 among asthma specialists as to how this management recommendation for moderate persistent asthma—now depicted at “step 3” in the EPR3 guidelines (Table 4)—should be implemented. The LABA controversy was reviewed previously in the Cleveland Clinic Journal of Medicine.41

THE ROLE OF OMALIZUMAB: WEIGHING COST VS BENEFIT

The 2002 update to the EPR2 guidelines3 was issued before omalizumab (Xolair) was approved in June 2003.

Patients with severe persistent asthma are categorized in steps 5 or 6 in the EPR3 guidelines (Table 5).1 Preferred management for these patients includes inhaled corticosteroids in high doses combined with long-acting beta agonists and, for step 6 patients, oral corticosteroids.

Omalizumab was approved for management of patients with moderate or severe persistent asthma who are not achieving the goals of asthma management on inhaled corticosteroids, who exhibit a wheal-flare reaction to a perennial allergen, and whose immunoglobulin E (IgE) level is in the range of 30 to 700 IU/mL.42 Omalizumab dosing is based on the serum IgE level and on body weight.

Omalizumab, an anti-IgE monoclonal antibody

Omalizumab is a recombinant, humanized, monoclonal anti-IgE antibody that binds to IgE at the same Fc site as the high-affinity IgE receptor. Its primary mechanism of action is the binding of free IgE in the circulation, forming biologically inert, small complexes that do not activate complement and are cleared by the reticuloendothelial system.42 Its secondary mechanism of action entails a reduction in the number of high-affinity receptors on basophils, from approximately 220,000 to 8,300 receptors per cell. The latter effect was associated with a 90% reduction in histamine release from basophils in response to ex vivo challenge with dust mite allergen.43

Benefit in randomized trials

Omalizumab has been associated with statistically and clinically significant benefit in randomized, double-blind, placebo-controlled trials.44,45

Humbert et al46 randomized 419 patients whose asthma was not adequately controlled on high-dose inhaled corticosteroids and long-acting beta agonists, who were 12 to 75 years old, with reduced lung function and a history of recent asthma exacerbation, to treatment with omalizumab or placebo. Omalizumab was associated with a statistically significant reduction in the rate of asthma exacerbations and severe asthma exacerbations, as well as statistically significant improvements in asthma-related quality of life, morning peak expiratory flow rate, and asthma symptom scores.

These data support the recommendation in EPR3 to consider a trial of omalizumab in properly selected patients with severe, persistent allergic asthma.

 

 

Omalizumab is cost-beneficial in properly selected patients

The current wholesale acquisition cost of omalizumab is $532 for one 150-mg vial (David Zito, personal communication). The cost of treatment varies based on body weight and IgE level but may range from a wholesale cost of $6,388 to $38,326 per year.

However, as asthma severity increases, both direct and indirect medical expenditures increase substantially.47,48 Annual costs are approximately four times higher for severe asthma compared with mild asthma49; not only are treatment and exacerbation costs higher, but indirect costs are also disproportionately greater. Annual costs for severe asthma are significantly greater if the disease is inadequately controlled.50 For these reasons, an intervention that leads to improved outcomes for severe, poorly controlled asthma carries the potential for the greatest cost-utility for society, as it can lower direct costs by reducing the frequency and severity of exacerbations, in addition to reducing indirect medical expenditures on the basis of increased productivity and fewer days of missed work or school. The cost of omalizumab in quality-adjusted life years compares favorably with that of biologicals used in managing rheumatoid arthritis, Crohn disease, and multiple sclerosis.50

Adverse effects of omalizumab

In pivotal trials,43,44 omalizumab was associated with a substantial rate of local reactions. The rate of anaphylaxis was slightly less than 1 in 1,000, and this has been confirmed by surveillance data recorded since approval of the drug in 2003. Based on the observed risk of anaphylaxis, in July 2007, the US Food and Drug Administration added a black-box warning to the omalizumab label and stipulated that a medication guide should be provided for patients.51 The warning indicates that health care providers administering omalizumab should be prepared to manage anaphylaxis and that patients should be closely observed for an appropriate period after omalizumab administration.

The package insert also describes a numerical, but not statistically significant, increase in the rate of malignancy in patients receiving omalizumab.42 Malignancy developed in 0.5% of patients receiving omalizumab, compared with 0.2% of patients who received placebo. Because these malignancies were diagnosed over a shorter period than the time required for oncogenesis (ie, 6 months in 60% of cases), and because a heterogeneous variety of tumors was observed, there is reason to doubt these tumors were causally associated with omalizumab.

Postmarketing surveillance studies are in progress that will provide more definitive data on the potential relationship between malignancy and omalizumab exposure.

Omalizumab: Guideline recommendations

The EPR3 guidelines1 state that omalizumab is the only adjunctive therapy to demonstrate efficacy when added to high-dose inhaled corticosteroids plus long-acting beta agonists in patients with severe, persistent, allergic asthma and that evidence does not support use of the following agents, which in some cases are approved for managing other conditions and have been advocated for management of severe, refractory asthma: methotrexate, soluble interleukin (IL)-4 receptor, anti-IL-5, anti-IL-12, cyclosporine A, intravenous immune globulin, gold, troleandomycin, and colchicine. The data supporting use of macrolides were characterized as “encouraging but insufficient to support a recommendation.”

The strength of evidence for the use of omalizumab for patients in steps 5 and 6 who fulfill the criteria for its use (see above) was classified in the EPR3 guidelines1 as category B. The guidelines also say that omalizumab may be considered for adjunctive therapy in properly selected patients in step 4, as a means to avoid higher doses of inhaled corticosteroids, but that additional studies are needed to establish its utility for such patients. This recommendation was classified as category D because of the lack of published comparator trials.

ALLERGEN IMMUNOTHERAPY FOR PATIENTS WITH ASTHMA

Many patients with asthma have clinically relevant, IgE-mediated (allergic) potential to inhaled allergens.1 For patients with persistent asthma (steps 2–6 in Table 5), allergic reactions can contribute to airway inflammation, provoke symptoms, and lead to more use of medications. For this reason, identification and management of clinically relevant allergy merits consideration.52

The EPR3 guidelines1 recommend considering allergen immunotherapy for patients with mild or moderate persistent asthma (steps 2–4) who have a clinically relevant component of allergy to inhaled substances.

Changing the immune response

Allergen immunotherapy entails the incremental administration of inhalant allergens by subcutaneous injection for the purpose of inducing immune system changes in the host response. The goal of immunotherapy is to protect against allergic reactions that can be expected to occur with ongoing exposure to clinically relevant allergens.53

The immunologic changes that develop with allergen immunotherapy are complex.53,54 Successful immunotherapy results in generation of a population of CD4+/CD25+ T lymphocytes producing IL-10, transforming growth factor beta, or both. Allergen immunotherapy has been shown to block the immediate- and late-phase allergic response; to decrease recruitment of mast cells, basophils, and eosinophils on provocation or natural exposure to allergens in the skin, nose, eye, and bronchial mucosa; to blunt the seasonal rise in specific IgE; and to suppress late-phase inflammatory responses in the skin and respiratory tract. However, the efficacy of immunotherapy in relation to these immunologic changes is not completely understood.54

 

 

Many patients need skin testing

Allergen immunotherapy may be considered for patients with asthma for whom a clear relationship exists between symptoms and exposure to an allergen to which the patient is sensitive.53 Because it is often not possible to determine whether a patient is sensitive to a perennial indoor allergen (eg, dust mite) on the basis of the medical history alone,55 many patients with asthma benefit from immediate hypersensitivity skin testing to objectively assess or rule out allergy to common inhalants. In certain situations, in vitro testing may be performed, but skin testing has a higher negative predictive value and is recommended as a better screening test.56

Benefits of allergen immunotherapy

Numerous randomized, double-blind, placebo-controlled trials have shown that allergen immunotherapy is associated with benefit for reducing symptoms and medication reliance.57–63

A meta-analysis of 75 randomized, placebo-controlled studies confirmed the effectiveness of immunotherapy in asthma, with a significant reduction in asthma symptoms and medication use and with improvement in bronchial hyperreactivity.64 This meta-analysis included 36 trials of dust mite allergen, 20 of pollen, and 10 of animal dander. Immunotherapy is efficacious for pollen, mold, dust mite, cockroach, and animal allergens; however, its effectiveness is more established for dust mite, animal dander, and pollen allergens, as fewer studies have been published demonstrating efficacy using mold and cockroach allergens.53

In addition, several studies have found that children with allergic rhinitis who receive allergen immunotherapy are significantly less likely to develop asthma.65–67 Immunotherapy has also been associated with a statistically significant reduction in future sensitization to other aeroallergens.68,69

Risk of systemic reaction from allergen immunotherapy

The decision to begin allergen immunotherapy should be individualized on the basis of symptom severity, relative benefit compared with drug therapy, and whether comorbid conditions such as cardiovascular disease or beta-blocker exposure are present. These comorbid conditions are associated with heightened risk of (more serious) anaphylaxis—the major hazard of allergen immunotherapy.70 Systemic reactions during allergen immunotherapy occur at a rate of approximately 3 to 5 per 1,000 injections; for this reason, allergen immunotherapy should only be administered in a medical facility where personnel, supplies, and equipment are available to treat anaphylaxis.5

