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American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 698-706, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.2601007

Pulmonary and Critical Care Updates

Update in Asthma 2005

Sally E. Wenzel and Ronina Covar

National Jewish Medical and Research Center for Immunology, Denver, Colorado

Correspondence and requests for reprints should be addressed to Sally E. Wenzel, M.D., Department of Medicine, 1400 Jackson Street, National Jewish Center for Immunology, Denver, CO 80206. E-mail: wenzels{at}njc.org

Asthma, an enormously common illness, has been a focus of research studies, many published in the journals of the American Thoracic Society and/or American Lung Association for more than 100 yr (1). In 2005, ongoing research focused on several emerging areas, including studies on the use of biomarkers to understand the clinical phenotypes and activity of the asthma, a renewed interest in the role infections play in both acute and chronic phases of asthma, an increased appreciation of the role that structural cells play in the pathogenesis of asthma, as well as studies focusing on treatment of both pediatric and adult patients.

PEDIATRIC ASTHMA

Pediatric asthma research published in 2005 extracted exciting updates from existing population-based cohorts, from characterizing phenotypes to identifying risk factors and genetic predisposition for the development of asthma. An appraisal of the utility of biomarkers, specifically exhaled nitric oxide, not only as a predictor of worsening asthma but also as a treatment strategy tool, was also performed. Investigators continued to explore means to evaluate key components of asthma such as airway hyperresponsiveness, airway inflammation, and remodeling in very young children.

Epidemiology of Asthma and Wheezing Phenotypes: Lessons from Cohort Studies
The association between early childhood lung function and the different wheeze phenotypes (i.e., transient, persistent, and late onset) has been explored, with some findings contrasting with those from the Tucson Children's Respiratory Study (2). In that study, the transient wheezers had lower airflows (based on VmaxFRC) in infancy compared with never wheezers (mean age) and remained so at age 6 yr. Persistent wheezers had similar lung function in infancy, but by age 6 yr they had developed more compromised lung function compared with never wheezers. The late-onset wheezers did not show alterations in airflow measurements. More recent observations of smaller samples have revealed additional insight into these associations. Turner and coworkers found reduced lung function in their cohort of persistent wheezers, as early as 1 mo of age, whereas their transient wheezers had airflows similar to never wheezers (3). From the National Asthma Campaign Manchester Asthma and Allergy Study cohort, both transient and persistent wheezers had reduced lung function (specific airway resistance; kPa/s) at age 3 and 5 yr compared with never wheezers, with persistent wheezers having the worst lung function compared with other groups (4). Among children who had wheezed by age 3 yr, multivariate analysis indicated that increasing specific airway resistance and the child's sensitization were significant predictors of persistent wheezing. There was no association between lung function at age 3 yr and late-onset wheeze in children.

It is unclear why a discrepancy in the relationships between lung function and wheeze phenotypes exists between studies. More recent studies indicate that persistent wheezers have the most consistently impaired lung function from early infancy through preschool years. Possible explanations are differences in inherent properties of the airways or variable timing of injury to the airway, which may be related to differences in the characteristics of the cohort.

Further characterization of the reported phenotypes of never, transient, late-onset, and persistent wheezers from the Tucson Children's Respiratory Study revealed that less than one-quarter of never and transient wheezers developed wheezing (mostly infrequent) in adolescence and that late-onset and persistent wheezers were more than three times more likely to continue wheezing compared with never wheezers (5). In adolescence, persistent and late-onset wheezers continued to be more atopic than never and transient wheezers. Relative to never wheezers, transient and persistent wheezers continued to have lower airflows, but no progressive deficits in lung function were observed in school-age children, using group estimates. However, a subgroup of children with progressive airflow limitation was identified independent of inhaled corticosteroid (ICS) use (6). Similarly, lung function deteriorated in children with moderate to severe asthma through adulthood (7).

New Risk Factors for Asthma
Studies have also elucidated novel factors that may contribute to wheezing and asthma, especially in childhood. Maternal vitamin E intake during pregnancy was found to be negatively associated with early childhood wheeze in the absence of a cold and eczema in children of atopic mothers; hence prenatal exposure including maternal diet may modulate immune susceptibility to asthma and allergy (8). The National Asthma Campaign Manchester Asthma and Allergy Study found that psychobehavioral variables in early life, such as attention problems and overactivity, preceded the development of late-onset wheeze, and may even be linked to its development (9). Similar relationships were found in adult patients with asthma, such that panic disorder and early childhood anxiety were suggested to predict subsequent asthma (10). The association between behavior and asthma is likely not a pure "cause–effect" phenomenon (e.g., anxiety may be triggered by severity of asthma and particular medications) but may be caused by either shared physiologic or immunologic correlates (e.g., hyperventilation) or risk factors contributing to the development of each condition (e.g., early childhood anxiety, stress, family history of allergy, smoking). The Cleveland Children's Sleep and Health Study confirmed a higher prevalence of wheeze or asthma in obese school-age children and that sleep-disordered breathing has a relative impact on this association (11). From the Dunedin Multidisciplinary Health and Development cohort, the association of obesity with asthma and atopy was female sex specific, and the attributable fraction estimate indicated that 28% of incident asthma in women beyond age 9 yr may be due to increased body mass index (12). Recognition of these factors and the extent of their contribution to asthma may be important in the pursuit of supplemental interventions to improve asthma control.

