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* From the Pulmonary Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA.
Correspondence to: Jeffrey M. Drazen, MD, FCCP, Editor-in-Chief, New England Journal of Medicine, 10 Shattuck St, Sixth Floor, Boston, MA 02115; e-mail: hstimpson{at}nejm.org
Asthma is at a crossroads. Although the clinical syndrome of asthma has been recognized for millennia, it was research performed in the middle of the last century that established the primary physiologic abnormality as obstruction of the airways to airflow. In addition to airflow obstruction, it was appreciated that the airways of patients were inflamed, that there was hypertrophy and hyperplasia of the mucus secretory apparatus with abnormal amounts of mucus in the airway lumen, and that treatment with adrenergic agonists led to rapid resolution of many of the signs and symptoms of asthma. This latter observation led to the deduction, which still stands, that constriction of the airway smooth muscle was responsible for a substantial proportion of the observed obstruction during an acute asthmatic attack. In the 1970s, as research into the physiology of airflow obstruction reached its peak, investigators began to apply the tools of cell and molecular biology to understanding the root causes of airway obstruction. This resulted in an explosion of new knowledge about the cell and immunobiology of the airway.1 There is now an unprecedented array of potential mechanisms that could lead to the airway obstruction that we recognize as asthma, but there has been little success in sorting out which are the truly active ones. Indeed, it is highly likely that the clinical syndrome of asthma derives from a number of distinct molecular mechanisms. The promise of the future is that the insights derived from the Human Genome Project will provide the keys needed to achieve this distinction at a causal level.
Asthma physiology, especially the events that limit maximal expiratory flow, has been the primary topic of previous Aspen Lung Conferences. The physics of forced exhalation are clearly understood.2
At any point in the airway airflow is limited by the local wave speed given as:
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is maximal expiratory flow, A is the cross-sectional area of the airway, PTM is the transmural pressure across the airway, (
A/PTM) is airway wall compliance, and 
is the density of the airway gas. We know that the physical site of flow limitation, the choke point, during a forced exhalation moves from the central to the peripheral airways. In patients with asthmatic airway obstruction, the site of flow limitation is in the small airways, ie, bronchioles, over much of the vital capacity. Although these relationships have been understood for many years, we continue to learn more about the asthmatic airway. Thickening of the wall limits airflow.3 In asthma, mechanisms are in play limiting the ability of airways to dilate when a large breath is taken, but their precise nature is not known.4 Although multiple mechanisms that could result in airway wall thickening have been elucidated, their relative roles remain undefined. Many different inflammatory processes have the potential to thicken the airway wall, through the accumulation of inflammatory cells, through the deposition of collagen by fibroblasts activated to assume a myofibroblastic phenotype, through hypertrophy and hyperplasia of the mucus secreting apparatus, by changes in the surface properties of the small airways, or by alterations in the characteristics of the subepithelial connective tissue.5 The mechanisms active in mild-to-moderate asthma may be distinct from those operative in severe asthma.6 Multiple mechanisms, including those activated through the adaptive immune response1 7 8 or the innate immune response can elicit these phenotypic changes. Many research groups have focused on the roles of interleukin-4 or interleukin-13 to mediate these changes, either through the cascade of events occurring following antigen exposure or through direct effects of these cytokines on constitutive airway cells.1 8
The number of potential mechanisms that could ultimately impact on the airway wall is multiplied substantially9 when one considers the effects of infectious agents such as viruses, especially respiratory syncytial virus, or atypical bacteria, such as Mycoplasma or Chlamydia species.7 These agents can engender an inflammatory response through both adaptive and innate immune mechanisms. A case can be made for many different mechanisms that could modify the airway wall10 ; unfortunately, it is difficult to gather evidence that clearly distinguishes among these mechanisms.
A mechanism that deserves substantial attention is smooth-muscle activation.4
Constriction of this tissue, which is often hypertrophic and hyperplastic in asthma, will diminish airway caliber, but will also stiffen the airway. If there was no smooth muscle, the airway would became very compliant, ie, (A/PTM) became very large, and maximal expiratory flows fall. If the airway were to become very stiff, ie, (A/PTM) became very small, flow rates could increase, but cough would become ineffective (Fig 1
). Since the exact effect will depend on both the lumen size and the airway wall compliance, interventions designed to permanently impact on smooth muscle, although they could ameliorate airway obstruction, will need to be viewed with great caution.
