Immunotherapy for Inner City Children with Asthma
A major component of ICAC 2 will be the design, development and implementation of clinical interventional protocols to evaluate immune-based therapies to control asthma in inner city children. To conduct the newly designed clinical trials, eight research sites have been identified and are responsible for the recruitment and conduct of these studies. They include Drs. Rebecca Gruchalla (Dallas, TX), Meyer Kattan (New York, NY), Andrew Liu (Denver, CO), George O’Connor (Boston, MA), Jacqueline Pongracic (Chicago, IL), Stephen Teach (Washington, DC), Robert Wood (Baltimore, MD), and Edward Zoratti (Detroit, MI). All of these sites have demonstrated access to inner city children and have extensive experience in the conduct of studies involving an urban population. As noted above, sensitization to cockroach is highly prevalent in the inner city pediatric populations, which comprise these networks and is an apparent major factor in determining the severity of asthma in this population. Morgan et al.7
have already shown the clinical benefit of reducing cockroach allergen exposure in sensitized children on relevant asthma control outcomes. Another approach to diminish the host’s allergic reaction to environmental allergens is to modify the immune-based responses to environmental allergens. Our evaluation of omalizumab in the ICATA trial has provided insight into how the use of a “broad-based” anti-IgE regulation can affect asthma and what clinical outcomes appear most responsive to this form of treatment. To extend these findings, it is known that IT, either subcutaneous or sublingual, has clinical benefit with pollens and house dust mite antigen in allergic rhinitis and asthma.9–14
However, there are no, or at best limited, data on the effects of IT with cockroach in inner city children with asthma.
Since IT has been shown to have sustained benefit associated with its use, this immune-based approach has considerable appeal for this highly exposed, allergen-sensitive population of inner city children, and raises the possibility that IT might be disease modifying, an outcome not noted with current pharmacological interventions.14
Studies in young children have shown that IT may attenuate the eventual expression of asthma in allergic sensitized children.15;16
Consequently, a major initiative over the next 5 years will be to establish the most effective IT program with cockroach allergen in inner city asthma, i.e., sublingual or parenteral, and begin to evaluate its effect, and effectiveness, in asthma. A key component to structuring these IT trials will be the identification of a patient biomarker, e.g., change in antigen-specific IgE or increase in IgG4 levels, which may reflect an immune response to treatment, potentially correlate to clinical outcomes, and provide insight into the immune basis of this therapy in an inner city population.
Reducing future risks – preventing exacerbations
The recent revision of the U.S. Guidelines for Asthma Diagnosis and Management17
has proposed two major domains to judge the effectiveness of asthma control: (1) impairment and (2) future risks. Measures of control that are based upon impairments include symptoms, need for short-acting beta agonists for rescue treatment, and lung function measurements. Instruments for these measurements are established, and current asthma treatments have shown efficacy based on impairment outcomes. Future risks in asthma control include exacerbations, progressive loss of lung function, and side effects from medication. Asthma exacerbations may have a profound effect on patients, and their families, due to the associated morbidity, costs, inconveniences, and general disruption of lifestyle, as well as the rare, but still real risk for a fatal outcome.
What is known about asthma exacerbations in children?
Our understanding and appreciation of asthma exacerbations has increased considerably in the last 15 years. For children, and adults to a lesser degree, viral respiratory infections, particularly the common cold virus, rhinovirus, are the major cause of these attacks.18
Secondly, there is a seasonal pattern to asthma exacerbations which shows a marked increase in September and October. These “September” epidemics occur predictably every year and coincide with children’s return to school and contracting a cold.19;20
For many children, these exacerbations occur despite optimal medical management and well-controlled asthma prior to development of a respiratory infection. Although respiratory viral infections “trigger” these exacerbations, underlying allergic sensitization also appears as another, and important, risk factor in this interaction. Treatment of asthma has been primarily directed towards reducing existing airway inflammation and not necessarily treating, or modifying, the underlying allergic processes, which may be a major factor in the susceptibility for viral respiratory infections. For most children with asthma, whether living in the inner city or elsewhere, treatment that targets airway inflammation has been of considerable benefit and has reduced both impairments and exacerbations.21
Despite the achievement of presumably good asthma control with anti-inflammatory medications, many children still have “breakthroughs” in their treatment coverage and experience exacerbations of asthma when they “catch a cold.” Improved control of exacerbations remains a major unmet need in the treatment of asthma.
Given this unmet need in treatment, protocols for ICAC2 are being developed that will focus on interventions which might be of greater effectiveness in reducing asthma exacerbations. Although our treatment will target a traditional outcome, i.e. exacerbations, the use of an anti-IgE intervention will also attempt to modify underlying allergic sensitization, as this patient characteristic appears as a major risk factor for wheezing with a respiratory infection.22–24
Thus, it is our hypothesis that underlying allergic sensitization and exposure to putative allergens make the host more susceptible to an exacerbation with a viral respiratory infection. Concomitant with this goal will be the conduct of mechanistic studies to determine how the interplay between allergic sensitization and respiratory viruses leads to a loss of asthma control and an exacerbation, and what are the biological mechanisms that drive this process and may be future targets for treatment.