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  24. Bleecker E, Postma D, Lawrance R, Meyers D, Ambrose H, Goldman M. Effect of ADRB2 polymorphisms on response to long-acting beta2-agonist therapy: a pharmacogenetic analysis of two randomized studies. Lancet 2007; 370:2118–2125.
  25. Bleecker E, Yancey S, Baitinger L, et al. Salmeterol response is not affected by beta-2 adrenergic receptor genotype in subjects with persistent asthma. J Allergy Clin Immunol 2006; 118:809–816.
  26. Nelson H, Bleecker E, Corren J, et al. Characterization of asthma exacerbations by Arg16Gly genotype in subjects with asthma receiving salmeterol alone or with fluticasone propionate. J Allergy Clin Immunol 2008; 121:S131.
  27. O’Byrne P, Barnes P, Rodriguez-Roisin R, et al. Low dose Inhaled budesonide and formoterol in mild persistent asthma. The OPTIMA Randomized Trial. Am J Respir Crit Care Med 2001; 164:1392–1397.
  28. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994; 344:219–224.
  29. Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153:1481–1488.
  30. Walters EH, Walters JAE, Gibson MDP. Long-acting beta2-agonists for stable chronic asthma. Cochrane Database Syst Rev 2003; (3):CD001385. doi:10.1002/14651858.CD001385.
  31. Masoli M, Weatherall M, Holt S, Beasley R. Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroid in symptomatic asthma. Thorax 2005; 60:730–734.
  32. Sin DD, Man J, Sharpe H, Gan WQ, Man SFP. Pharmacological management to reduce exacerbations in adults with asthma. A systematic review and meta-analysis. JAMA 2004; 292:367–376.
  33. Mann RD, Kubota K, Pearce G, Wilton L. Salmeterol: a study by prescription event monitoring in a UK cohort of 15,407 patients. J Clin Epidemiol 1996; 49:247–250.
  34. Lanes S, Lanza L, Wentworth C. Risk of emergency care, hospitalization, and ICU stays for acute asthma among recipients of salmeterol. Am J Respir Crit Care Med 1998; 158:857–861.
  35. Meier CR, Jick H. Drug use and pulmonary death rates in increasingly symptomatic asthma patients in the UK. Thorax 1997; 52:612–617.
  36. Williams C, Crossland L, Finnerty J, et al. A case control study of salmeterol and near-fatal attacks of asthma. Thorax 1998; 53:7–13.
  37. Lanes S, Garcia Rodriguez LA, Herta C. Respiratory medications and risk of asthma death. Thorax 2002; 57:683–686.
  38. Anderson HR, Ayres JG, Sturdy PM, et al. Bronchodilator treatment and deaths from asthma: case control study. Br Med J 2005; 330:117–124.
  39. Martinez FD. Safety of long-acting beta agonists—an urgent need to clear the air. N Engl J Med 2005; 353:2637–2639.
  40. Nelson HS. Long-acting beta-agonists in adult asthma: evidence that these drugs are safe. Prim Care Respir J 2006; 15:271–277.
  41. Lang DM. The long-acting beta agonist controversy: a critical examination of the evidence. Cleve Clin J Med 2006; 73:973–992.
  42. Rambasek T, Lang DM, Kavuru M. Omalizumab: where does it fit in current asthma management? Cleve Clin J Med 2004; 71:251–261.
  43. McGlashan D, Bochner B, Adelman D, et al. Down regulation of Fc(epsilon)RI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997; 158:1438–1445.
  44. Busse W, Corren J, Lanier B, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001; 108:184–190.
  45. Soler M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reduces asthma exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001; 18:254–261.
  46. Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60:309–316.
  47. Van Ganse E, Antonicelli L, Zhang Q, et al. Asthma-related resource use and cost by GINA classification of severity in three European countries. Respir Med 2006; 100:140–147.
  48. Godard P, Chanez P, Siraudin L, Nicoloyannis N, Duru G. Costs of asthma are correlated with severity: a 1-yr prospective study. Eur Respir J 2002; 19:61–67.
  49. Cisternas MG, Blanc PH, Yen IH, et al. A comprehensive study of the direct and indirect costs of adult asthma. J Allergy Clin Immunol 2003; 111:1212–1218.
  50. Sullivan S, Turk F. An evaluation of the cost effectiveness of omalizumab for the treatment of severe persistent asthma. Allergy 2008; 63:670–684.
  51. US Food and Drug Administration. Omalizumab (marketed as Xolair) information. www.fda.gov/cder/drug/infopage/omalizumab/default.htm. Accessed August 31, 2007.
  52. Williams SG, Schmidt DK, Redd SC, Storms W. Key clinical activities for quality asthma care. Recommendations of the National Asthma Education and Prevention Program. MMWR Recomm Rep 2003; 52 RR-6:1–8.
  53. Cox L, Li J, Nelson H, Lockey R, et al. Allergy Immunotherapy: a practice parameter second update. J Allergy Clin Immunol 2007; 120:S25–S85.
  54. Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol 2007; 119:780–789.
  55. Murray AB, Milner RA. The accuracy of features in the clinical history for predicting atopic sensitization to airborne allergens in children. J Allergy Clin Immunol 1995; 96:588–596.
  56. Bernstein IL, Li JT, Bernstein DI, et al. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol 2008; 100 suppl 3:1S–148S.
  57. Walker S, Pajno GB, Lima MT, Wilson DR, Durham SR. Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial. J Allergy Clin Immunol 2001; 107:87–93.
  58. Varney VA, Edwards J, Tabbah K, Brewster H, Mavroleon G, Frew AJ. Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebo-controlled trial. Clin Exp Allergy 1997; 27:860–867.
  59. Cantani A, Arcese G, Lucenti P, Gagliesi D, Bartolucci M. A three-year prospective study of specific immunotherapy to inhalant allergens: evidence of safety and efficacy in 300 children with allergic asthma. J Investig Allergol Clin Immunol 1997; 7:90–97.
  60. Hedlin G, Wille S, Browaldh L, et al. Immunotherapy in children with allergic asthma: effect on bronchial hyperreactivity and pharmacotherapy. J Allergy Clin Immunol 1999; 103:609–614.
  61. Arvidsson MB, Löwhagen O, Rak S. Allergen specific immunotherapy attenuates early and late phase reactions in lower airways of birch pollen asthmatic patients: a double blind placebo-controlled study. Allergy 2004; 59:74–80.
  62. Pichler CE, Helbling A, Pichler WJ. Three years of specific immunotherapy with house-dust-mite extracts in patients with rhinitis and asthma: significant improvement of allergen-specific parameters and of nonspecific bronchial hyperreactivity. Allergy 2001; 56:301–306.
  63. Mirone C, Albert F, Tosi A, et al. Efficacy and safety of subcutaneous immunotherapy with a biologically standardized extract of Ambrosia artemisiifolia pollen: a double-blind, placebo-controlled study. Clin Exp Allergy 2004; 34:1408–1414.
  64. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2003; (4):CD001186.
  65. Jacobsen L. Preventive aspects of immunotherapy: prevention for children at risk of developing asthma. Ann Allergy Asthma Immunol 2001; 87:43–46.
  66. Moller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT study). J Allergy Clin Immunol 2002; 109:251–256.
  67. Niggemann B, Jacobsen L, Dreborg S, et al; PAT Investigator Group. Five year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy 2006: 61:855–859.
  68. Des Roches A, Paradis L, Menardo JL, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract VI: specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997; 99:450–453.
  69. Pajno GB, Barberio G, DeLuca F, et al. Prevention of new sensitizations in asthmatic children monosensitized to the house dust mite by specific immunotherapy: a six year follow up study. Clin Exp Allergy 2001; 31:1392–1397.
  70. Lang DM. Do beta blockers really enhance the risk of anaphylaxis during immunotherapy? Curr Allergy Asthma Rep 2008; 8:37–44.
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This review focuses on several elements in the National Asthma Education and Prevention Program’s new guidelines, the third Expert Panel Report (EPR3),1 that differ substantially from those in EPR2,2 issued in 1997 and updated in 2002.3 These differences in approach to the management of asthma described in EPR3 offer a clear potential for reducing the gap between optimal asthma care outcomes as described in guidelines and normative asthma care outcomes in the “real world.”

GREATER EMPHASIS ON CONTROL

The EPR2 guidelines2 recommended that asthma management be carried out in an algorithmic manner. Patients were classified into four severity categories: mild intermittent, mild persistent, moderate persistent, and severe persistent asthma, based on assessment of the level of symptoms (day/night), reliance on “reliever” medication, and lung function at the time of presentation. Pharmacologic management was then assigned according to each respective categorization in an evidence-based fashion.

In an ideal world, this would result in patients with asthma receiving appropriate pharmacotherapeutic agents associated with favorable asthma care outcomes, which were also advantageous from both cost- and risk-benefit standpoints. In the real world, however, this paradigm was flawed, as it relied on accurate categorization of patients in order for pharmacotherapy to be prescribed appropriately. Both providers and patients are prone to underestimate asthma severity,4,5 and for this reason many patients managed on the basis of this paradigm were undertreated.

A new paradigm, based on the assessment of asthma control, has been encouraged in the EPR3 guidelines.1

Severity and control are not synonymous

More than a decade ago, Cockroft and Swystun6 pointed out that asthma control (or lack thereof) is often used inappropriately to define asthma severity: ie, well-controlled asthma is seen as synonymous with mild asthma, and poorly controlled asthma with severe asthma.

Asthma severity can be defined as the intrinsic intensity of the disease process, while asthma control is the degree to which the manifestations of asthma are minimized. Asthma severity is clearly a determinant of asthma control, but its impact is affected by a variety of factors, including but not limited to:

  • Whether appropriate medication is prescribed
  • Patterns of therapeutic adherence
  • The degree to which recommended measures for avoiding for clinically relevant aeroallergens are pursued.

Health care utilization, including hospitalizations and emergency department visits, correlates more closely with asthma control than with asthma severity.7–9 Indeed, a patient with severe persistent asthma who is treated appropriately with multiple “controller” medications and who takes his or her medications and avoids allergens as directed can achieve well-controlled or totally controlled asthma, and is not likely to require hospitalization or emergency department management, to miss school or work, or to experience nocturnal awakening or limitation in routine activities due to asthma. This patient has severe persistent asthma that is well controlled.

In contrast, a patient with mild or moderate persistent asthma who does not receive appropriate instructions for avoiding allergens or taking controller medication regularly or who is poorly adherent will likely have poor asthma control. This patient is more likely to require hospitalization or emergency department management, to miss school or work, and to experience nocturnal awakening or limitation in routine activities due to asthma. This patient has mild persistent asthma that is poorly controlled.

Assess asthma severity in the first visit, and control in subsequent visits

Li JT, et al. Attaining optimal asthma control: a practice parameter J Allergy Clin Immunol 2005; 116:S3-S11.
Figure 1. The revised paradigm for asthma management recommends that asthma be categorized initially on the basis of severity, with management assigned in an evidence-based manner, but that subsequently, asthma control should be assessed at every clinical encounter, with management decisions based on the level of asthma control.
The revised algorithm for asthma management (Figure 1) recommends that asthma care providers categorize asthma severity at the initial visit (Table 1) and assess asthma control in subsequent visits (Table 2).

How to assess severity

The previous guidelines proposed that asthma severity be assessed before starting long-term therapy. However, many patients are already taking controller medications when initially seen. In the EPR3 guidelines,1 asthma severity can be inferred on the basis of response or lack of response to drug therapy. Responsiveness is defined as the ease with which asthma control can be achieved by therapy. At the initial visit, severity is assessed on the basis of impairment and risk (Table 1), whether or not the patient is regularly taking controller medication. In assessing impairment, we focus on the present, eg, ascertaining symptom frequency and intensity, functional limitation, lung function, and whether the patient follows the treatment and is satisfied with it.

In assessing risk, we focus on the future, with the aim of preventing exacerbations, minimizing the need for emergency department visits or hospitalizations, reducing the tendency for progressive decline in lung function, and providing the least amount of drug therapy required to maintain control in order to minimize risk of untoward effects. The impairment and risk domains may respond differently to treatment.

How to measure control

For all patients with asthma, regardless of severity, the goal is the same: to achieve control by reducing both impairment and risk. Asthma is classified as well controlled, not well controlled, or poorly controlled (Table 2).1

 

 

Validated tests are available to assess control

Asthma control is multidimensional9 and can be assessed by use of validated tests such as the Asthma Control Questionnaire (ACQ), Asthma Therapy Assessment Questionnaire (ATAQ), and the Asthma Control Test (ACT) (Table 3). These tests were designed to gauge asthma control over time in a user-friendly fashion. They are valid, reliable, and responsive to asthma control over time.9–13

In the case of the ACT (Table 4), the patient answers five questions (each on a scale of 1 to 5) about symptoms and the use of rescue medications in the previous 4 weeks. In general, the higher the score (range 5–25), the better the control of the asthma; a cut-point of 19 yields the best balance of sensitivity (71%) and specificity (71%) for classifying asthma as well controlled or not well controlled.13

Serial testing as a quality indicator

Serial ACT scores give an objective measure of the degree to which the goals of management1 are being achieved, and in so doing can encourage optimal outcomes.14

Another use of these tests is to document whether asthma control improves over time when patients receive care from a particular physician or group. This use may become increasingly important in view of efforts underway to implement a pay-for-performance model for asthma care, in which providers will be financially rewarded for improved patient care outcomes and adherence to standards of practice based on Health Plan Employer Data and Information Set measures.15

Figure 2. Mean scores on the Asthma Control Test (ACT) from patients seen in the Section of Allergy/Immunology at Cleveland Clinic in 2005. Among patients who accomplished initial and follow-up ACT measurements, mean scores reflecting self-reported asthma control increased from 14.54 to 19.06.

