Nancy Otto, PharmD
The most common chronic childhood illness is asthma, placing a significant burden on healthcare and educational systems. In this interview, Nancy Otto, PharmD, Scientific Director, Medscape, shares clinical insights from childhood asthma expert Bradley E. Chipps, MD, Medical Director, Cystic Fibrosis Center, Capital Allergy & Respiratory Disease Center, Sacramento, California, and Associate Medical Director, Sleep Laboratory of Sutter Community Hospitals, Sacramento, California.
Medscape: We'll begin our discussion with risk factors for childhood asthma. Dr. Chipps, please discuss the pathogenesis of childhood asthma, specifically with respect to genetic and environmental factors.
Dr. Chipps: The genetic factors for asthma are quite significant. There are many candidate genes for asthma. There is almost daily change in the number of genetic programming factors that give the chance for what is called gene by environment and interaction. This means that the right gene pool put in the right environment leads to asthma.
Rhinovirus infections are the most common viral infections to cause airway injury, which then leads to asthma. This is also seen in respiratory syncytial virus, but to a lesser extent.
Patients have confounding variables when they have significant allergy as a driving factor. This was particularly shown in the Tucson Children's Respiratory Study,[1] which is now in its 30th year, as well as in the Multicenter Allergy Study (MAS)[2] from Germany highlighting a cohort of over 1300 children who have been followed up to 13 years of age. These studies found the early sensitization and exposure to house dust mite; dog and cat was the major predictor for persistence of symptoms. Ninety percent of the children who wheezed but didn't have that exposure lost their symptoms of recurrent wheezing by the early school-age years and retained normal lung function. The early sensitization and early exposure were even greater risk factors than the later development of seasonal allergic rhinitis. The dye is cast very early. This supports the data from the Mayo Clinic that was published over 2 decades ago,[3] again suggesting that 80% of asthma begins before 5 years of age.
Very clearly, we have an early inception, early-injury viral infection, and concurrent acquisition of an allergic diathesis leading to persistence of the phenotypic expression of asthma.
Medscape: What role does the hygiene hypothesis play in childhood asthma?
Dr. Chipps: It's yet to be clearly defined. The hygiene hypothesis is just that, a hypothesis. There are surely patients who have exposure even in utero. This was defined in an article published in the European Respiratory Journal in 2008.[4] This was a cross-sectional survey, also from New Zealand, suggesting that in utero exposure to a farm environment protects against asthma, hay fever, and eczema. We also know that the multitude of studies on the hygiene hypothesis suggests that early exposure to day care or having more than 2 siblings in the home is epidemiologically associated with less asthma over time.
High exposures to LPS (lipopolysaccharides) result when one is exposed to multiple pets in the home or a farm environment. This leads to the immunologic stimulus early in life resulting in tolerization or movement to a TH1 lymphocyte-mediated paradigm. This will then lead to a protective effect in regard to the expression of these allergically mediated diseases over time.
In contrast, there's an emerging body of data around an increased incidence of asthma with early exposure to acetaminophen, even in utero during the third trimester of pregnancy, and postbirth smoke exposure as well as low vitamin D levels.
Not all studies have clearly shown us that the hygiene hypothesis fully explains the determinants for the onset of wheezing and persistence of wheezing, but there are surely enough studies to suggest that we believe it is true, for the most part.
Medscape: What are key host factors that contribute to childhood asthma?
Dr. Chipps: Some of the most interesting data have been published from the group in Madison, Wisconsin, called the Childhood Origins of ASThma (COAST) study.[5] In this study, Dr. Lemanske, Dr. Gurn, and colleagues have been able to show that a particular cytokine profile is seen even in the cord blood of newborns, in which interferon levels are inversely associated with the development of asthma.[6] This may be predictive in a high-risk group of patients, those children with at least 1 parent with asthma. There are markers, even in the newborn, that may suggest either protection or increased risk for asthma. These data are applicable to the first 6 years of life because this is a study that's been going on since 2000.
Medscape: Is there a difference between boys and girls with respect to developing asthma?
