Published ahead of print on June 23, 2004, doi:10.1164/rccm.200311-1539WS
© 2004 American Thoracic Society doi: 10.1164/rccm.200311-1539WS
Future Research Directions in AsthmaAn NHLBI Working Group ReportDepartment of Medicine, University of Wisconsin Hospital and Clinics, Madison, Wisconsin; Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland; and Department of Internal Medicine, Yale University, New Haven, Connecticut Correspondence and requests for reprints should be addressed to Susan Banks-Schlegel, Ph.D., DLD/NHLBI, Two Rockledge Center, Room 10018, 6701 Rockledge Drive, Bethesda, MD 20892-7952. E-mail: Schleges{at}nih.gov
Over the last 20 years, the prevalence of asthma has nearly doubled and now affects 8–10% of the population in the United States. Asthma also remains a major illness in terms of morbidity and suffering, and is the leading cause of hospitalizations in children under 15 years of age. Because asthma poses a lifelong burden to patients and society, efforts to increase the understanding of its pathogenesis are a key factor leading to its control and cure. Consequently, the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of extramural experts, entitled "Future Research Directions in Asthma," on April 9–10, 2003, to identify research areas of greatest promise and opportunity in the field of asthma. The priority areas identified for research in asthma include: (1) innate immunity, adaptive immunity, and tolerance; (2) mechanisms and consequences of persistent asthma and asthma exacerbations; (3) airway remodeling: clinical consequences and reversibility (clinical relevance and resolution); (4) genetics/gene–environment interactions, pharmacogenetics; (5) intervention/prevention/therapeutics; and (6) vascular basis of asthma.
Key Words: airway lung disease • asthma • innate immunity, asthma genetics • asthma exacerbations In the world and in the United States, the prevalence of asthma continues to increase. Although there has been a plateau of the markers of asthma severity, i.e., hospitalization and deaths, the impact of this disease on individuals of all ages continues to be a major health risk. Furthermore, asthma begins early in life, and, for most patients, the consequences of this disease on airway function are apparent within a few years of onset and experienced for years to come. Therefore, despite the high prevalence of asthma and the recent advances from research applied to its understanding and control, asthma remains a major illness in terms of morbidity, suffering, and cost. Moreover, because remission of asthma is uncommon, this disease is likely to be one of a lifelong compromise. The Lung Division of the National Heart, Lung, and Blood Institute of the National Institutes of Health routinely convenes a group of investigators to review the direction for future research within asthma and to identify the opportunities for the scientific advancement, including basic, clinical, behavioral, and health education, and from this review develop short- and long-range strategic direction for supported investigation. On April 9 and 10, 2003, a group of investigators met to review the progress and direction of asthma research and from these discussions provide the Institute with recommendations and priorities for new research opportunities in the broad aspects of asthma. Asthma, for most patients, begins in early life, and prenatal and immediate postnatal events have emerged as important in the early development and establishment of asthma. Central to these early-life processes are immune-related responses and their interaction with environmental factors such as allergens and infections, and the eventual development of either a normal immune response or an altered immune response, which may lead to the development of airway injury. Regulation of these inflammatory events is complex, interactive, and determined by gene–gene and gene–environmental interactions. Moreover, genetic processes are emerging as important in determining the response to therapy. It is also well appreciated that airway inflammation in asthma is complex and likely involves innate and adaptive responses, pathologic Th2 sensitization, and alterations in tolerance. It is also believed that this resulting inflammation and airway injury, in some manner, alters airway function and generates clinical symptomatology. Moreover, the appreciation that asthma is a disease characterized by chronic inflammation and repeated inflammatory exacerbations has led to the belief that these responses induce cycles of injury and repair that produce airway remodeling (1). Although it has not been convincingly proven, a variety of lines of evidence suggest that remodeling processes play an important role in disease pathogenesis, natural history, and physiologic dysregulation (Figure 1) (2).
Given this background from advances in asthma, the availability of new techniques for study, and an emerging state of knowledge, the advisory group evaluated areas of potentially important research. The background, potential opportunities, and focus of new research areas were presented and discussed. The potential impact and importance of these research areas were considered by the advisory panel and then prioritized into subject areas that likely hold the most promise and opportunity to gain new insights into mechanisms of asthma, improved diagnosis, and more effective treatment. The research areas identified to have the greatest interest to the overall field of asthma are listed in order of priority (Table 1).