We have used the ACT in the Section of Allergy/Immunology at Cleveland Clinic for 3 years on a routine basis. All patients with asthma being seen either for the first time or as follow-up complete the ACT, which has been entered in a flow sheet in our electronic medical record, at the same time they undergo spirometry. We have shown that care in the Section of Allergy/Immunology is associated with improvement in asthma control over time, in patients who have completed serial ACT measurements at initial visits and at follow-up visits (Figure 2).

Objective measurement of lung function is also important

Serial monitoring of lung function at every patient visit with spirometry is also important, as some patients may be “poor perceivers,”16 ie, they may have little or no subjective awareness of moderate or even severe ventilatory impairment. A number of studies17,18 support the contention that symptoms and lung function are separate and independent dimensions of asthma control, and that both of them need to be assessed.

Responding to changes in control

If the disease is well controlled, the provider, in collaboration with the patient, may consider continuing the current regimen or “stepping down” to a less aggressive treatment. If the patient’s asthma is not well controlled, it is appropriate to “step up” the treatment. The EPR3 guidelines outline a stepwise approach to therapy (Table 5), from intermittent asthma (step 1) to severe persistent asthma (steps 5 and 6).9 If asthma is poorly controlled, the patient is at risk of exacerbation of asthma and on this basis is clearly a candidate for intervention.11–13,19

THE STEP 3 CONTROVERSY

Salmeterol Multicenter Asthma Research Trial

In the Salmeterol Multicenter Asthma Research Trial (SMART), patients randomized to the long-acting beta agonist (LABA) salmeterol (Serevent)—particularly African Americans—had a statistically significant increase in the risk of untoward asthma care outcomes.20

SMART was launched in 1996. Patients were randomized in a double-blind fashion to receive either salmeterol 42 μg twice a day or placebo in addition to their usual asthma therapy for 28 weeks. The rate of the primary outcome (respiratory-related deaths or life-threatening experiences) was not significantly different with salmeterol than with placebo (relative risk [RR] = 1.40, 95% confidence interval [CI] 0.91–2.14). However, in 2003, the study was halted prematurely because of difficulty enrolling the targeted number of 60,000 patients, and an interim analysis that revealed significantly higher rates of secondary outcomes in subjects randomized to salmeterol. Compared with the placebo group, the salmeterol group had significantly higher rates of respiratory-related deaths (RR 2.16, 95% CI 1.06–4.41), asthma-related deaths (RR = 4.37, 95% CI = 1.25–15.34), and combined asthma-related deaths or life-threatening experiences (RR = 1.71, 95% CI 1.01–2.89). There were 13 asthma-related deaths and 37 combined asthma-related deaths or life-threatening experiences in the salmeterol group, compared with 3 and 22, respectively, in the placebo group. Of the 16 asthma deaths in the study, 13 (81%) occurred in the initial phase of SMART, when patients were recruited via print, radio, and television advertising; afterward, patients were recruited directly by investigators.

Statistically significant differences in outcomes occurred primarily in African Americans. African Americans who received salmeterol had higher rates of respiratory death or life-threatening experiences (RR = 4.10, 95% CI 1.54–10.90), the primary end point for the study, as well as higher rates of combined asthma-related deaths or life-threatening experiences (RR = 10.46, 95% CI 1.34–81.58), a secondary end point. No statistically significant differences were observed in white patients randomized to salmeterol with respect to the primary end point (RR = 1.05, 95% = 0.62–1.76); the secondary end point of combined asthma-related deaths or life-threatening experiences (RR = 1.08, 95% CI 0.55–2.14); or other end points.

Medication exposures were not tracked during the study, and allocation to inhaled corticosteroids combined with salmeterol was not randomized, so the effect of concomitant inhaled corticosteroid use cannot be determined from these data.

As a result of SMART, medications that contain either of the two LABAs, salmeterol or formoterol (Foradil), carry a black-box warning.

 

 

LABAs: Risks and benefits

Two studies21,22 have suggested that asthmatic patients who are homozygous for Arg/Arg at codon 16 of the beta-2 adrenergic receptor are predisposed to untoward asthma outcomes with regular exposure to LABAs. However, other data23–25 do not support the contention that B16 Arg/Arg patients experience adverse asthma outcomes with LABA exposure. In two recently published studies, no difference in rates of exacerbations, severe exacerbations, lung function, frequency of reliance on SABA, or nocturnal awakenings was observed in patients receiving formoterol combined with budesonide24 or salmeterol combined with fluticasone25 according to genotype. A prospective study26 also found no statistically significant difference in exacerbation rates according to beta adrenergic receptor genotype in individuals randomized to LABA monotherapy, or LABA combined with inhaled corticosteroids.

The updated EPR2 asthma guidelines,3 published in November 2002, stipulated that LABAs were the preferred controller agent to “add on” to low-dose inhaled corticosteroids for patients with moderate persistent asthma, and that the combination of low-dose inhaled corticosteroids and LABA was associated with superior outcomes: reduction of symptoms, including nocturnal awakening, increase in lung function, improvement in health-related quality of life, decreased use of “rescue” medication, and reduced rate of exacerbations and severe exacerbations, compared with higher-dose inhaled corticosteroid monotherapy. This management recommendation was categorized as level A, on the basis of data from multiple randomized, controlled, double-blinded trials.27–29 Additional evidence14,30 and data from two meta-analyses31,32 have provided further support for this recommendation, while no evidence linking LABA exposure to risk for fatal or near-fatal asthma has been found in cohort or case-control studies.33–38

Based on safety concerns, the EPR3 guidelines1 recommend that medium-dose inhaled corticosteroids be regarded as equivalent to adding LABAs to low-dose inhaled corticosteroids, and state: “the established, beneficial effects of LABA for the great majority of patients whose asthma is not well controlled with [inhaled corticosteroids] alone should be weighed against the increased risk for severe exacerbations, although uncommon, associated with daily use of LABA.”1

There is currently an honest difference of opinion39,40 among asthma specialists as to how this management recommendation for moderate persistent asthma—now depicted at “step 3” in the EPR3 guidelines (Table 4)—should be implemented. The LABA controversy was reviewed previously in the Cleveland Clinic Journal of Medicine.41

THE ROLE OF OMALIZUMAB: WEIGHING COST VS BENEFIT

The 2002 update to the EPR2 guidelines3 was issued before omalizumab (Xolair) was approved in June 2003.

Patients with severe persistent asthma are categorized in steps 5 or 6 in the EPR3 guidelines (Table 5).1 Preferred management for these patients includes inhaled corticosteroids in high doses combined with long-acting beta agonists and, for step 6 patients, oral corticosteroids.

Omalizumab was approved for management of patients with moderate or severe persistent asthma who are not achieving the goals of asthma management on inhaled corticosteroids, who exhibit a wheal-flare reaction to a perennial allergen, and whose immunoglobulin E (IgE) level is in the range of 30 to 700 IU/mL.42 Omalizumab dosing is based on the serum IgE level and on body weight.

Omalizumab, an anti-IgE monoclonal antibody

Omalizumab is a recombinant, humanized, monoclonal anti-IgE antibody that binds to IgE at the same Fc site as the high-affinity IgE receptor. Its primary mechanism of action is the binding of free IgE in the circulation, forming biologically inert, small complexes that do not activate complement and are cleared by the reticuloendothelial system.42 Its secondary mechanism of action entails a reduction in the number of high-affinity receptors on basophils, from approximately 220,000 to 8,300 receptors per cell. The latter effect was associated with a 90% reduction in histamine release from basophils in response to ex vivo challenge with dust mite allergen.43

Benefit in randomized trials

Omalizumab has been associated with statistically and clinically significant benefit in randomized, double-blind, placebo-controlled trials.44,45

Humbert et al46 randomized 419 patients whose asthma was not adequately controlled on high-dose inhaled corticosteroids and long-acting beta agonists, who were 12 to 75 years old, with reduced lung function and a history of recent asthma exacerbation, to treatment with omalizumab or placebo. Omalizumab was associated with a statistically significant reduction in the rate of asthma exacerbations and severe asthma exacerbations, as well as statistically significant improvements in asthma-related quality of life, morning peak expiratory flow rate, and asthma symptom scores.

These data support the recommendation in EPR3 to consider a trial of omalizumab in properly selected patients with severe, persistent allergic asthma.

 

 

Omalizumab is cost-beneficial in properly selected patients

The current wholesale acquisition cost of omalizumab is $532 for one 150-mg vial (David Zito, personal communication). The cost of treatment varies based on body weight and IgE level but may range from a wholesale cost of $6,388 to $38,326 per year.

However, as asthma severity increases, both direct and indirect medical expenditures increase substantially.47,48 Annual costs are approximately four times higher for severe asthma compared with mild asthma49; not only are treatment and exacerbation costs higher, but indirect costs are also disproportionately greater. Annual costs for severe asthma are significantly greater if the disease is inadequately controlled.50 For these reasons, an intervention that leads to improved outcomes for severe, poorly controlled asthma carries the potential for the greatest cost-utility for society, as it can lower direct costs by reducing the frequency and severity of exacerbations, in addition to reducing indirect medical expenditures on the basis of increased productivity and fewer days of missed work or school. The cost of omalizumab in quality-adjusted life years compares favorably with that of biologicals used in managing rheumatoid arthritis, Crohn disease, and multiple sclerosis.50

Adverse effects of omalizumab

In pivotal trials,43,44 omalizumab was associated with a substantial rate of local reactions. The rate of anaphylaxis was slightly less than 1 in 1,000, and this has been confirmed by surveillance data recorded since approval of the drug in 2003. Based on the observed risk of anaphylaxis, in July 2007, the US Food and Drug Administration added a black-box warning to the omalizumab label and stipulated that a medication guide should be provided for patients.51 The warning indicates that health care providers administering omalizumab should be prepared to manage anaphylaxis and that patients should be closely observed for an appropriate period after omalizumab administration.

The package insert also describes a numerical, but not statistically significant, increase in the rate of malignancy in patients receiving omalizumab.42 Malignancy developed in 0.5% of patients receiving omalizumab, compared with 0.2% of patients who received placebo. Because these malignancies were diagnosed over a shorter period than the time required for oncogenesis (ie, 6 months in 60% of cases), and because a heterogeneous variety of tumors was observed, there is reason to doubt these tumors were causally associated with omalizumab.

Postmarketing surveillance studies are in progress that will provide more definitive data on the potential relationship between malignancy and omalizumab exposure.

Omalizumab: Guideline recommendations

The EPR3 guidelines1 state that omalizumab is the only adjunctive therapy to demonstrate efficacy when added to high-dose inhaled corticosteroids plus long-acting beta agonists in patients with severe, persistent, allergic asthma and that evidence does not support use of the following agents, which in some cases are approved for managing other conditions and have been advocated for management of severe, refractory asthma: methotrexate, soluble interleukin (IL)-4 receptor, anti-IL-5, anti-IL-12, cyclosporine A, intravenous immune globulin, gold, troleandomycin, and colchicine. The data supporting use of macrolides were characterized as “encouraging but insufficient to support a recommendation.”