The incorporation of basic science or translational projects in ICAC2
A new component to ICAC2 will be the inclusion of two basic science projects. The goal behind the addition of this research effort to ICAC2 is to apply novel, basic science investigation to asthma in the inner city, and, through these interactions, determine basic, underlying mechanisms of asthma, and mechanisms that are potentially unique to this high risk group of patients. Moreover, it is anticipated that the application of innovative investigation, through the inclusion of basic mechanisms, to the inner city population of patients will provide insights to novel treatments and management that are potentially more effective for asthma patients in these environments.
Multiple genes have been identified in asthma and with features of asthma.25;26
Expanded exploration into the genetic regulation of asthma will need to take advantage of genomic-wide investigations to more fully determine the “pattern” of gene products which may be involved and related to clinical features of asthma. To date, however, studies have not given us definitive information on how asthma in the inner city is regulated, is possibly unique, or how asthma in the inner city may be differentiated from asthma in non-inner city environments.
Epigenetics is an approach that should allow us to explore the possibility that environmental exposures can bring about functional changes by methylating, for example, selective genes, and, through this process, lead to altered function that is relevant to asthma.27
As methylation, or other changes to genes, can arise from environmental influences and can occur relatively quickly, an epigenetic investigative approach of well defined and characterized populations promises to provide novel and unexplored insights into how environmental influences of the inner city may have an influence on asthma, particularly, for inner city patients. David Schwartz from National Jewish Health, Denver, CO will lead this effort.
Microbes also have a tremendous influence on host immune responses. However, the microbes in our intestine or our environment are not one organism but a family of different organisms, i.e. bacteria, fungi, etc. The collective influence of this microbiota on the host’s immune system can arise from a variety of environmental sources.28;29
To begin to determine whether differences exist in the microbiota of inner city home environments, collections of household dust will be analyzed to define the mixture of bacteria, fungi, chitin, and allergens, and, eventually, assess the overall influence of this microbiota on asthma. It is hypothesized that inner city home environments have a unique microbiota profile given high concentrations of cockroach, mouse droppings, and house dust mite found in these dwellings. Moreover, as there are interactions between bacteria, allergen proteases, fungus, and chitin, for example, the pattern of microbes that emerges in this mixture may influence the environment’s allergenicity and the resulting immune response in the host. Dr. Homer Boushey from the University of California in San Francisco will lead these studies.
What is known about asthma phenotypes in the inner city and what has been learned from ICAC?
Studies from ICAC1 have begun to shed some light on this question. The ACE study has, indirectly, addressed differences in asthma severity, as a potential feature, or phenotype, and can be assessed by the amount of treatment necessary to achieve asthma control.21
The conduct and results of the ACE trial are reviewed in greater detail in the article by Stanley Szefler et al. in this issue.5
Briefly and relevant to a discussion of disease severity, the recruitment of patients for ACE identified subjects between 12 and 20 years of age, who had an established diagnosis of asthma and symptoms of persistent asthma or evidence of uncontrolled disease. At the initial study visit for ACE, each subject was assessed for ongoing symptoms, measures of pulmonary function, and the overall level of asthma control. Based upon these entry assessments, the recruited subjects were treated according to six-step escalating algorithm designed to achieve asthma control; treatment began with fluticasone, 100 mcg/day, and ranged up to fluticasone 500 mcg/Salmeterol 50 mcg, twice a day, along with either montelukast or low dose theophylline.
Despite the use of asthma control medication at the screening visit, the recruited subjects recorded an average (SD) of 5.6 (4.6) maximum days/2 weeks of asthma symptoms (). These values promptly fell to 2.1 (2.7) and 2.4 (3.0) days in the FeNO-treated and control treatment groups, respectively, and were sustained at this level of control for the entire study. Although some subjects in the FeNO group reached a higher level of step care, based upon elevated FeNO levels, the level of symptom control was similar in the two groups.
Figure 1 A comparison of the addition of NO monitoring with Guideline directed care to Guideline directed care alone on maximum number of days with symptoms. During the “run-in,” patients asthma treatment was adjusted prior to entering the control (more ...)
As noted by Szefler et al.,21
the majority of enrolled subjects, in both the guideline and FeNO plus guideline directed groups, achieved a level 1 control status, which reflects 0–3 days of symptoms and 0–1 nights of symptoms over the 2 week interval, and FEV1
values were ≥ 80% predicted. Therefore, under the “right” management strategy and proper medication doses, asthma control can be achieved and maintained in an inner city group of asthma patients.