Dr. Chipps: Yes; boys younger than 3 years of age have larger lungs but smaller airways; this is so-called disynaptic lung growth. A very interesting study published in the American Journal of Respiratory and Critical Care Medicine last year[7] showed that when one looks at bronchial hyperreactivity and follows that from early childhood past puberty, bronchial hyperreactivity diminishes in boys past puberty, whereas bronchial hyperreactivity increases in girls in this age group. This is a reanalysis of the Childhood Asthma Management Program (CAMP) study.[8] That may be one of the reasons why there is a switch around the time of puberty and more girls begin to develop wheezing. This is the extremely intriguing study that was just published, and it's the first time that it's ever been shown in a peer-reviewed journal. I think it has a lot of interest to all of us.
Medscape: Looking at both boys and girls, how do environmental factors relate to childhood asthma?
Dr. Chipps: With increased time spent indoors in an environment with fewer air changes, such as in front of the computer, the greater is the exposure to indoor allergens and the chance for indoor environmental tobacco exposure. There's a greater chance for sensitization, and girls tend to have a slightly more sedentary lifestyle than boys during the childhood and prepubertal years. That can play a role in asthma development.
Medscape: You mentioned in utero exposure relative to the hygiene hypothesis. What's the influence of exposure to tobacco smoke in utero?
Dr. Chipps: In utero exposure to tobacco smoke is a risk factor for asthma and a risk factor for sudden infant death syndrome. In utero smoke exposure has been linked as a cause for both.
Medscape: Let's turn to the diagnosis of asthma. What are some key challenges to diagnosing asthma in childhood?
Dr. Chipps: When we're looking at patients who have 1, 2, or 3 episodes of wheezing, we often don't know whether that patient will have just a few episodes or more persistent wheezing. More than half of children wheeze at least 1 time, but only 10% to 15% will go on to have persistent wheezing.
We can apply what's called the Modified Asthma Predictive Index to get a better idea of what the future may hold. If a child has 1 major criterion or 2 minor criteria, he or she has a 75% chance of having persistent asthma. The major criterion would be one of the following: having eczema; a family history or either parent with asthma; or sensitization to aeroallergens, such as house dust mites, dogs, cats, or pollen. The minor criteria are wheezing other than with colds, allergic rhinitis, or dietary protein sensitivity to eggs, milk, or peanuts. Therefore, 1 major criterion or 2 minor criteria indicate a 75% chance of persistent asthma.
Alternatively, if the child has a negative Modified Asthma Predictive Index, he or she has a 68% chance of not having persistent asthma past the early school-age years. Applying the Modified Asthma Predictive Index provides a better chance to prognosticate for a particular patient at a point in time.
It's often difficult to measure lung function in children, so there is a lack of objective measurements. We could do a spirogram flow-volume loop and quantitate it to a degree of airflow obstruction. Without being able to do that in the young child, you're left with your and the parents' assessment of response to therapy.
Medscape: Looking now at management strategies, what do you see as the goals of asthma management in children?
Dr. Chipps: The goals of asthma management are to reduce the 2 domains of asthma burden, the impairment domain and the risk domain. Both are equally important.
The impairment domain embodies daytime symptoms, nighttime symptoms, exercise tolerance, need for short-acting beta2-agonists, and the measurement of lung function when appropriate. There are now validated measurement tools with which to quantify this. The Asthma Control Test and the Children's Asthma Control Test are both available on online: www.asthmacontrol.com. Another tool, the Track Questionnaire,[9] published in the April issue of The Journal of Allergy and Clinical Immunology -- of which I am one of the authors -- is the first validated questionnaire for children who are 0-5 years of age.
Now we have validated questionnaires that are very important to employ because caregivers and physicians usually overestimate the true degree of a patient's asthma control. These questionnaires allow caregivers, that is, the parents or the patients -- if they're older -- to understand what constitutes good asthma control, and the current status of the patient. The validated tools also allow the healthcare professional to immediately know the score upon entering the room to examine the patient. Clinicians can know whether patients are well controlled even before discussions with patients. Then they can embellish the history on the basis of how the questionnaire was completed. It literally puts everybody on the same page in terms of understanding what constitutes asthma control and the current level of asthma control of the patient. It also then allows for an objective number to be followed over time in assessing the patient's clinical course.
Medscape: Let's discuss asthma management in children of different ages. What are the current recommendations for children who are 0-4 years old?