Background The interplay between the immune system and the development of host-defense mechanisms is pivotal to the pathogenesis of respiratory illnesses and asthma. In the last five years, considerable progress has been achieved in understanding the complexities and division of the immune response into separate but interdependent compartments (3). The innate immune system is intrinsically present in the host and is the early or initial responder to various environmental insults, i.e., infections. In addition, toll-like receptors have been identified, and their importance in the regulation of these responses is just beginning to be understood (3–6). The adaptive immune response, in contrast, is closely linked to pathogenic factors in asthma (7). Critical in these responses are subpopulations of lymphocytes, Th1, and Th2, and their role in adaptive response to allergens, for example, which result in IgE synthesis and have been a focus of ongoing research in asthma and important in understanding some mechanisms of allergic sensitivity. Tolerance is also an expanded component of the immune response and is a self-protective host response to prevent the development of allergy. Evidence now suggests that development of a specific T cell subpopulation, T regulatory cells, is important in this process. Early life events condition the immune response, and the initial response of the immune system is dictated and directed by the innate immune system. An understanding of the contribution and influence of the innate immune response to immunology, in general, has just begun to emerge and its role in the eventual development of asthma and its persistence has yet to be explored or established. There are a number of areas of research that appear to be of great potential to discover mechanisms of asthma and, as a consequence, hold considerable promise for new and novel investigation. As the innate immune system is likely a key event in the initiation of asthma, this is an area of considerable priority.
Research Opportunities
Background In the majority of patients with asthma, the first symptoms of disease occur before six years of age. Furthermore, data also suggest that events occurring either during fetal or early life are important risk factors for asthma, among these events are the development of immune responses, cytokine dysregulation, and responses to microbes. Changes in airway function associated with asthma also appear to develop early in life and early in the course of asthma. Given the importance of early life events in the origins of asthma, this "window of opportunity" appears to be a key to gain new insights into mechanisms of asthma and treatments directed toward prevention. Longitudinal studies have suggested that early events in the setting of genetic predisposition can result in the eventual presentation and eventual initiation of asthma in some individuals and possibly its persistence and severity. These early-life events may be related to many factors including nutrition during pregnancy, infection, or hormonal influences (8). Therefore, early identification of the high-risk individual may serve to alter the natural history of the disease by prompt therapy and/or environmental modification and to provide further insight into mechanisms of asthma (9). In addition, an enhanced understanding of the mechanisms that underlie these interventions may allow for specific interventions that can be applied later in life that will also alter the disease's natural history and its severity. The mechanisms driving the gene-by-environment interaction that result in altered airway structure are poorly understood but are an important factor in asthma determination. Furthermore, the effects of basic cellular mechanisms on the physiology and exacerbations of asthma are important, but not fully defined. The consequences of asthma chronicity and its relationship both to persistence and disease severity are not well defined. Nonetheless, epidemiologic studies have shown that lung function may decline at a greater rate in some patients with asthma than in normal subjects (10, 11). The role of remodeling in this response and the degree to which the response is a consequence of persistence or severity has yet to be established. Furthermore, even potent antiinflammatory therapy, which controls symptoms, does not lead to disease modification as asthma symptoms and other physiologic abnormalities return with withdrawal of medication (12, 13). Thus, understanding the factors leading to chronicity, possibly severity, and loss of lung function appear central to future therapy and modification of asthma's natural history. The mechanisms that underlie asthma severity are equally poorly defined. Many factors likely play a role in defining asthma severity. For example, the immune (innate, adaptive, or immune tolerance) and inflammatory responses in patients with severe asthma may be different than in patients with mild disease (14). Alternatively, they can differ in their remodeling responses or in ways that alter the sensitivity of their airway target tissues. Although there is considerable information on the immunopathology of asthma, the translation of these responses to asthma persistence and severity, and, most importantly, structural and functional