The strength of evidence for the use of omalizumab for patients in steps 5 and 6 who fulfill the criteria for its use (see above) was classified in the EPR3 guidelines1 as category B. The guidelines also say that omalizumab may be considered for adjunctive therapy in properly selected patients in step 4, as a means to avoid higher doses of inhaled corticosteroids, but that additional studies are needed to establish its utility for such patients. This recommendation was classified as category D because of the lack of published comparator trials.

ALLERGEN IMMUNOTHERAPY FOR PATIENTS WITH ASTHMA

Many patients with asthma have clinically relevant, IgE-mediated (allergic) potential to inhaled allergens.1 For patients with persistent asthma (steps 2–6 in Table 5), allergic reactions can contribute to airway inflammation, provoke symptoms, and lead to more use of medications. For this reason, identification and management of clinically relevant allergy merits consideration.52

The EPR3 guidelines1 recommend considering allergen immunotherapy for patients with mild or moderate persistent asthma (steps 2–4) who have a clinically relevant component of allergy to inhaled substances.

Changing the immune response

Allergen immunotherapy entails the incremental administration of inhalant allergens by subcutaneous injection for the purpose of inducing immune system changes in the host response. The goal of immunotherapy is to protect against allergic reactions that can be expected to occur with ongoing exposure to clinically relevant allergens.53

The immunologic changes that develop with allergen immunotherapy are complex.53,54 Successful immunotherapy results in generation of a population of CD4+/CD25+ T lymphocytes producing IL-10, transforming growth factor beta, or both. Allergen immunotherapy has been shown to block the immediate- and late-phase allergic response; to decrease recruitment of mast cells, basophils, and eosinophils on provocation or natural exposure to allergens in the skin, nose, eye, and bronchial mucosa; to blunt the seasonal rise in specific IgE; and to suppress late-phase inflammatory responses in the skin and respiratory tract. However, the efficacy of immunotherapy in relation to these immunologic changes is not completely understood.54

 

 

Many patients need skin testing

Allergen immunotherapy may be considered for patients with asthma for whom a clear relationship exists between symptoms and exposure to an allergen to which the patient is sensitive.53 Because it is often not possible to determine whether a patient is sensitive to a perennial indoor allergen (eg, dust mite) on the basis of the medical history alone,55 many patients with asthma benefit from immediate hypersensitivity skin testing to objectively assess or rule out allergy to common inhalants. In certain situations, in vitro testing may be performed, but skin testing has a higher negative predictive value and is recommended as a better screening test.56

Benefits of allergen immunotherapy

Numerous randomized, double-blind, placebo-controlled trials have shown that allergen immunotherapy is associated with benefit for reducing symptoms and medication reliance.57–63

A meta-analysis of 75 randomized, placebo-controlled studies confirmed the effectiveness of immunotherapy in asthma, with a significant reduction in asthma symptoms and medication use and with improvement in bronchial hyperreactivity.64 This meta-analysis included 36 trials of dust mite allergen, 20 of pollen, and 10 of animal dander. Immunotherapy is efficacious for pollen, mold, dust mite, cockroach, and animal allergens; however, its effectiveness is more established for dust mite, animal dander, and pollen allergens, as fewer studies have been published demonstrating efficacy using mold and cockroach allergens.53

In addition, several studies have found that children with allergic rhinitis who receive allergen immunotherapy are significantly less likely to develop asthma.65–67 Immunotherapy has also been associated with a statistically significant reduction in future sensitization to other aeroallergens.68,69

Risk of systemic reaction from allergen immunotherapy

The decision to begin allergen immunotherapy should be individualized on the basis of symptom severity, relative benefit compared with drug therapy, and whether comorbid conditions such as cardiovascular disease or beta-blocker exposure are present. These comorbid conditions are associated with heightened risk of (more serious) anaphylaxis—the major hazard of allergen immunotherapy.70 Systemic reactions during allergen immunotherapy occur at a rate of approximately 3 to 5 per 1,000 injections; for this reason, allergen immunotherapy should only be administered in a medical facility where personnel, supplies, and equipment are available to treat anaphylaxis.5

This review focuses on several elements in the National Asthma Education and Prevention Program’s new guidelines, the third Expert Panel Report (EPR3),1 that differ substantially from those in EPR2,2 issued in 1997 and updated in 2002.3 These differences in approach to the management of asthma described in EPR3 offer a clear potential for reducing the gap between optimal asthma care outcomes as described in guidelines and normative asthma care outcomes in the “real world.”

GREATER EMPHASIS ON CONTROL

The EPR2 guidelines2 recommended that asthma management be carried out in an algorithmic manner. Patients were classified into four severity categories: mild intermittent, mild persistent, moderate persistent, and severe persistent asthma, based on assessment of the level of symptoms (day/night), reliance on “reliever” medication, and lung function at the time of presentation. Pharmacologic management was then assigned according to each respective categorization in an evidence-based fashion.

In an ideal world, this would result in patients with asthma receiving appropriate pharmacotherapeutic agents associated with favorable asthma care outcomes, which were also advantageous from both cost- and risk-benefit standpoints. In the real world, however, this paradigm was flawed, as it relied on accurate categorization of patients in order for pharmacotherapy to be prescribed appropriately. Both providers and patients are prone to underestimate asthma severity,4,5 and for this reason many patients managed on the basis of this paradigm were undertreated.

A new paradigm, based on the assessment of asthma control, has been encouraged in the EPR3 guidelines.1

Severity and control are not synonymous

More than a decade ago, Cockroft and Swystun6 pointed out that asthma control (or lack thereof) is often used inappropriately to define asthma severity: ie, well-controlled asthma is seen as synonymous with mild asthma, and poorly controlled asthma with severe asthma.

Asthma severity can be defined as the intrinsic intensity of the disease process, while asthma control is the degree to which the manifestations of asthma are minimized. Asthma severity is clearly a determinant of asthma control, but its impact is affected by a variety of factors, including but not limited to:

  • Whether appropriate medication is prescribed
  • Patterns of therapeutic adherence
  • The degree to which recommended measures for avoiding for clinically relevant aeroallergens are pursued.

Health care utilization, including hospitalizations and emergency department visits, correlates more closely with asthma control than with asthma severity.7–9 Indeed, a patient with severe persistent asthma who is treated appropriately with multiple “controller” medications and who takes his or her medications and avoids allergens as directed can achieve well-controlled or totally controlled asthma, and is not likely to require hospitalization or emergency department management, to miss school or work, or to experience nocturnal awakening or limitation in routine activities due to asthma. This patient has severe persistent asthma that is well controlled.

In contrast, a patient with mild or moderate persistent asthma who does not receive appropriate instructions for avoiding allergens or taking controller medication regularly or who is poorly adherent will likely have poor asthma control. This patient is more likely to require hospitalization or emergency department management, to miss school or work, and to experience nocturnal awakening or limitation in routine activities due to asthma. This patient has mild persistent asthma that is poorly controlled.

Assess asthma severity in the first visit, and control in subsequent visits

Li JT, et al. Attaining optimal asthma control: a practice parameter J Allergy Clin Immunol 2005; 116:S3-S11.
Figure 1. The revised paradigm for asthma management recommends that asthma be categorized initially on the basis of severity, with management assigned in an evidence-based manner, but that subsequently, asthma control should be assessed at every clinical encounter, with management decisions based on the level of asthma control.
The revised algorithm for asthma management (Figure 1) recommends that asthma care providers categorize asthma severity at the initial visit (Table 1) and assess asthma control in subsequent visits (Table 2).

How to assess severity

The previous guidelines proposed that asthma severity be assessed before starting long-term therapy. However, many patients are already taking controller medications when initially seen. In the EPR3 guidelines,1 asthma severity can be inferred on the basis of response or lack of response to drug therapy. Responsiveness is defined as the ease with which asthma control can be achieved by therapy. At the initial visit, severity is assessed on the basis of impairment and risk (Table 1), whether or not the patient is regularly taking controller medication. In assessing impairment, we focus on the present, eg, ascertaining symptom frequency and intensity, functional limitation, lung function, and whether the patient follows the treatment and is satisfied with it.

In assessing risk, we focus on the future, with the aim of preventing exacerbations, minimizing the need for emergency department visits or hospitalizations, reducing the tendency for progressive decline in lung function, and providing the least amount of drug therapy required to maintain control in order to minimize risk of untoward effects. The impairment and risk domains may respond differently to treatment.

How to measure control

For all patients with asthma, regardless of severity, the goal is the same: to achieve control by reducing both impairment and risk. Asthma is classified as well controlled, not well controlled, or poorly controlled (Table 2).1

 

 

Validated tests are available to assess control

Asthma control is multidimensional9 and can be assessed by use of validated tests such as the Asthma Control Questionnaire (ACQ), Asthma Therapy Assessment Questionnaire (ATAQ), and the Asthma Control Test (ACT) (Table 3). These tests were designed to gauge asthma control over time in a user-friendly fashion. They are valid, reliable, and responsive to asthma control over time.9–13

In the case of the ACT (Table 4), the patient answers five questions (each on a scale of 1 to 5) about symptoms and the use of rescue medications in the previous 4 weeks. In general, the higher the score (range 5–25), the better the control of the asthma; a cut-point of 19 yields the best balance of sensitivity (71%) and specificity (71%) for classifying asthma as well controlled or not well controlled.13

Serial testing as a quality indicator

Serial ACT scores give an objective measure of the degree to which the goals of management1 are being achieved, and in so doing can encourage optimal outcomes.14

Another use of these tests is to document whether asthma control improves over time when patients receive care from a particular physician or group. This use may become increasingly important in view of efforts underway to implement a pay-for-performance model for asthma care, in which providers will be financially rewarded for improved patient care outcomes and adherence to standards of practice based on Health Plan Employer Data and Information Set measures.15

Figure 2. Mean scores on the Asthma Control Test (ACT) from patients seen in the Section of Allergy/Immunology at Cleveland Clinic in 2005. Among patients who accomplished initial and follow-up ACT measurements, mean scores reflecting self-reported asthma control increased from 14.54 to 19.06.

We have used the ACT in the Section of Allergy/Immunology at Cleveland Clinic for 3 years on a routine basis. All patients with asthma being seen either for the first time or as follow-up complete the ACT, which has been entered in a flow sheet in our electronic medical record, at the same time they undergo spirometry. We have shown that care in the Section of Allergy/Immunology is associated with improvement in asthma control over time, in patients who have completed serial ACT measurements at initial visits and at follow-up visits (Figure 2).

Objective measurement of lung function is also important

Serial monitoring of lung function at every patient visit with spirometry is also important, as some patients may be “poor perceivers,”16 ie, they may have little or no subjective awareness of moderate or even severe ventilatory impairment. A number of studies17,18 support the contention that symptoms and lung function are separate and independent dimensions of asthma control, and that both of them need to be assessed.