Dr. Chipps: For persistent asthma in all levels of asthma, a low dose of inhaled corticosteroid is the initial treatment strategy. In children who are 0-5 years old, there are positive data around the other controllers that are available, such as long-acting beta2-agonists and antileukotrienes.
Therefore, the recommendations about stepping up care, ie, increasing the dose of inhaled steroid and adding long-acting beta2-agonist and/or an antileukotriene drug, are based primarily on C and D evidence. This is evidence that's not supported by large, randomized, placebo-controlled trials. We have a definite need for more research and better definition of treatment options past the use of single-entity inhaled corticosteroids. There's a systematic review with meta-analysis on the comparative efficacy of corticosteroids in young children in the March issue of Pediatrics by Castro-Rodriguez and Rodrigo.[10]
Medscape: We just talked about young children. How about older children, ages 5-11 years? What are some asthma management recommendations for this age group?
Dr. Chipps: At this age range the level of evidence switches and favors the use of long-acting beta2-agonists in addition to inhaled corticosteroids in patients who are not controlled with single-entity inhaled corticosteroids. In fact, fluticasone propionate and salmeterol oral inhaler is approved by the FDA [US Food and Drug Administration] down to age 4 years; it's approved for ages 4-11 years, to answer your question.
Medscape: What are some new developments in the treatment of asthma for very young children?
Dr. Chipps: There have not been many new developments lately. We are working on better and more user-friendly delivery systems. That's really where the next wave of research is moving, and there are several nebulizers that are currently in development that have delivery times of a fraction of the standard jet nebulizers. Instead of 6-10 minutes, the delivery time will be about 1-3 minutes. These nebulizers are not quite ready for prime time. Another development to look forward to is the next generation of breath-actuated inhalers. You will not have to coordinate the actuation device to inhalation. It will make it easier for younger children to deliver the low dose of inhaled steroid to the lower airway.
Medscape: How can oral and systemic bioavailability of inhaled corticosteroids be minimized?
Dr. Chipps: We have to make sure with the transition to HFA [hydrofluoroalkane] inhalers that we understand that the drugs that go into the HFA solution have 2 to 4 times the deposition in the lower airway as the previous CFC [chlorofluorocarbon]-containing compounds. Each individual drug that's being used has to be reevaluated in regard to its delivery system and the characteristics of the lower airway deposition so the appropriate dosing is used. It's different for each one.
Medscape: What are some closing remarks that you'd like to share?
Dr. Chipps: It is important that we realize in children with asthma that the medicines we currently use do not have disease-modifying capabilities, including inhaled corticosteroids, leukotriene receptor antagonists, long-acting bronchodilators, short-acting bronchodilators, nasal antihistamines, nasal steroids, and oral antihistamines.
As we discussed earlier, the primary reason for persistence of symptoms relates to the acquisition of an allergic component to the disease and early high-level exposure. Therefore, we need to be searching for disease-modification strategies.
There is some very minimal evidence that environmental control in young children may help to obviate persistent exposure and acquisition of an increasing allergic sensitivity.
I think we still need to pay attention to the story with acetaminophen and its role in depleting glutathione in the lower airway, which can lead to increased airway inflammation. I think there's a signal there.
There may be a signal about vitamin D, too. Vitamin D deficiency may play a significant role in the acquisition of both allergic rhinitis and asthma. It's entirely possible that the vitamin D recommended intake that was just increased last year may change again. They were doubled basically, but that may not be enough yet. We have to keep our eye on this.
I think it's important that we also understand that allergy immunotherapy is the only disease-modifying strategy that's ever been proven to be efficacious and in prepubertal patients who have allergic rhinitis who have not yet developed significant asthma. There is more than a significant chance that the appropriate administration of allergy immunotherapy may be a disease-modifying strategy to reduce the relative risk of developing persistent asthma symptoms to between 2.4 and 2.8, which is a huge decrease in the risk. Also, we don't have data but would like to have data and suspect that omalizumab (Xolair®) anti-IgE [anti-immunoglobulinE] could potentially have a similar disease-modifying potential.
Also, many other anti-single-target agents, including IL-5 [interleukin-5], IL-13, and TNF-alpha [tumor necrosis factor-alpha], will address 1 specific mediator cytokine that causes airway inflammation and bronchospasm.