A number of factors were felt to lead to this level of asthma control. First, the enrolled patients were closely monitored throughout the trial by skilled personnel. Second, medications were provided as part of the study, thus relieving the patient of the need to secure their own drugs. Finally, considerable effort was extended to maintain regular use of the medications and a high level of treatment adherence, an approach that resulted in a mean adherence of 86.6% during the study. These data suggest that with guideline-directed treatment and medication adherence, asthma control can be achieved and maintained in an inner city group of patients.
A number of conclusions may be derived from the ACE study as to the treatment of asthma, in general, and, specifically, to an inner city population and whether asthma severity is greater in these populations.21
Of considerable interest was the observation that an “algorithm-directed treatment” with step-care adjustments, based on guideline recommendations, led to good asthma control in a large portion of inner city patients. At face value, these observations raise the possibility that asthma severity in the inner city may not be as different from other populations, and facilitated efforts to use the correct medications and at the correct dosages, along with a dedication to adherence on the part of the patient, will lead to good asthma control.
Does this really mean that asthma severity may not be distinct in inner city children? For a number of reasons, such a conclusion is premature and speculative at the present. First, recruitment for ACE did not include the patients with more severe disease. Second, the relative responsiveness to the step-care approach did not include a non-inner city comparative group. Finally, recruitment was not random, but rather included patients known to the study centers and interested in being part of this trial. The question as to whether greater asthma severity exists in inner city children with asthma remains, largely, unanswered, but may be an important facet of disease in this population and factor in determining the most appropriate treatment for individual patients.
Are there any distinct asthma phenotypes in inner city populations?
In an editorial accompanying their issue devoted to asthma in 2006, Lancet
issued a challenge and “a plea to abandon asthma as a disease concept.” They went on to say, “The general consensus now emerging is that, even in adults, asthma is unlikely to be a single disease entity. Sally Wenzel30
describes an approach to distinguish different phenotypes and subphenotypes, aspirin-sensitive, late onset, and obesity-related, for example. Whether these phenotypes simply represent different aspects of disease in a single underlying pathological process – airway inflammation – in people with different predispositions who are susceptible to different triggers driven by specific cellular and molecular responses, is not known. Or perhaps, asthma, as a symptom is really only the clinical manifestations of several “distinct diseases.”31
The latter is most likely.
To gain insight into the existence of various phenotypes, or subgroups, various investigative groups have begun to explore the features of different asthma populations. As part of the NIH-supported Severe Asthma Research Program (SARP), Moore et al.32
recruited patients and from this cohort has begun to define the clinical features of patients with severe disease. In the study by Moore et al.,32
recruited patients, who were classified with severe asthma, had clinical characteristics defined by an American Thoracic Society (ATS) Workshop, which proposed two major and seven minor criteria to define this group.33
The suggested major criteria centered on the need for large doses of inhaled corticosteroids, with, or without, systemic corticosteroids, to maintain asthma control.
When clinical features of asthma patients with mild and moderate asthma were compared to those meeting the ATS criteria for severe disease, a number of differentiating features emerged between the severe and non-severe asthma clusters. First, by recruiting based on the definition of the ATS Workshop, patients with severe asthma required more medications, particularly corticosteroids, to achieve disease control. However, when compared to subjects with moderate asthma, indices of airflow obstruction were similar to severe asthma. In contrast, when patients with mild, moderate and severe asthma were assessed for frequency of health care utilization, distinctions between these groups became strikingly apparent. Patients with severe asthma had a greater use of emergency care and hospitalizations as well as need for treatment in intensive care units or requiring assisted ventilation and intubation ().
Figure 2 Urgent HCU increased with disease severity. Data are shown as lifetime (ever) events and visits in the past year. Hosp, Inpatient hospitalizations; Vent, need for mechanical ventilation. White bars, mild (n 5 164); hatched bars, moderate; black bars, (more ...)
These differences were consistently noted at two timeframes, ‘ever in a lifetime’ or ‘in the past year.’ Therefore, a feature of severe asthma is a greater frequency and need for health care utilization, likely arising as the result of asthma exacerbations, which occurred despite aggressive treatment with corticosteroids. An obvious question arising from these assessments is whether patients with more severe disease are unresponsive or partially responsive to corticosteroids.
Characterization of clinical features associated with severity in children with asthma have not been extensively defined. However, when Fitzpatrick et al.34
compared features of severe and non-severe asthma in school-age children in Atlanta, GA, a number of clinical aspects emerged to distinguish these levels of disease severity. Children with more severe asthma had increased symptoms, greater airflow obstruction, and higher prevalence of allergen sensitization, a feature that contrasted with the adult population, where skin test positivity tended to be less in patients with more severe disease. In patients with severe asthma, there was also a greater variability in airflow obstruction and FeNO, a marker felt to reflect underlying inflammation that was not responsive to treatment, including large doses of inhaled corticosteroids, again raising the possibility of resistance to the effects of corticosteroids. Finally, the frequency of exacerbations was greater in those with severe disease, a characteristic shared with the adult population.