Responding to changes in control

If the disease is well controlled, the provider, in collaboration with the patient, may consider continuing the current regimen or “stepping down” to a less aggressive treatment. If the patient’s asthma is not well controlled, it is appropriate to “step up” the treatment. The EPR3 guidelines outline a stepwise approach to therapy (Table 5), from intermittent asthma (step 1) to severe persistent asthma (steps 5 and 6).9 If asthma is poorly controlled, the patient is at risk of exacerbation of asthma and on this basis is clearly a candidate for intervention.11–13,19

THE STEP 3 CONTROVERSY

Salmeterol Multicenter Asthma Research Trial

In the Salmeterol Multicenter Asthma Research Trial (SMART), patients randomized to the long-acting beta agonist (LABA) salmeterol (Serevent)—particularly African Americans—had a statistically significant increase in the risk of untoward asthma care outcomes.20

SMART was launched in 1996. Patients were randomized in a double-blind fashion to receive either salmeterol 42 μg twice a day or placebo in addition to their usual asthma therapy for 28 weeks. The rate of the primary outcome (respiratory-related deaths or life-threatening experiences) was not significantly different with salmeterol than with placebo (relative risk [RR] = 1.40, 95% confidence interval [CI] 0.91–2.14). However, in 2003, the study was halted prematurely because of difficulty enrolling the targeted number of 60,000 patients, and an interim analysis that revealed significantly higher rates of secondary outcomes in subjects randomized to salmeterol. Compared with the placebo group, the salmeterol group had significantly higher rates of respiratory-related deaths (RR 2.16, 95% CI 1.06–4.41), asthma-related deaths (RR = 4.37, 95% CI = 1.25–15.34), and combined asthma-related deaths or life-threatening experiences (RR = 1.71, 95% CI 1.01–2.89). There were 13 asthma-related deaths and 37 combined asthma-related deaths or life-threatening experiences in the salmeterol group, compared with 3 and 22, respectively, in the placebo group. Of the 16 asthma deaths in the study, 13 (81%) occurred in the initial phase of SMART, when patients were recruited via print, radio, and television advertising; afterward, patients were recruited directly by investigators.

Statistically significant differences in outcomes occurred primarily in African Americans. African Americans who received salmeterol had higher rates of respiratory death or life-threatening experiences (RR = 4.10, 95% CI 1.54–10.90), the primary end point for the study, as well as higher rates of combined asthma-related deaths or life-threatening experiences (RR = 10.46, 95% CI 1.34–81.58), a secondary end point. No statistically significant differences were observed in white patients randomized to salmeterol with respect to the primary end point (RR = 1.05, 95% = 0.62–1.76); the secondary end point of combined asthma-related deaths or life-threatening experiences (RR = 1.08, 95% CI 0.55–2.14); or other end points.

Medication exposures were not tracked during the study, and allocation to inhaled corticosteroids combined with salmeterol was not randomized, so the effect of concomitant inhaled corticosteroid use cannot be determined from these data.

As a result of SMART, medications that contain either of the two LABAs, salmeterol or formoterol (Foradil), carry a black-box warning.

 

 

LABAs: Risks and benefits

Two studies21,22 have suggested that asthmatic patients who are homozygous for Arg/Arg at codon 16 of the beta-2 adrenergic receptor are predisposed to untoward asthma outcomes with regular exposure to LABAs. However, other data23–25 do not support the contention that B16 Arg/Arg patients experience adverse asthma outcomes with LABA exposure. In two recently published studies, no difference in rates of exacerbations, severe exacerbations, lung function, frequency of reliance on SABA, or nocturnal awakenings was observed in patients receiving formoterol combined with budesonide24 or salmeterol combined with fluticasone25 according to genotype. A prospective study26 also found no statistically significant difference in exacerbation rates according to beta adrenergic receptor genotype in individuals randomized to LABA monotherapy, or LABA combined with inhaled corticosteroids.

The updated EPR2 asthma guidelines,3 published in November 2002, stipulated that LABAs were the preferred controller agent to “add on” to low-dose inhaled corticosteroids for patients with moderate persistent asthma, and that the combination of low-dose inhaled corticosteroids and LABA was associated with superior outcomes: reduction of symptoms, including nocturnal awakening, increase in lung function, improvement in health-related quality of life, decreased use of “rescue” medication, and reduced rate of exacerbations and severe exacerbations, compared with higher-dose inhaled corticosteroid monotherapy. This management recommendation was categorized as level A, on the basis of data from multiple randomized, controlled, double-blinded trials.27–29 Additional evidence14,30 and data from two meta-analyses31,32 have provided further support for this recommendation, while no evidence linking LABA exposure to risk for fatal or near-fatal asthma has been found in cohort or case-control studies.33–38

Based on safety concerns, the EPR3 guidelines1 recommend that medium-dose inhaled corticosteroids be regarded as equivalent to adding LABAs to low-dose inhaled corticosteroids, and state: “the established, beneficial effects of LABA for the great majority of patients whose asthma is not well controlled with [inhaled corticosteroids] alone should be weighed against the increased risk for severe exacerbations, although uncommon, associated with daily use of LABA.”1

There is currently an honest difference of opinion39,40 among asthma specialists as to how this management recommendation for moderate persistent asthma—now depicted at “step 3” in the EPR3 guidelines (Table 4)—should be implemented. The LABA controversy was reviewed previously in the Cleveland Clinic Journal of Medicine.41

THE ROLE OF OMALIZUMAB: WEIGHING COST VS BENEFIT

The 2002 update to the EPR2 guidelines3 was issued before omalizumab (Xolair) was approved in June 2003.

Patients with severe persistent asthma are categorized in steps 5 or 6 in the EPR3 guidelines (Table 5).1 Preferred management for these patients includes inhaled corticosteroids in high doses combined with long-acting beta agonists and, for step 6 patients, oral corticosteroids.

Omalizumab was approved for management of patients with moderate or severe persistent asthma who are not achieving the goals of asthma management on inhaled corticosteroids, who exhibit a wheal-flare reaction to a perennial allergen, and whose immunoglobulin E (IgE) level is in the range of 30 to 700 IU/mL.42 Omalizumab dosing is based on the serum IgE level and on body weight.

Omalizumab, an anti-IgE monoclonal antibody

Omalizumab is a recombinant, humanized, monoclonal anti-IgE antibody that binds to IgE at the same Fc site as the high-affinity IgE receptor. Its primary mechanism of action is the binding of free IgE in the circulation, forming biologically inert, small complexes that do not activate complement and are cleared by the reticuloendothelial system.42 Its secondary mechanism of action entails a reduction in the number of high-affinity receptors on basophils, from approximately 220,000 to 8,300 receptors per cell. The latter effect was associated with a 90% reduction in histamine release from basophils in response to ex vivo challenge with dust mite allergen.43

Benefit in randomized trials

Omalizumab has been associated with statistically and clinically significant benefit in randomized, double-blind, placebo-controlled trials.44,45

Humbert et al46 randomized 419 patients whose asthma was not adequately controlled on high-dose inhaled corticosteroids and long-acting beta agonists, who were 12 to 75 years old, with reduced lung function and a history of recent asthma exacerbation, to treatment with omalizumab or placebo. Omalizumab was associated with a statistically significant reduction in the rate of asthma exacerbations and severe asthma exacerbations, as well as statistically significant improvements in asthma-related quality of life, morning peak expiratory flow rate, and asthma symptom scores.

These data support the recommendation in EPR3 to consider a trial of omalizumab in properly selected patients with severe, persistent allergic asthma.

 

 

Omalizumab is cost-beneficial in properly selected patients

The current wholesale acquisition cost of omalizumab is $532 for one 150-mg vial (David Zito, personal communication). The cost of treatment varies based on body weight and IgE level but may range from a wholesale cost of $6,388 to $38,326 per year.

However, as asthma severity increases, both direct and indirect medical expenditures increase substantially.47,48 Annual costs are approximately four times higher for severe asthma compared with mild asthma49; not only are treatment and exacerbation costs higher, but indirect costs are also disproportionately greater. Annual costs for severe asthma are significantly greater if the disease is inadequately controlled.50 For these reasons, an intervention that leads to improved outcomes for severe, poorly controlled asthma carries the potential for the greatest cost-utility for society, as it can lower direct costs by reducing the frequency and severity of exacerbations, in addition to reducing indirect medical expenditures on the basis of increased productivity and fewer days of missed work or school. The cost of omalizumab in quality-adjusted life years compares favorably with that of biologicals used in managing rheumatoid arthritis, Crohn disease, and multiple sclerosis.50

Adverse effects of omalizumab

In pivotal trials,43,44 omalizumab was associated with a substantial rate of local reactions. The rate of anaphylaxis was slightly less than 1 in 1,000, and this has been confirmed by surveillance data recorded since approval of the drug in 2003. Based on the observed risk of anaphylaxis, in July 2007, the US Food and Drug Administration added a black-box warning to the omalizumab label and stipulated that a medication guide should be provided for patients.51 The warning indicates that health care providers administering omalizumab should be prepared to manage anaphylaxis and that patients should be closely observed for an appropriate period after omalizumab administration.

The package insert also describes a numerical, but not statistically significant, increase in the rate of malignancy in patients receiving omalizumab.42 Malignancy developed in 0.5% of patients receiving omalizumab, compared with 0.2% of patients who received placebo. Because these malignancies were diagnosed over a shorter period than the time required for oncogenesis (ie, 6 months in 60% of cases), and because a heterogeneous variety of tumors was observed, there is reason to doubt these tumors were causally associated with omalizumab.

Postmarketing surveillance studies are in progress that will provide more definitive data on the potential relationship between malignancy and omalizumab exposure.

Omalizumab: Guideline recommendations

The EPR3 guidelines1 state that omalizumab is the only adjunctive therapy to demonstrate efficacy when added to high-dose inhaled corticosteroids plus long-acting beta agonists in patients with severe, persistent, allergic asthma and that evidence does not support use of the following agents, which in some cases are approved for managing other conditions and have been advocated for management of severe, refractory asthma: methotrexate, soluble interleukin (IL)-4 receptor, anti-IL-5, anti-IL-12, cyclosporine A, intravenous immune globulin, gold, troleandomycin, and colchicine. The data supporting use of macrolides were characterized as “encouraging but insufficient to support a recommendation.”

The strength of evidence for the use of omalizumab for patients in steps 5 and 6 who fulfill the criteria for its use (see above) was classified in the EPR3 guidelines1 as category B. The guidelines also say that omalizumab may be considered for adjunctive therapy in properly selected patients in step 4, as a means to avoid higher doses of inhaled corticosteroids, but that additional studies are needed to establish its utility for such patients. This recommendation was classified as category D because of the lack of published comparator trials.

ALLERGEN IMMUNOTHERAPY FOR PATIENTS WITH ASTHMA

Many patients with asthma have clinically relevant, IgE-mediated (allergic) potential to inhaled allergens.1 For patients with persistent asthma (steps 2–6 in Table 5), allergic reactions can contribute to airway inflammation, provoke symptoms, and lead to more use of medications. For this reason, identification and management of clinically relevant allergy merits consideration.52

The EPR3 guidelines1 recommend considering allergen immunotherapy for patients with mild or moderate persistent asthma (steps 2–4) who have a clinically relevant component of allergy to inhaled substances.