The problem is that asthma is not a disease. Asthma is a syndrome, and knocking out 1 particular effector molecule (IL-5, IL-13, TNF-alpha, or ~50 others) will not cure asthma. It takes a much broader stroke approach, and as we're beginning to learn more, we're putting the puzzle together. We're making progress; we're just clearly not there yet.
Medscape: We'll begin our discussion with risk factors for childhood asthma. Dr. Chipps, please discuss the pathogenesis of childhood asthma, specifically with respect to genetic and environmental factors.
Dr. Chipps: The genetic factors for asthma are quite significant. There are many candidate genes for asthma. There is almost daily change in the number of genetic programming factors that give the chance for what is called gene by environment and interaction. This means that the right gene pool put in the right environment leads to asthma.
Rhinovirus infections are the most common viral infections to cause airway injury, which then leads to asthma. This is also seen in respiratory syncytial virus, but to a lesser extent.
Patients have confounding variables when they have significant allergy as a driving factor. This was particularly shown in the Tucson Children's Respiratory Study,[1] which is now in its 30th year, as well as in the Multicenter Allergy Study (MAS)[2] from Germany highlighting a cohort of over 1300 children who have been followed up to 13 years of age. These studies found the early sensitization and exposure to house dust mite; dog and cat was the major predictor for persistence of symptoms. Ninety percent of the children who wheezed but didn't have that exposure lost their symptoms of recurrent wheezing by the early school-age years and retained normal lung function. The early sensitization and early exposure were even greater risk factors than the later development of seasonal allergic rhinitis. The dye is cast very early. This supports the data from the Mayo Clinic that was published over 2 decades ago,[3] again suggesting that 80% of asthma begins before 5 years of age.
Very clearly, we have an early inception, early-injury viral infection, and concurrent acquisition of an allergic diathesis leading to persistence of the phenotypic expression of asthma.
Medscape: What role does the hygiene hypothesis play in childhood asthma?
Dr. Chipps: It's yet to be clearly defined. The hygiene hypothesis is just that, a hypothesis. There are surely patients who have exposure even in utero. This was defined in an article published in the European Respiratory Journal in 2008.[4] This was a cross-sectional survey, also from New Zealand, suggesting that in utero exposure to a farm environment protects against asthma, hay fever, and eczema. We also know that the multitude of studies on the hygiene hypothesis suggests that early exposure to day care or having more than 2 siblings in the home is epidemiologically associated with less asthma over time.
High exposures to LPS (lipopolysaccharides) result when one is exposed to multiple pets in the home or a farm environment. This leads to the immunologic stimulus early in life resulting in tolerization or movement to a TH1 lymphocyte-mediated paradigm. This will then lead to a protective effect in regard to the expression of these allergically mediated diseases over time.
In contrast, there's an emerging body of data around an increased incidence of asthma with early exposure to acetaminophen, even in utero during the third trimester of pregnancy, and postbirth smoke exposure as well as low vitamin D levels.
Not all studies have clearly shown us that the hygiene hypothesis fully explains the determinants for the onset of wheezing and persistence of wheezing, but there are surely enough studies to suggest that we believe it is true, for the most part.
Medscape: What are key host factors that contribute to childhood asthma?
Dr. Chipps: Some of the most interesting data have been published from the group in Madison, Wisconsin, called the Childhood Origins of ASThma (COAST) study.[5] In this study, Dr. Lemanske, Dr. Gurn, and colleagues have been able to show that a particular cytokine profile is seen even in the cord blood of newborns, in which interferon levels are inversely associated with the development of asthma.[6] This may be predictive in a high-risk group of patients, those children with at least 1 parent with asthma. There are markers, even in the newborn, that may suggest either protection or increased risk for asthma. These data are applicable to the first 6 years of life because this is a study that's been going on since 2000.
Medscape: Is there a difference between boys and girls with respect to developing asthma?
Dr. Chipps: Yes; boys younger than 3 years of age have larger lungs but smaller airways; this is so-called disynaptic lung growth. A very interesting study published in the American Journal of Respiratory and Critical Care Medicine last year[7] showed that when one looks at bronchial hyperreactivity and follows that from early childhood past puberty, bronchial hyperreactivity diminishes in boys past puberty, whereas bronchial hyperreactivity increases in girls in this age group. This is a reanalysis of the Childhood Asthma Management Program (CAMP) study.[8] That may be one of the reasons why there is a switch around the time of puberty and more girls begin to develop wheezing. This is the extremely intriguing study that was just published, and it's the first time that it's ever been shown in a peer-reviewed journal. I think it has a lot of interest to all of us.