Therefore, a pattern is emerging that distinguishes severe asthma from other forms of this disease. First, clinical features that reflect ongoing impairments are greater – symptoms, airflow obstruction, and interference with day-to-day activity. Furthermore, those with more severe disease have a greater frequency for future risks, i.e., asthma exacerbations, as reflected in the need for more healthcare utilizations. These markers of disease exist despite the use of more medications, particularly inhaled and systemic corticosteroids. The underlying mechanisms, particularly those associated with airway inflammation, which likely contribute to these clinical characteristics, are not well established. Nor is known whether certain phenotypes for asthma constitute clusters of greater disease severity and whether one aspect of this differential is resistance to treatment, including corticosteroids.
What have we learned about subpopulations in inner city asthma?
Observations from ACE may have begun to shed insight on clinical characteristics in inner city children that may reflect more severe disease and possibly distinct phenotypes. Higher doses of ICS were required to achieve asthma control in subjects who were obese, a greater frequency of allergen sensitization and higher IgE levels.21
There has been considerable interest in the role of obesity in asthma as a distinct phenotype and as a potential risk factor for more severe disease.35;36
The mechanisms by which obesity affects asthma severity in our inner city population are not established, but because of the greater frequency of obesity in the inner city, this relationship will continue to be of considerable interest and importance. We have already discussed the importance of allergen sensitivity for asthma exacerbations with viral respiratory infections. Whether sensitization to inner city allergens, like cockroach, results in a distinct phenotype has not been explored in detail, but will be of interest as we define differences between asthma in inner city and non-inner city populations where unique characteristics may arise in the cockroach vs. house dust sensitized asthmatic patient. Important in these comparisons will be an evaluation of responses to treatment.
What have we learned from our ICAC studies?
Analyzing the ACE population, which had a number of historical characteristics and biomarkers determined prior to initiating the intervention protocol, Gruchalla et al.37
evaluated a panel of patient factors which might predict future asthma control. Included in this evaluation were determinations of FeNO, total IgE, allergen-specific IgE, allergen skin test reactivity, asthma symptoms prior to enrollment, peripheral blood eosinophils, airway hyperresponsiveness, and sputum eosinophils. Using this approach, maximum symptom days during the ACE trial were modestly predicted by entry levels of symptoms, use and need for rescue beta-agonists, and a history of exacerbations. To a similarly modest degree, symptoms, albuterol use, previous exacerbations, and lung functions predicted future exacerbations. Overall, these findings in ACE suggest that the control domains of impairment and future risk are influenced by similar factors, at least in this particular population. Unfortunately, these assessments did not appear sufficient to serve as highly sensitive surrogates to link to future asthma outcomes.
What should be the next steps in establishing the various phenotypes of asthma in the inner city?
These findings from the ACE trial in ICAC-1 have been, nonetheless, helpful in directing what future assessments of asthma are needed to define existing phenotypes, and from these data to be able to more fully determine and predict responsiveness to treatment. We know, and now appreciate, that asthma is influenced by a wide variety of environmental factors, including allergens, obesity, nutrition, and stress, for example, and these stimuli likely interact differently within individual patients (.). Each of these external factors has the capacity to generate an immune inflammatory pattern, which may, in turn, determine the clinical features, or phenotype, of asthma, the response to treatment, and, possibly, the inherent potential for impairment and future risks.
Figure 3 A multiplicity of environmental factors influence the development of asthma and resulting phenotype. The resulting phenotypes will also have variable levels of severity, which, in turn, will influence the response to treatment and eventual asthma control. (more ...)
A critical “next” step to define inner city asthma phenotypes, cockroach-sensitive, obesity associated, viral respiratory tract infection prone, and/or cigarette smoke exposed, for example, and to determine how these phenotypes may determine the patient’s response to treatment as well as risk for loss of asthma control, is the need to link assessments of immune and inflammatory response patterns to the existing clinical profiles. It is likely that such a “fingerprint” will be a “pattern” of inflammation and not necessarily a single cellular marker, cytokine or chemokine. Moreover, it is also likely that there will be additional variabilities in these inflammatory response patterns which will be dependent upon developmental aspects of the patient. The peeling back of the multiple features that eventually constitute the clinical expression, or phenotype, of an individual asthma patient is likely to reveal a complex picture which is influenced, to a large degree, by the genetic background and broad description of the environment. Therefore, to more fully understand the asthmatic portraits of patients living in the inner cities will require a careful and systematic approach to define the unique features, both clinical and immunological, of asthma in this population and from this information more effectively design management approaches, including a selection of medications most likely to lead to improved disease control.