Changing the immune response

Allergen immunotherapy entails the incremental administration of inhalant allergens by subcutaneous injection for the purpose of inducing immune system changes in the host response. The goal of immunotherapy is to protect against allergic reactions that can be expected to occur with ongoing exposure to clinically relevant allergens.53

The immunologic changes that develop with allergen immunotherapy are complex.53,54 Successful immunotherapy results in generation of a population of CD4+/CD25+ T lymphocytes producing IL-10, transforming growth factor beta, or both. Allergen immunotherapy has been shown to block the immediate- and late-phase allergic response; to decrease recruitment of mast cells, basophils, and eosinophils on provocation or natural exposure to allergens in the skin, nose, eye, and bronchial mucosa; to blunt the seasonal rise in specific IgE; and to suppress late-phase inflammatory responses in the skin and respiratory tract. However, the efficacy of immunotherapy in relation to these immunologic changes is not completely understood.54

 

 

Many patients need skin testing

Allergen immunotherapy may be considered for patients with asthma for whom a clear relationship exists between symptoms and exposure to an allergen to which the patient is sensitive.53 Because it is often not possible to determine whether a patient is sensitive to a perennial indoor allergen (eg, dust mite) on the basis of the medical history alone,55 many patients with asthma benefit from immediate hypersensitivity skin testing to objectively assess or rule out allergy to common inhalants. In certain situations, in vitro testing may be performed, but skin testing has a higher negative predictive value and is recommended as a better screening test.56

Benefits of allergen immunotherapy

Numerous randomized, double-blind, placebo-controlled trials have shown that allergen immunotherapy is associated with benefit for reducing symptoms and medication reliance.57–63

A meta-analysis of 75 randomized, placebo-controlled studies confirmed the effectiveness of immunotherapy in asthma, with a significant reduction in asthma symptoms and medication use and with improvement in bronchial hyperreactivity.64 This meta-analysis included 36 trials of dust mite allergen, 20 of pollen, and 10 of animal dander. Immunotherapy is efficacious for pollen, mold, dust mite, cockroach, and animal allergens; however, its effectiveness is more established for dust mite, animal dander, and pollen allergens, as fewer studies have been published demonstrating efficacy using mold and cockroach allergens.53

In addition, several studies have found that children with allergic rhinitis who receive allergen immunotherapy are significantly less likely to develop asthma.65–67 Immunotherapy has also been associated with a statistically significant reduction in future sensitization to other aeroallergens.68,69

Risk of systemic reaction from allergen immunotherapy

The decision to begin allergen immunotherapy should be individualized on the basis of symptom severity, relative benefit compared with drug therapy, and whether comorbid conditions such as cardiovascular disease or beta-blocker exposure are present. These comorbid conditions are associated with heightened risk of (more serious) anaphylaxis—the major hazard of allergen immunotherapy.70 Systemic reactions during allergen immunotherapy occur at a rate of approximately 3 to 5 per 1,000 injections; for this reason, allergen immunotherapy should only be administered in a medical facility where personnel, supplies, and equipment are available to treat anaphylaxis.5