Medscape: Looking at both boys and girls, how do environmental factors relate to childhood asthma?
Dr. Chipps: With increased time spent indoors in an environment with fewer air changes, such as in front of the computer, the greater is the exposure to indoor allergens and the chance for indoor environmental tobacco exposure. There's a greater chance for sensitization, and girls tend to have a slightly more sedentary lifestyle than boys during the childhood and prepubertal years. That can play a role in asthma development.
Medscape: You mentioned in utero exposure relative to the hygiene hypothesis. What's the influence of exposure to tobacco smoke in utero?
Dr. Chipps: In utero exposure to tobacco smoke is a risk factor for asthma and a risk factor for sudden infant death syndrome. In utero smoke exposure has been linked as a cause for both.
Medscape: Let's turn to the diagnosis of asthma. What are some key challenges to diagnosing asthma in childhood?
Dr. Chipps: When we're looking at patients who have 1, 2, or 3 episodes of wheezing, we often don't know whether that patient will have just a few episodes or more persistent wheezing. More than half of children wheeze at least 1 time, but only 10% to 15% will go on to have persistent wheezing.
We can apply what's called the Modified Asthma Predictive Index to get a better idea of what the future may hold. If a child has 1 major criterion or 2 minor criteria, he or she has a 75% chance of having persistent asthma. The major criterion would be one of the following: having eczema; a family history or either parent with asthma; or sensitization to aeroallergens, such as house dust mites, dogs, cats, or pollen. The minor criteria are wheezing other than with colds, allergic rhinitis, or dietary protein sensitivity to eggs, milk, or peanuts. Therefore, 1 major criterion or 2 minor criteria indicate a 75% chance of persistent asthma.
Alternatively, if the child has a negative Modified Asthma Predictive Index, he or she has a 68% chance of not having persistent asthma past the early school-age years. Applying the Modified Asthma Predictive Index provides a better chance to prognosticate for a particular patient at a point in time.
It's often difficult to measure lung function in children, so there is a lack of objective measurements. We could do a spirogram flow-volume loop and quantitate it to a degree of airflow obstruction. Without being able to do that in the young child, you're left with your and the parents' assessment of response to therapy.
Medscape: Looking now at management strategies, what do you see as the goals of asthma management in children?
Dr. Chipps: The goals of asthma management are to reduce the 2 domains of asthma burden, the impairment domain and the risk domain. Both are equally important.
The impairment domain embodies daytime symptoms, nighttime symptoms, exercise tolerance, need for short-acting beta2-agonists, and the measurement of lung function when appropriate. There are now validated measurement tools with which to quantify this. The Asthma Control Test and the Children's Asthma Control Test are both available on online: www.asthmacontrol.com. Another tool, the Track Questionnaire,[9] published in the April issue of The Journal of Allergy and Clinical Immunology -- of which I am one of the authors -- is the first validated questionnaire for children who are 0-5 years of age.
Now we have validated questionnaires that are very important to employ because caregivers and physicians usually overestimate the true degree of a patient's asthma control. These questionnaires allow caregivers, that is, the parents or the patients -- if they're older -- to understand what constitutes good asthma control, and the current status of the patient. The validated tools also allow the healthcare professional to immediately know the score upon entering the room to examine the patient. Clinicians can know whether patients are well controlled even before discussions with patients. Then they can embellish the history on the basis of how the questionnaire was completed. It literally puts everybody on the same page in terms of understanding what constitutes asthma control and the current level of asthma control of the patient. It also then allows for an objective number to be followed over time in assessing the patient's clinical course.
Medscape: Let's discuss asthma management in children of different ages. What are the current recommendations for children who are 0-4 years old?
Dr. Chipps: For persistent asthma in all levels of asthma, a low dose of inhaled corticosteroid is the initial treatment strategy. In children who are 0-5 years old, there are positive data around the other controllers that are available, such as long-acting beta2-agonists and antileukotrienes.