changes has not been established. There is also little information on the role of central nervous system factors in determining asthma severity and the relationship of psychoneurologic processes either to the regulation of these features of asthma or disease severity (15). In addition, it is possible, but not proven, that patient behavior and compliance during treatment may influence these processes. As noted above, a large number of risk factors for asthma have been identified, e.g., genetics, infections, allergens, early use of antibiotics, and urban versus rural living. There is also mounting evidence that obesity is a risk factor in the development of asthma. In light of an increasing prevalence of obesity in our population, obesity may assume considerable significance and importance in the pathogenesis of asthma. Furthermore, it is not established whether obesity per se, or physical inactivity, is a predisposing factor to obesity or a comorbid problem. A number of other unexplained and unidentified factors likely contribute to the effect of obesity on asthma: endocrine (particularly hormones associated with growth and reproduction), diet (antioxidants, etc.), environment, physical activity and exercise, or lack thereof. Furthermore, there is evidence that sex (female > male), ethnicity, and inner-city dwelling may also contribute to this process. Areas for study also include the influence of stress, the interaction of obesity with immunity, inflammation and injury/repair, and genetics. Furthermore, novel therapeutic interventions are needed to accomplish these goals; not only are human studies needed, but also the development of animal models. Asthma exacerbations are a major cause of deaths and largely determine health care costs, and often occur despite ongoing and appropriate therapy (16). The mechanisms of asthma exacerbations have not been well defined, nor have the relationships of asthma exacerbations to persistence, chronicity, and severity of disease. It is not established or understood why minority groups appear to have more frequent and severe exacerbations (17). Although considerable progress has been made through studies and lessons from cellular and animal models to human asthma, the correlation between structure and function should be emphasized. However, these same approaches have not been explored in studies to determine the causes, mechanisms, and translation of environmental and airway responses in asthma exacerbations. Although current therapy of asthma can prevent some exacerbations of asthma, these events still occur and are associated with increased risk for the patient and cost. As exacerbations area major source of morbidity in asthma, this area of research is of great interest and importance.
Research Opportunities
Background The recognition that airway inflammation is a central feature of asthma is important to an understanding of its persistence and chronicity (see above). Furthermore, the linkage of airway inflammation to the persistence and severity of clinical disease has, in turn, led to a greater employment of treatment whose principal action is the regulation of these processes. The discovery of subpopulations of lymphocytes (i.e., Th1/Th2), and other cell types, has also provided insight into the regulation of cellular events in inflammation. Precisely how these inflammatory events cause airway hyperresponsiveness, intermittent or persistent airflow obstruction, and exacerbations remains a puzzle, as well as the heterogeneity in different patients or the same patient under different conditions. Important in the initiation of allergic inflammation is an activation of many airway cells including subpopulations of T-helper lymphocytes, i.e., Th2. The role and contribution of Th1/Th2 lymphocytes and their products to allergic inflammation have been a major advance in understanding asthma and focus of current research efforts. At present, however, the mechanisms by which environmental factors, i.e., infections (viral and bacteria) or allergens, initiate, promote, and/or modulate airway inflammation, and the mechanisms by which these processes alter airway function, have yet to be fully established. Furthermore, the mechanisms by which Th2 cytokines mediate their tissue and physiologic effects, the importance of genetic control of Th2 cytokine effector function and cytokine regulation of resident effector cell populations (for example, epithelial cells, fibroblasts, airway smooth muscle, mucus gland cells, mast cells, and neural cells) versus inflammatory cells in the generation of asthmatic inflammation, remodeling, and physiologic dysregulation have not been fully defined. Cytokines and chemokines have contributed to the processes of inflammation, and they have a major effect on both migrating and resident lung cells from which they are also a source (19, 20). Finally, toll-like receptors have been identified as essential to innate immune responses (see discussion on innate immunity), but little is known about their role and contribution to the initiation and regulation of airway inflammation, injury/repair and bronchial dysfunction (Figure 1). This area of research remains a high priority as it is important to link immune function, or dysfunction, to altered airway physiology.