References
  1. National Heart, Lung, and Blood institute, National Asthma education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and management of asthma. www.nhlbi.nih.gov/guidelines/asthma. Accessed 8/7/08.
  2. Expert Panel Report 2: Guidelines for the diagnosis and management of asthma. U.S. Department of Health and Human Services. Publication No. 97-4051; 1997.
  3. Expert Panel Report: Guidelines for the diagnosis and management of asthma. Update on Selected Topics—2002. J Allergy Clin Immunol 2002; 110:S141–S207.
  4. FitzGerald JM, Boulet LP, McIvor RA, Zimmerman S, Chapman KR. Asthma control in Canada remains suboptimal: the Reality of Asthma Control (TRAC) study. Can Respir J 2006; 13:253–259.
  5. Braganza S, Sharif I, Ozuah P. Documenting asthma severity: do we get it right? J Asthma 2003; 40:661–665.
  6. Cockcroft DW, Swystun VA. Asthma control versus asthma severity. J Allergy Clin Immunol 1996; 98:1016–1018.
  7. Peters SP, Jones CA, Haselkorn T, Mink DR, Valacer DJ, Weiss ST. Real-world Evaluation of Asthma Control and Treatment (REACT): findings from a national Web-based survey. J Allergy Clin Immunol. 2007; 119:1454–1461.
  8. Osborne ML, Vollmer WM, Pedula KL, Wilkins J, Buist AS, O’Hollaren M. Lack of correlation of symptoms with specialist-assessed long-term asthma severity. Chest 1999; 115:85–91.
  9. Li JT, Oppenheimer J, Bernstein IL, et al. Attaining optimal asthma control: a practice parameter. J Allergy Clin Immunol 2005; 116:S3–S11.
  10. Nathan RA, Sorkness C, Kosinski M, et al. Development of the Asthma Control Test: a survey for assessing asthma control. J Allergy Clin Immunol 2004; 113:59–65.
  11. Schatz M, Zeiger RS, Drane A, et al. Reliability and predictive validity of the Asthma Control Test administered by telephone calls using speech recognition technology. J Allergy Clin Immunol 2007; 119:336–343.
  12. Peters D, Chen C, Markson LE, Allen-Ramey FC, Vollmer WM. Using an asthma control questionnaire and administrative data to predict healthcare utilization. Chest 2006; 129:918–924.
  13. Schatz M, Sorkness C, Li JT, et al. Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists. J Allergy Clin Immunol 2006; 117:549–556.
  14. Bateman E, Boushey H, Bousquet J, et al. Can guideline-defined asthma control be achieved? Am J Respir Crit Care Med 2004; 170:836–844.
  15. Davies TJ, Bunn WB, Fromer L, Gelfand EW, Colice GL. A focus on the asthma HEDIS measure and its implications for clinical practice. Manag Care Interface 2006; 19:29–36.
  16. Rubinfeld AR, Pain MC. Perception of asthma. Lancet 1976; 1:882–884.
  17. Teeter J, Bleecker E. Relationship between airway obstruction and respiratory symptoms in adult asthmatics. Chest 1998; 113:272–277.
  18. Shingo S, Zhang J, Reiss T. Correlation of airway obstruction and patient reported endpoints in clinical studies. Eur Resp J 2001; 17:220–224.
  19. Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med 2006; 100:616–621.
  20. Nelson H, Weiss S, Bleecker E, Yancey S, Dorinsky P. The Salmeterol Multicenter Asthma Research Trial. Chest 2006; 129:15–26.
  21. Wechsler M, Lehman E, Lazarus S, et al. ß-Adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006; 173:519–526.
  22. Palmer CNA, Lipworth BJ, Lee S, Ismail T, MacGregor DF, Mukhopadhyay S. Arginine-16 beta-2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax 2006; 61:940–944.
  23. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term beta agonist use: influence of beta 2 adrenoceptor polymorphism. Thorax 2000; 55:762–727.
  24. Bleecker E, Postma D, Lawrance R, Meyers D, Ambrose H, Goldman M. Effect of ADRB2 polymorphisms on response to long-acting beta2-agonist therapy: a pharmacogenetic analysis of two randomized studies. Lancet 2007; 370:2118–2125.
  25. Bleecker E, Yancey S, Baitinger L, et al. Salmeterol response is not affected by beta-2 adrenergic receptor genotype in subjects with persistent asthma. J Allergy Clin Immunol 2006; 118:809–816.
  26. Nelson H, Bleecker E, Corren J, et al. Characterization of asthma exacerbations by Arg16Gly genotype in subjects with asthma receiving salmeterol alone or with fluticasone propionate. J Allergy Clin Immunol 2008; 121:S131.
  27. O’Byrne P, Barnes P, Rodriguez-Roisin R, et al. Low dose Inhaled budesonide and formoterol in mild persistent asthma. The OPTIMA Randomized Trial. Am J Respir Crit Care Med 2001; 164:1392–1397.
  28. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994; 344:219–224.
  29. Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153:1481–1488.
  30. Walters EH, Walters JAE, Gibson MDP. Long-acting beta2-agonists for stable chronic asthma. Cochrane Database Syst Rev 2003; (3):CD001385. doi:10.1002/14651858.CD001385.
  31. Masoli M, Weatherall M, Holt S, Beasley R. Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroid in symptomatic asthma. Thorax 2005; 60:730–734.
  32. Sin DD, Man J, Sharpe H, Gan WQ, Man SFP. Pharmacological management to reduce exacerbations in adults with asthma. A systematic review and meta-analysis. JAMA 2004; 292:367–376.
  33. Mann RD, Kubota K, Pearce G, Wilton L. Salmeterol: a study by prescription event monitoring in a UK cohort of 15,407 patients. J Clin Epidemiol 1996; 49:247–250.
  34. Lanes S, Lanza L, Wentworth C. Risk of emergency care, hospitalization, and ICU stays for acute asthma among recipients of salmeterol. Am J Respir Crit Care Med 1998; 158:857–861.
  35. Meier CR, Jick H. Drug use and pulmonary death rates in increasingly symptomatic asthma patients in the UK. Thorax 1997; 52:612–617.
  36. Williams C, Crossland L, Finnerty J, et al. A case control study of salmeterol and near-fatal attacks of asthma. Thorax 1998; 53:7–13.
  37. Lanes S, Garcia Rodriguez LA, Herta C. Respiratory medications and risk of asthma death. Thorax 2002; 57:683–686.
  38. Anderson HR, Ayres JG, Sturdy PM, et al. Bronchodilator treatment and deaths from asthma: case control study. Br Med J 2005; 330:117–124.
  39. Martinez FD. Safety of long-acting beta agonists—an urgent need to clear the air. N Engl J Med 2005; 353:2637–2639.
  40. Nelson HS. Long-acting beta-agonists in adult asthma: evidence that these drugs are safe. Prim Care Respir J 2006; 15:271–277.
  41. Lang DM. The long-acting beta agonist controversy: a critical examination of the evidence. Cleve Clin J Med 2006; 73:973–992.
  42. Rambasek T, Lang DM, Kavuru M. Omalizumab: where does it fit in current asthma management? Cleve Clin J Med 2004; 71:251–261.
  43. McGlashan D, Bochner B, Adelman D, et al. Down regulation of Fc(epsilon)RI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997; 158:1438–1445.
  44. Busse W, Corren J, Lanier B, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001; 108:184–190.
  45. Soler M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reduces asthma exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001; 18:254–261.
  46. Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60:309–316.
  47. Van Ganse E, Antonicelli L, Zhang Q, et al. Asthma-related resource use and cost by GINA classification of severity in three European countries. Respir Med 2006; 100:140–147.
  48. Godard P, Chanez P, Siraudin L, Nicoloyannis N, Duru G. Costs of asthma are correlated with severity: a 1-yr prospective study. Eur Respir J 2002; 19:61–67.
  49. Cisternas MG, Blanc PH, Yen IH, et al. A comprehensive study of the direct and indirect costs of adult asthma. J Allergy Clin Immunol 2003; 111:1212–1218.
  50. Sullivan S, Turk F. An evaluation of the cost effectiveness of omalizumab for the treatment of severe persistent asthma. Allergy 2008; 63:670–684.
  51. US Food and Drug Administration. Omalizumab (marketed as Xolair) information. www.fda.gov/cder/drug/infopage/omalizumab/default.htm. Accessed August 31, 2007.
  52. Williams SG, Schmidt DK, Redd SC, Storms W. Key clinical activities for quality asthma care. Recommendations of the National Asthma Education and Prevention Program. MMWR Recomm Rep 2003; 52 RR-6:1–8.
  53. Cox L, Li J, Nelson H, Lockey R, et al. Allergy Immunotherapy: a practice parameter second update. J Allergy Clin Immunol 2007; 120:S25–S85.
  54. Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol 2007; 119:780–789.
  55. Murray AB, Milner RA. The accuracy of features in the clinical history for predicting atopic sensitization to airborne allergens in children. J Allergy Clin Immunol 1995; 96:588–596.
  56. Bernstein IL, Li JT, Bernstein DI, et al. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol 2008; 100 suppl 3:1S–148S.
  57. Walker S, Pajno GB, Lima MT, Wilson DR, Durham SR. Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial. J Allergy Clin Immunol 2001; 107:87–93.
  58. Varney VA, Edwards J, Tabbah K, Brewster H, Mavroleon G, Frew AJ. Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebo-controlled trial. Clin Exp Allergy 1997; 27:860–867.
  59. Cantani A, Arcese G, Lucenti P, Gagliesi D, Bartolucci M. A three-year prospective study of specific immunotherapy to inhalant allergens: evidence of safety and efficacy in 300 children with allergic asthma. J Investig Allergol Clin Immunol 1997; 7:90–97.
  60. Hedlin G, Wille S, Browaldh L, et al. Immunotherapy in children with allergic asthma: effect on bronchial hyperreactivity and pharmacotherapy. J Allergy Clin Immunol 1999; 103:609–614.
  61. Arvidsson MB, Löwhagen O, Rak S. Allergen specific immunotherapy attenuates early and late phase reactions in lower airways of birch pollen asthmatic patients: a double blind placebo-controlled study. Allergy 2004; 59:74–80.
  62. Pichler CE, Helbling A, Pichler WJ. Three years of specific immunotherapy with house-dust-mite extracts in patients with rhinitis and asthma: significant improvement of allergen-specific parameters and of nonspecific bronchial hyperreactivity. Allergy 2001; 56:301–306.
  63. Mirone C, Albert F, Tosi A, et al. Efficacy and safety of subcutaneous immunotherapy with a biologically standardized extract of Ambrosia artemisiifolia pollen: a double-blind, placebo-controlled study. Clin Exp Allergy 2004; 34:1408–1414.
  64. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2003; (4):CD001186.
  65. Jacobsen L. Preventive aspects of immunotherapy: prevention for children at risk of developing asthma. Ann Allergy Asthma Immunol 2001; 87:43–46.
  66. Moller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT study). J Allergy Clin Immunol 2002; 109:251–256.
  67. Niggemann B, Jacobsen L, Dreborg S, et al; PAT Investigator Group. Five year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy 2006: 61:855–859.
  68. Des Roches A, Paradis L, Menardo JL, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract VI: specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997; 99:450–453.
  69. Pajno GB, Barberio G, DeLuca F, et al. Prevention of new sensitizations in asthmatic children monosensitized to the house dust mite by specific immunotherapy: a six year follow up study. Clin Exp Allergy 2001; 31:1392–1397.
  70. Lang DM. Do beta blockers really enhance the risk of anaphylaxis during immunotherapy? Curr Allergy Asthma Rep 2008; 8:37–44.
References
  1. National Heart, Lung, and Blood institute, National Asthma education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and management of asthma. www.nhlbi.nih.gov/guidelines/asthma. Accessed 8/7/08.
  2. Expert Panel Report 2: Guidelines for the diagnosis and management of asthma. U.S. Department of Health and Human Services. Publication No. 97-4051; 1997.
  3. Expert Panel Report: Guidelines for the diagnosis and management of asthma. Update on Selected Topics—2002. J Allergy Clin Immunol 2002; 110:S141–S207.
  4. FitzGerald JM, Boulet LP, McIvor RA, Zimmerman S, Chapman KR. Asthma control in Canada remains suboptimal: the Reality of Asthma Control (TRAC) study. Can Respir J 2006; 13:253–259.
  5. Braganza S, Sharif I, Ozuah P. Documenting asthma severity: do we get it right? J Asthma 2003; 40:661–665.
  6. Cockcroft DW, Swystun VA. Asthma control versus asthma severity. J Allergy Clin Immunol 1996; 98:1016–1018.
  7. Peters SP, Jones CA, Haselkorn T, Mink DR, Valacer DJ, Weiss ST. Real-world Evaluation of Asthma Control and Treatment (REACT): findings from a national Web-based survey. J Allergy Clin Immunol. 2007; 119:1454–1461.
  8. Osborne ML, Vollmer WM, Pedula KL, Wilkins J, Buist AS, O’Hollaren M. Lack of correlation of symptoms with specialist-assessed long-term asthma severity. Chest 1999; 115:85–91.
  9. Li JT, Oppenheimer J, Bernstein IL, et al. Attaining optimal asthma control: a practice parameter. J Allergy Clin Immunol 2005; 116:S3–S11.
  10. Nathan RA, Sorkness C, Kosinski M, et al. Development of the Asthma Control Test: a survey for assessing asthma control. J Allergy Clin Immunol 2004; 113:59–65.
  11. Schatz M, Zeiger RS, Drane A, et al. Reliability and predictive validity of the Asthma Control Test administered by telephone calls using speech recognition technology. J Allergy Clin Immunol 2007; 119:336–343.
  12. Peters D, Chen C, Markson LE, Allen-Ramey FC, Vollmer WM. Using an asthma control questionnaire and administrative data to predict healthcare utilization. Chest 2006; 129:918–924.
  13. Schatz M, Sorkness C, Li JT, et al. Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists. J Allergy Clin Immunol 2006; 117:549–556.
  14. Bateman E, Boushey H, Bousquet J, et al. Can guideline-defined asthma control be achieved? Am J Respir Crit Care Med 2004; 170:836–844.
  15. Davies TJ, Bunn WB, Fromer L, Gelfand EW, Colice GL. A focus on the asthma HEDIS measure and its implications for clinical practice. Manag Care Interface 2006; 19:29–36.
  16. Rubinfeld AR, Pain MC. Perception of asthma. Lancet 1976; 1:882–884.
  17. Teeter J, Bleecker E. Relationship between airway obstruction and respiratory symptoms in adult asthmatics. Chest 1998; 113:272–277.
  18. Shingo S, Zhang J, Reiss T. Correlation of airway obstruction and patient reported endpoints in clinical studies. Eur Resp J 2001; 17:220–224.
  19. Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med 2006; 100:616–621.
  20. Nelson H, Weiss S, Bleecker E, Yancey S, Dorinsky P. The Salmeterol Multicenter Asthma Research Trial. Chest 2006; 129:15–26.
  21. Wechsler M, Lehman E, Lazarus S, et al. ß-Adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006; 173:519–526.
  22. Palmer CNA, Lipworth BJ, Lee S, Ismail T, MacGregor DF, Mukhopadhyay S. Arginine-16 beta-2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax 2006; 61:940–944.
  23. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term beta agonist use: influence of beta 2 adrenoceptor polymorphism. Thorax 2000; 55:762–727.
  24. Bleecker E, Postma D, Lawrance R, Meyers D, Ambrose H, Goldman M. Effect of ADRB2 polymorphisms on response to long-acting beta2-agonist therapy: a pharmacogenetic analysis of two randomized studies. Lancet 2007; 370:2118–2125.
  25. Bleecker E, Yancey S, Baitinger L, et al. Salmeterol response is not affected by beta-2 adrenergic receptor genotype in subjects with persistent asthma. J Allergy Clin Immunol 2006; 118:809–816.
  26. Nelson H, Bleecker E, Corren J, et al. Characterization of asthma exacerbations by Arg16Gly genotype in subjects with asthma receiving salmeterol alone or with fluticasone propionate. J Allergy Clin Immunol 2008; 121:S131.
  27. O’Byrne P, Barnes P, Rodriguez-Roisin R, et al. Low dose Inhaled budesonide and formoterol in mild persistent asthma. The OPTIMA Randomized Trial. Am J Respir Crit Care Med 2001; 164:1392–1397.
  28. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994; 344:219–224.
  29. Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153:1481–1488.
  30. Walters EH, Walters JAE, Gibson MDP. Long-acting beta2-agonists for stable chronic asthma. Cochrane Database Syst Rev 2003; (3):CD001385. doi:10.1002/14651858.CD001385.
  31. Masoli M, Weatherall M, Holt S, Beasley R. Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroid in symptomatic asthma. Thorax 2005; 60:730–734.
  32. Sin DD, Man J, Sharpe H, Gan WQ, Man SFP. Pharmacological management to reduce exacerbations in adults with asthma. A systematic review and meta-analysis. JAMA 2004; 292:367–376.
  33. Mann RD, Kubota K, Pearce G, Wilton L. Salmeterol: a study by prescription event monitoring in a UK cohort of 15,407 patients. J Clin Epidemiol 1996; 49:247–250.
  34. Lanes S, Lanza L, Wentworth C. Risk of emergency care, hospitalization, and ICU stays for acute asthma among recipients of salmeterol. Am J Respir Crit Care Med 1998; 158:857–861.
  35. Meier CR, Jick H. Drug use and pulmonary death rates in increasingly symptomatic asthma patients in the UK. Thorax 1997; 52:612–617.
  36. Williams C, Crossland L, Finnerty J, et al. A case control study of salmeterol and near-fatal attacks of asthma. Thorax 1998; 53:7–13.
  37. Lanes S, Garcia Rodriguez LA, Herta C. Respiratory medications and risk of asthma death. Thorax 2002; 57:683–686.
  38. Anderson HR, Ayres JG, Sturdy PM, et al. Bronchodilator treatment and deaths from asthma: case control study. Br Med J 2005; 330:117–124.
  39. Martinez FD. Safety of long-acting beta agonists—an urgent need to clear the air. N Engl J Med 2005; 353:2637–2639.
  40. Nelson HS. Long-acting beta-agonists in adult asthma: evidence that these drugs are safe. Prim Care Respir J 2006; 15:271–277.
  41. Lang DM. The long-acting beta agonist controversy: a critical examination of the evidence. Cleve Clin J Med 2006; 73:973–992.
  42. Rambasek T, Lang DM, Kavuru M. Omalizumab: where does it fit in current asthma management? Cleve Clin J Med 2004; 71:251–261.
  43. McGlashan D, Bochner B, Adelman D, et al. Down regulation of Fc(epsilon)RI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997; 158:1438–1445.
  44. Busse W, Corren J, Lanier B, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001; 108:184–190.
  45. Soler M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reduces asthma exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001; 18:254–261.
  46. Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60:309–316.
  47. Van Ganse E, Antonicelli L, Zhang Q, et al. Asthma-related resource use and cost by GINA classification of severity in three European countries. Respir Med 2006; 100:140–147.
  48. Godard P, Chanez P, Siraudin L, Nicoloyannis N, Duru G. Costs of asthma are correlated with severity: a 1-yr prospective study. Eur Respir J 2002; 19:61–67.
  49. Cisternas MG, Blanc PH, Yen IH, et al. A comprehensive study of the direct and indirect costs of adult asthma. J Allergy Clin Immunol 2003; 111:1212–1218.
  50. Sullivan S, Turk F. An evaluation of the cost effectiveness of omalizumab for the treatment of severe persistent asthma. Allergy 2008; 63:670–684.
  51. US Food and Drug Administration. Omalizumab (marketed as Xolair) information. www.fda.gov/cder/drug/infopage/omalizumab/default.htm. Accessed August 31, 2007.
  52. Williams SG, Schmidt DK, Redd SC, Storms W. Key clinical activities for quality asthma care. Recommendations of the National Asthma Education and Prevention Program. MMWR Recomm Rep 2003; 52 RR-6:1–8.
  53. Cox L, Li J, Nelson H, Lockey R, et al. Allergy Immunotherapy: a practice parameter second update. J Allergy Clin Immunol 2007; 120:S25–S85.
  54. Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol 2007; 119:780–789.
  55. Murray AB, Milner RA. The accuracy of features in the clinical history for predicting atopic sensitization to airborne allergens in children. J Allergy Clin Immunol 1995; 96:588–596.
  56. Bernstein IL, Li JT, Bernstein DI, et al. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol 2008; 100 suppl 3:1S–148S.
  57. Walker S, Pajno GB, Lima MT, Wilson DR, Durham SR. Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial. J Allergy Clin Immunol 2001; 107:87–93.
  58. Varney VA, Edwards J, Tabbah K, Brewster H, Mavroleon G, Frew AJ. Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebo-controlled trial. Clin Exp Allergy 1997; 27:860–867.
  59. Cantani A, Arcese G, Lucenti P, Gagliesi D, Bartolucci M. A three-year prospective study of specific immunotherapy to inhalant allergens: evidence of safety and efficacy in 300 children with allergic asthma. J Investig Allergol Clin Immunol 1997; 7:90–97.
  60. Hedlin G, Wille S, Browaldh L, et al. Immunotherapy in children with allergic asthma: effect on bronchial hyperreactivity and pharmacotherapy. J Allergy Clin Immunol 1999; 103:609–614.
  61. Arvidsson MB, Löwhagen O, Rak S. Allergen specific immunotherapy attenuates early and late phase reactions in lower airways of birch pollen asthmatic patients: a double blind placebo-controlled study. Allergy 2004; 59:74–80.
  62. Pichler CE, Helbling A, Pichler WJ. Three years of specific immunotherapy with house-dust-mite extracts in patients with rhinitis and asthma: significant improvement of allergen-specific parameters and of nonspecific bronchial hyperreactivity. Allergy 2001; 56:301–306.
  63. Mirone C, Albert F, Tosi A, et al. Efficacy and safety of subcutaneous immunotherapy with a biologically standardized extract of Ambrosia artemisiifolia pollen: a double-blind, placebo-controlled study. Clin Exp Allergy 2004; 34:1408–1414.
  64. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2003; (4):CD001186.
  65. Jacobsen L. Preventive aspects of immunotherapy: prevention for children at risk of developing asthma. Ann Allergy Asthma Immunol 2001; 87:43–46.
  66. Moller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT study). J Allergy Clin Immunol 2002; 109:251–256.
  67. Niggemann B, Jacobsen L, Dreborg S, et al; PAT Investigator Group. Five year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy 2006: 61:855–859.
  68. Des Roches A, Paradis L, Menardo JL, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract VI: specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997; 99:450–453.
  69. Pajno GB, Barberio G, DeLuca F, et al. Prevention of new sensitizations in asthmatic children monosensitized to the house dust mite by specific immunotherapy: a six year follow up study. Clin Exp Allergy 2001; 31:1392–1397.
  70. Lang DM. Do beta blockers really enhance the risk of anaphylaxis during immunotherapy? Curr Allergy Asthma Rep 2008; 8:37–44.
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New asthma guidelines emphasize control, regular monitoring
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  • The EPR3 recommends that management decisions be based initially on asthma severity, and subsequently on asthma control as assessed serially by validated tests.
  • Omalizumab, a monoclonal antibody against immunoglobulin E, is the only adjunctive therapy to demonstrate efficacy when added to high-dose inhaled corticosteroids plus long-acting beta agonists in patients with severe, persistent, allergic asthma.
  • The EPR3 guidelines recommend consideration of allergen immunotherapy for patients with mild or moderate persistent allergic asthma.
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The controversy over long-acting beta agonists: Examining the evidence