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There have been a few successful treatments that provide new information about the biology of asthma. For example, the clinical utility of omalizumab, a humanized monoclonal antibody directed against IgE, provides evidence that IgE-driven mechanisms participate in asthmatic responses.14 Agents with the capacity to inhibit the formation or action of the cysteinyl leukotrienes have been shown to be effective asthma treatments.15 Interestingly, among a population of patients with asthma there is widespread variability in the therapeutic response achieved.16 This variability is not unique to the antileukotrienes but is also observed when patients are treated with the inhaled steroids.17 An inference that can be drawn from this observed population variability of response is that there are characteristics of the various subjects studied that render them either sensitive or insensitive to specific forms of treatments. This inference is supported by calculations of the repeatability of the therapeutic response, which is the degree to which an individual subject's response, be it a salutary or an adverse one, is sustained over time.18 Observations with antileukotriene treatment, ß-agonist treatment, or inhaled steroid treatments support the concept that an individual's response is reasonably repeatable.
There are many mechanisms that could explain the observed variance in asthma treatment response. These include structural differences in the airway, differences in environmental exposures, the time of day of the asthmatic event, or differences in the genetic makeup of the individual subjects.19 20 In the case of the latter, there could be genetic differences among patients in drug uptake, distribution, or metabolism. Although these genetic differences could explain variations in the treatment response to various agents, the differences that hold the greatest promise to be biologically informative are genetic differences that result in different mechanisms leading to the asthmatic phenotype.
For example, in one patient with asthma, enhanced availability of the cysteinyl leukotrienes at the level of airway smooth muscle could account for a large proportion of the airway smooth-muscle constriction, while in another patient, with an identical clinical phenotype, airway obstruction could result from an entirely distinct mechanism.11 If, in a given patient, the mechanism of airway obstruction is fixed over time, then it is possible that there are genetic differences among individuals accounting for the different biochemical phenotypes underlying the airway obstruction. That is, in one patient, their genetic makeup results in the availability of cysteinyl leukotrienes in the airway smooth muscle, while in other patients, their genetic makeup results in the enhanced availability of neuropeptides and hence airway smooth-muscle constriction and obstruction, but leading to the same clinical phenotype. Thus, the physiological phenotype of asthma could result from various distinct genetic predispositions to the condition.
If this is the case, then one could use the response to specific asthma treatments as a way to assign patients to various subcategories within a given disease phenotype. Although the response to asthma treatment in a given individual is somewhat variable, it is possible to assign people to treatment response categories, such as "responder" or "nonresponder." This treatment response phenotype, especially when the treatments are targeted at specific mechanisms, such as inhaled ß-agonists, antileukotrienes, or anti-IgE, provides useful information about the underlying biology of the asthma. Thus, new treatments may have their most important role as a way to establish specific disease phenotypes. If a specific disease phenotype is established, for example a "responder to anti-IgE treatment," then it may be possible to use genetic approaches to ascertain the specific genes associated with a given treatment phenotype.
Once a panel of asthma susceptibility genes are identified, the process could go full circle. Suppose a patient presents with a clinical syndrome clearly indicative of asthma. In this case, in 2003 most physicians may order an eosinophil count and an IgE level as confirmatory laboratory studies; however, if a blood test panel to scan for both asthma causing and treatment response genetic defects was also ordered, it would be possible to solidify the diagnosis of asthma and to determine if the patient had a defect that was associated with a specific treatment response, eg, a positive response to antileukotriene treatment. In this scenario, genetic profiling helps establish the diagnosis, eg, what inflammatory pathways are likely to be activated, and delineates treatment, eg, what treatment pathways are likely to be effective.
Because the clinical expression of asthma requires both a genetic predisposition and exposure to certain environmental influences, not everyone with a genetic profile consistent with asthma will manifest the phenotype. Furthermore, because asthma is a complex condition, it seems likely that not everyone with the condition will have an identifiable genetic predisposition. However, since there is clear heritability to asthma, we will probably be able to identify such predispositions in a majority of patients with asthma. Thus, genetic testing combined with our current understanding of asthma pathobiology should result in improved diagnosis and treatment of asthma. This 45th Thomas A. Petty Aspen Lung Conference marks the beginning of the use of the fruits of the Human Genome Project to help physicians better understand, diagnose, and treat asthma.
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  R. H. Brown, W. Wizeman, C. Danek, and W. Mitzner Effect of bronchial thermoplasty on airway distensibility Eur. Respir. J., August 1, 2005; 26(2): 277 - 282. [Abstract] [Full Text] [PDF]
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