Future Research Opportunities
Background Asthma genetics has made significant progress in the past decade. Regions of the genome with detectable effects have been identified through genomic scans. In addition, the specific genes that are responsible for these effects, in many cases, have been identified, for example, ADAM33, IL4RA, IL13, and CD14 (23). Furthermore, new evidence has emerged to highlight the importance of environmental exposures in the development of asthma. For example, interactions with environmental tobacco smoke have been reported in linkage studies (24) and associations have been noted between polymorphisms in the CD14 and TLR4 genes and endotoxin expososure (25, 26). This information has become important to explain the lower prevalence of asthma in rural areas and possible risk for asthma with cigarette smoke exposure. Studies have also provided evidence of genotypes influencing the response of patients to various asthma medications in the treatment of their asthma. For example, bronchodilator response to ß-agonists is associated with polymorphisms in the ß2-adrenergic receptor gene (27–30). In addition, leukotriene synthesis genes may determine the effectiveness of drugs designed to regulate these processes (31). Along with the need to continue to identify all significant asthma susceptibility loci, future research needs in asthma genetics fall into two broad categories of investigation. First, there is the need to apply functional genomics approaches to better understand how specific genetic variants contribute to pathogenesis. This will need to be done in a context that allows for appropriate investigations of variations in asthma susceptibility and response to drugs in environment-specific and population-specific contexts. Second, improved methodologic tools for studying gene–gene and gene–environment interaction in asthma (i.e., pharmacogenetics, ecogenetics, and epistasis) are required. This research is judged important, as it will provide tremendous opportunities to uncover the heterogeneity and complexities of the asthma syndrome.
Research Opportunities
Background In the past four years, nearly 1,700 citations have considered the approaches of intervention and prevention in asthma. From these observations, asthma prevention has been considered at the primary, secondary, and tertiary levels. For example, environmental control of allergen exposure has been explored as a treatment of asthma, with variable results (32, 33). The basis for such differences in these various studies has not been defined but might hold clues as to mechanisms of disease and phenotypic variation. Early life events have also been found to be risk factors for asthma or as factors that may modify expression of the disease (34, 35). For example, cigarette smoke, even during the prenatal period, has been found to be a risk factor for asthma (36, 37). Conversely, a rural environment appears to be protective from the expression of asthma (38). Finally, recent evidence has begun to suggest that early exposure to animals, i.e., cats and/or dogs, can reduce the risk of asthma (39, 40). With the recognition that immune factors, even early in life, may contribute to the pathogenesis of asthma, research has begun to focus on understanding the links between innate and adaptive immunity (see above) in early life and how these responses can be modulated to allow for correction of cytokine and/or other types of immunologic dysregulation and their subsequent effects on the development of the asthmatic phenotype (41, 42). Recently, standard immunotherapy with environmental allergens during childhood has been evaluated and shown to reduce the likelihood that asthma will develop in a high-risk population (children with allergic rhinitis only at the start of immunotherapy) (43). Other approaches that may modulate immune development, such as DNA vaccination, are also under active investigation (44). The treatment of asthma is a multiphased and multifaceted approach with variable outcomes. Although current therapeutics for asthma are effective and safe, successful and far-reaching control of asthma has been incomplete. To advance the translation of the understanding of asthma mechanisms to clinical intervention, a number of important areas of research were identified. These include the importance of adherence in asthma treatment, not only at the level of application but also understanding factors that determine this behavior and its importance to asthma phenotypes and genotypes. The mechanisms underlying behavior, and behavior modification to therapy of asthma and possibly underlying mechanisms, are needed. Research into how ethnicities, sex, and age, as well as other disparities of certain groups have effects on asthma and the response to asthma treatment (medications, perception, and environmental control, for example) is needed. Furthermore, the differences in response to treatment in different severities of asthma have yet to be explored. Therapeutics also needs to be studied in relationship to genetic factors, i.e., pharmacogenetics. Finally, therapeutics, which addresses asthma prevention, disease modification, and reversal of underlying mechanisms, are of particular need and importance. The effectiveness of intervention with antiinflammatory therapies, such as inhaled corticosteroids, has also been explored through cooperative studies such as Childhood Asthma Management Program (CAMP) and the Childhood Asthma Research and Education (CARE) Network, along with the Asthma Clinical Research Network (ACRN). These "networks" have not only been successful in evaluating the efficacy and effectiveness of asthma treatment, but they have provided new insights into characteristics of the disease and basic mechanisms as well. During discussions, it became clear to the advisory group that there were many agents/approaches that have already been developed for other purposes that could have a favorable impact on asthma, and that this area of study was also of considerable importance. Although available asthma management is generally effective, this area of research can be important to improve effectiveness (adherence and behavior modification), to seek out disease-modifying approaches, and to provide insight into basic mechanisms of disease and pharmacogenetics.