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David M. Lang, MD
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David M. Lang, MD
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David M. Lang, MD
Head, Allergy and Clinical Immunology Section, Department of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic

Address: David M. Lang, MD, Allergy and Clinical Immunology Section, Department of Pulmonary, Allergy, and Critical Care Medicine, C22, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail langd@ccf.org

Dr. Lang has disclosed that he has received honoraria, consulting fees, or other benefits for teaching, speaking, consulting, or conducting research for the AstraZeneca, Centocor, Critical Therapeutics, Genentech, Novartis, GlaxoSmithKline, MedPointe, Merck, Sanofi-Aventis, and Schering-Plough/Key corporations.

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David M. Lang, MD
Head, Allergy and Clinical Immunology Section, Department of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic

Address: David M. Lang, MD, Allergy and Clinical Immunology Section, Department of Pulmonary, Allergy, and Critical Care Medicine, C22, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail langd@ccf.org

Dr. Lang has disclosed that he has received honoraria, consulting fees, or other benefits for teaching, speaking, consulting, or conducting research for the AstraZeneca, Centocor, Critical Therapeutics, Genentech, Novartis, GlaxoSmithKline, MedPointe, Merck, Sanofi-Aventis, and Schering-Plough/Key corporations.

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Cleveland Clinic Journal of Medicine - 73(11)
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Cleveland Clinic Journal of Medicine - 73(11)
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973-976, 978, 981-984, 986, 989, 992
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973-976, 978, 981-984, 986, 989, 992
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Cleveland Clinic Journal of Medicine
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The controversy over long-acting beta agonists: Examining the evidence
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Evaluating and managing hypogammaglobulinemia

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Evaluating and managing hypogammaglobulinemia
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Mark E. Rose, MD
David M. Lang, MD
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David M. Lang, MD
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Address: David M. Lang, MD, Department of Allergy and Immunology, C22, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195

Dr. Lang has indicated that he has received honoraria from, has served as a consultant for, or has carried out clinical research with the AstraZeneca, Aventis, Genetech, GlaxoSmithKline, Ivax, Merck, Novartis, Pfizer, and Schering/Key corporations.

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David M. Lang, MD
Head, Section of Adult Department of Allergy and Immunology, Department of Pulmonary, Allergy, and Critical Care Medicine, The Cleveland Clinic Foundation

Address: David M. Lang, MD, Department of Allergy and Immunology, C22, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195

Dr. Lang has indicated that he has received honoraria from, has served as a consultant for, or has carried out clinical research with the AstraZeneca, Aventis, Genetech, GlaxoSmithKline, Ivax, Merck, Novartis, Pfizer, and Schering/Key corporations.

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David M. Lang, MD
Head, Section of Adult Department of Allergy and Immunology, Department of Pulmonary, Allergy, and Critical Care Medicine, The Cleveland Clinic Foundation

Address: David M. Lang, MD, Department of Allergy and Immunology, C22, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195

Dr. Lang has indicated that he has received honoraria from, has served as a consultant for, or has carried out clinical research with the AstraZeneca, Aventis, Genetech, GlaxoSmithKline, Ivax, Merck, Novartis, Pfizer, and Schering/Key corporations.

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Cleveland Clinic Journal of Medicine - 73(2)
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Omalizumab: Where does it fit into current asthma management?

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Omalizumab: Where does it fit into current asthma management?
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David M. Lang, MD
Mani S. Kavuru, MD
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Todd E. Rambasek, MD
Section of Allergy and Immunology, Department of Pulmonary, Allergy, and Critical
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David M. Lang, MD
Head, Section of Allergy and Immunology, Department of Pulmonary, Allergy, and Critical Care Medicine, The Cleveland Clinic Foundation

Mani S. Kavuru, MD
Director, Pulmonary Function Laboratory, Department of Pulmonary, Allergy, and Critical Care Medicine, The Cleveland Clinic Foundation

Address: Mani S. Kavuru, MD, Director, Pulmonary Function Laboratory, Department of Pulmonary and Critical Care Medicine, A72, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail kavurum@ccf.org

Dr. Lang has indicated that he has received honoraria from, carried out clinical research with, or served as a consultant for the Abbott, AstraZeneca, Aventis, Genentech/Novartis, GlaxoSmithKline, Merck, Pfizer, and Schering/Key corporations.

Dr. Kavuru has indicated that he has received grant or research support from and serves on the speakers’ bureaus of the Genentech/Novartis and GlaxoSmithKline corporations.

This paper discusses therapies that are experimental or are not approved by the US Food and Drug Administration for the use under discussion.

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Cleveland Clinic Journal of Medicine - 71(3)
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Todd E. Rambasek, MD
David M. Lang, MD
Mani S. Kavuru, MD
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Todd E. Rambasek, MD
David M. Lang, MD
Mani S. Kavuru, MD
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Todd E. Rambasek, MD
Section of Allergy and Immunology, Department of Pulmonary, Allergy, and Critical
Care Medicine, The Cleveland Clinic Foundation

David M. Lang, MD
Head, Section of Allergy and Immunology, Department of Pulmonary, Allergy, and Critical Care Medicine, The Cleveland Clinic Foundation

Mani S. Kavuru, MD
Director, Pulmonary Function Laboratory, Department of Pulmonary, Allergy, and Critical Care Medicine, The Cleveland Clinic Foundation

Address: Mani S. Kavuru, MD, Director, Pulmonary Function Laboratory, Department of Pulmonary and Critical Care Medicine, A72, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail kavurum@ccf.org

Dr. Lang has indicated that he has received honoraria from, carried out clinical research with, or served as a consultant for the Abbott, AstraZeneca, Aventis, Genentech/Novartis, GlaxoSmithKline, Merck, Pfizer, and Schering/Key corporations.

Dr. Kavuru has indicated that he has received grant or research support from and serves on the speakers’ bureaus of the Genentech/Novartis and GlaxoSmithKline corporations.

This paper discusses therapies that are experimental or are not approved by the US Food and Drug Administration for the use under discussion.

Author and Disclosure Information

Todd E. Rambasek, MD
Section of Allergy and Immunology, Department of Pulmonary, Allergy, and Critical
Care Medicine, The Cleveland Clinic Foundation

David M. Lang, MD
Head, Section of Allergy and Immunology, Department of Pulmonary, Allergy, and Critical Care Medicine, The Cleveland Clinic Foundation

Mani S. Kavuru, MD
Director, Pulmonary Function Laboratory, Department of Pulmonary, Allergy, and Critical Care Medicine, The Cleveland Clinic Foundation

Address: Mani S. Kavuru, MD, Director, Pulmonary Function Laboratory, Department of Pulmonary and Critical Care Medicine, A72, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail kavurum@ccf.org

Dr. Lang has indicated that he has received honoraria from, carried out clinical research with, or served as a consultant for the Abbott, AstraZeneca, Aventis, Genentech/Novartis, GlaxoSmithKline, Merck, Pfizer, and Schering/Key corporations.

Dr. Kavuru has indicated that he has received grant or research support from and serves on the speakers’ bureaus of the Genentech/Novartis and GlaxoSmithKline corporations.

This paper discusses therapies that are experimental or are not approved by the US Food and Drug Administration for the use under discussion.

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Cleveland Clinic Journal of Medicine - 71(3)
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Cleveland Clinic Journal of Medicine - 71(3)
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Omalizumab: Where does it fit into current asthma management?
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