Therefore, the recommendations about stepping up care, ie, increasing the dose of inhaled steroid and adding long-acting beta2-agonist and/or an antileukotriene drug, are based primarily on C and D evidence. This is evidence that's not supported by large, randomized, placebo-controlled trials. We have a definite need for more research and better definition of treatment options past the use of single-entity inhaled corticosteroids. There's a systematic review with meta-analysis on the comparative efficacy of corticosteroids in young children in the March issue of Pediatrics by Castro-Rodriguez and Rodrigo.[10]
Medscape: We just talked about young children. How about older children, ages 5-11 years? What are some asthma management recommendations for this age group?
Dr. Chipps: At this age range the level of evidence switches and favors the use of long-acting beta2-agonists in addition to inhaled corticosteroids in patients who are not controlled with single-entity inhaled corticosteroids. In fact, fluticasone propionate and salmeterol oral inhaler is approved by the FDA [US Food and Drug Administration] down to age 4 years; it's approved for ages 4-11 years, to answer your question.
Medscape: What are some new developments in the treatment of asthma for very young children?
Dr. Chipps: There have not been many new developments lately. We are working on better and more user-friendly delivery systems. That's really where the next wave of research is moving, and there are several nebulizers that are currently in development that have delivery times of a fraction of the standard jet nebulizers. Instead of 6-10 minutes, the delivery time will be about 1-3 minutes. These nebulizers are not quite ready for prime time. Another development to look forward to is the next generation of breath-actuated inhalers. You will not have to coordinate the actuation device to inhalation. It will make it easier for younger children to deliver the low dose of inhaled steroid to the lower airway.
Medscape: How can oral and systemic bioavailability of inhaled corticosteroids be minimized?
Dr. Chipps: We have to make sure with the transition to HFA [hydrofluoroalkane] inhalers that we understand that the drugs that go into the HFA solution have 2 to 4 times the deposition in the lower airway as the previous CFC [chlorofluorocarbon]-containing compounds. Each individual drug that's being used has to be reevaluated in regard to its delivery system and the characteristics of the lower airway deposition so the appropriate dosing is used. It's different for each one.
Medscape: What are some closing remarks that you'd like to share?
Dr. Chipps: It is important that we realize in children with asthma that the medicines we currently use do not have disease-modifying capabilities, including inhaled corticosteroids, leukotriene receptor antagonists, long-acting bronchodilators, short-acting bronchodilators, nasal antihistamines, nasal steroids, and oral antihistamines.
As we discussed earlier, the primary reason for persistence of symptoms relates to the acquisition of an allergic component to the disease and early high-level exposure. Therefore, we need to be searching for disease-modification strategies.
There is some very minimal evidence that environmental control in young children may help to obviate persistent exposure and acquisition of an increasing allergic sensitivity.
I think we still need to pay attention to the story with acetaminophen and its role in depleting glutathione in the lower airway, which can lead to increased airway inflammation. I think there's a signal there.
There may be a signal about vitamin D, too. Vitamin D deficiency may play a significant role in the acquisition of both allergic rhinitis and asthma. It's entirely possible that the vitamin D recommended intake that was just increased last year may change again. They were doubled basically, but that may not be enough yet. We have to keep our eye on this.
I think it's important that we also understand that allergy immunotherapy is the only disease-modifying strategy that's ever been proven to be efficacious and in prepubertal patients who have allergic rhinitis who have not yet developed significant asthma. There is more than a significant chance that the appropriate administration of allergy immunotherapy may be a disease-modifying strategy to reduce the relative risk of developing persistent asthma symptoms to between 2.4 and 2.8, which is a huge decrease in the risk. Also, we don't have data but would like to have data and suspect that omalizumab (Xolair®) anti-IgE [anti-immunoglobulinE] could potentially have a similar disease-modifying potential.
Also, many other anti-single-target agents, including IL-5 [interleukin-5], IL-13, and TNF-alpha [tumor necrosis factor-alpha], will address 1 specific mediator cytokine that causes airway inflammation and bronchospasm.
The problem is that asthma is not a disease. Asthma is a syndrome, and knocking out 1 particular effector molecule (IL-5, IL-13, TNF-alpha, or ~50 others) will not cure asthma. It takes a much broader stroke approach, and as we're beginning to learn more, we're putting the puzzle together. We're making progress; we're just clearly not there yet.
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