Research Opportunities
Background Acute antigen challenge of the airways can lead to rapid edema and appearance of plasma proteins in the airways. Furthermore, the airways of patients with asthma have elevated levels of macromolecules derived from blood compared with normal airways (45). Numerous pathways exist for the regulation of vascular tone, diameter, and leakage. More information is desirable to better understand the molecular processes by which vascular tissue and infiltrating cells alter the tone, permeability, and development of airway blood vessels. In addition, pathways for movement of macromolecules from extravascular sites into the airways are worthy of further study (46–48). The role of the vasculature in responses of the airways to exercise, hyperosmolarity, and cold air challenges is also an important area that is likely to improve our knowledge and treatment of asthma. Although there is increased vascularization in the lung associated with greater severity of asthma, little is understood about the angiogenic factors in asthma (49). In addition, although vascular endothelial growth factor (VEGF), for example, has been produced in an exaggerated fashion in asthma, the role that it and other growth factors play in asthma pathogenesis is poorly defined. Interestingly, this is one of the few components of airway remodeling that appears to be fully reversible with treatment with glucocorticoids. The role of growth factors, such as VEGF and angiopoietin, and other factors involved in regulating this process, and the importance of regulation by glucocorticoids and other drugs, are all areas worthy of further investigation. In addition, the possibility that vascular regulators can have nonvascular effects in the lung has not been considered (50). Neuropeptides appear to have effects on angiogenesis in the lung, but there is little knowledge of how the nervous system may affect the vascularization process. There is increasing support for the idea that in asthma the efferent and afferent nerve fibers may be changed in their capacity to be stimulated. More work is necessary to delineate whether this could be one of the driving forces for increased vascularization. Endothelial cells express adhesion molecules in response to inflammatory cytokines, and these adhesion molecules are important in the recruitment of inflammatory cells (51, 52). There is evidence for cell type–selective adhesion molecules (e.g., VCAM-1), which can shape the nature of the inflammatory cell infiltrate. Endothelial cell–derived chemokines can be important in transendothelial migration. The presence of chemokines alone, however, is inadequate to induce inflammatory cell infiltration of the airways, suggesting that activation of endothelium is an essential component of the pathway for cell recruitment to the lungs. Blood vessels are very important in asthma. They are involved in the recruitment of inflammatory cells to the airway, contribute to the altered airway physiology, and secrete a variety of mediators that may determine or regulate the inflammatory response. Despite the recognized importance of vascular tissues to asthma pathophysiology, there are major gaps in our knowledge of this area. Identification of these gaps and the application of research to these areas is a priority.
Research Opportunities
Participants: Co-Chairs—William Busse, M.D. (Madison, WI) and Jack Elias, M.D. (New Haven, CT); Group leaders—Group 1, Carole Ober, Ph.D. (Chicago, IL); Group 2, Reynold Panettieri, M.D. (Philadelphia, PA); Group 3, Robert Lemanske, M.D. (Madison, WI); Group 4, Dale Umetsu (Stanford, CA); Group 5, Mario Castro, M.D. (St. Louis, MO); Group 6, Scott Weiss, M.D. (Boston, MA); Group7, Cynthia Rand, Ph.D. (Baltimore, MD); Group 8, Robert Schleimer, Ph.D. (Baltimore, MD); Group 9, Monica Kraft (Denver, CO); Susan Banks-Schlegel, Ph.D. (Bethesda, MD), James Kiley, Ph.D. (Bethesda, MD), Patricia Noel, Ph.D. (Bethesda, MD), Hector Ortega, M.D., Sc.D. (Bethesda, MD), Thomas Platts-Mills, M.D., Ph.D. (Charlottesville, VA), Virginia Taggart, M.P.H. (Bethesda, MD), Yohannes Tesfaigzi, Ph.D. (Albuquerque, NM), Gail Weinmann, M.D. (Bethesda, MD), and Sandra Wilson, Ph.D. (Palo Alto, CA). The authors are very grateful to Kathryn Purcell for her excellent assistance in preparing this manuscript.
Conflict of Interest Statement: W.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.B.-S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; P.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; V.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form November 12, 2003; accepted in final form June 16, 2004
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PRIORITY 1: INNATE IMMUNITY,...