Discrete parental influence on airway hyperresponsiveness was determined from the Childhood Asthma Management Program cohort. Paternal history of asthma was shown to be the predominant determinant of airway responsiveness, independent of other factors. Its influence on airway responsiveness in children with mild to moderate asthma persisted over time (13). Although speculative, this association could be related to airway responsiveness–specific genes that are preferentially sex expressed.

Although airway hyperresponsiveness, low lung function, and parental/personal history of atopy are associated with childhood wheeze in both males and females, there are variables that influence the development of adolescent-onset wheeze differently between males and females. Whereas prenatal maternal smoking and atopy were significant predictors of adolescent wheeze in males, change in body mass index predicted female adolescent wheeze. In contrast, early dog ownership was protective against adolescent-onset wheeze only in females (14).

Asthma and Environmental Exposures
Investigations into the association between infections or environmental tobacco smoke (ETS) exposure and asthma have provided provocative observations. There is now good evidence that severe respiratory syncytial virus bronchiolitis in infancy is a strong risk factor not only for asthma but also allergy (e.g., animal dander sensitivity), even in adolescence (15). The mechanisms involved in and implications of finding Chlamydia pneumoniae in the airway of individuals with asthma are also uncertain. Two pediatric studies have reported an increased prevalence of C. pneumoniae in the lower respiratory tract of children with asthma, and they present contrasting associations with atopy (16, 17).

Passive ETS exposure has been linked to wheezing and severity of asthma in childhood. A study of healthy infants exposed to ETS suggested that wheezing relates more to effects on airway size rather than increased airway reactivity, with the latter linked to atopy (18). There is growing evidence that exposure to ETS in early childhood can be related to late-onset disease. From the Dunedin Multidisciplinary Health and Development cohort, maternal smoking during pregnancy was associated with adolescent-onset wheeze in males (14). In another study, approximately one-quarter of incident adult-onset asthma could be attributed to childhood ETS exposure (19). It is possible that a threshold must be reached before changes in the airway manifest as symptoms or that interactions with other genetic or environmental factors are required. Similar to ETS exposures, air pollutants such as particulate matter, nitrogen dioxide, and ozone, a prime component of air pollution, have also been linked to worsening asthma and exacerbations (20, 21).

Application of Biomarkers in Pediatric Asthma
There are now studies not only in adults but also in children that support the use of fractional exhaled nitric oxide (FENO) levels and sputum eosinophilia to predict loss of asthma control after ICS reduction (22). In the first pediatric study that integrated FENO in the treatment algorithm, this approach allowed for greater improvement in bronchial responsiveness and reduction of FENO levels than a symptom-based approach (23).

Remodeling in Pediatric Asthma
Evaluation of airway inflammation and remodeling in young children remains a challenging field of research because of ethical constraints. Research bronchoscopy studies are just beginning to give valuable insight into the origins and development of asthma. Children less than 2 yr of age with severe wheeze and/or cough, decreased specific airway conductance, and/or bronchodilator reversibility had no evidence of eosinophilic inflammation or thicker epithelial reticular basement membrane on biopsy suggestive of airway remodeling compared with control subjects and subjects with established asthma (24). These findings suggest that (1) young symptomatic children with airflow limitation do not necessarily have structural remodeling or eosinophilic inflammation and (2) ICS therapy may have limited benefit given the paucity of eosinophilic airway inflammation.

Treatment of Pediatric Asthma
Not all patients with asthma will respond to available medications uniformly. The Childhood Asthma Research and Education Network evaluated features that determine the differential response of children with mild to moderate asthma to ICS or to the leukotriene receptor antagonist montelukast (25). More than half the children did not have improvement in lung function to either drug, whereas 23, 5, and 17% showed favorable responses to ICS, montelukast, or both, respectively. Response to ICS was seen in those children with lower lung function, greater airway reactivity, and allergic inflammation, whereas younger children with shorter disease duration were likely to improve with montelukast.

Clinical guidelines have recommended treatment for young children based on persistent symptoms and atopic risk. However, many children present with "episodes" long before they develop persistent symptoms. New studies in this age group have evaluated the beneficial effects of controller therapy on objective measures such as lung function (18). A favorable effect of ICSs on lung function was not replicated in a shorter term study in infants not preselected for atopic risk (26). The contrasting findings from these two studies suggest that there is a subgroup of recurrent wheezers with a different inflammatory process that is not steroid sensitive. Preschool children with intermittent wheezing episodes associated with viral-induced exacerbations are able to reduce their risk of an exacerbation with once-daily treatment with a leukotriene receptor antagonist (27). Additional studies are still necessary to identify young children who will benefit from specific antiinflammatory therapy.

More precise evaluation of the different components of asthma, including bronchial hyperresponsiveness, airflow limitation, and airway inflammation, in the pediatric age group should be pursued. Measuring bronchial hyperresponsiveness indirectly, using cold air or dry air challenge with specific airway resistance as an outcome, may be a practical alternative to pharmacologic challenges in young children (28).

Genetics
Genetic studies of pediatric cohorts are still few in number. Polymorphisms in the asthma susceptibility gene ADAM33 on chromosome 20p13 have been associated with both excessive decline in the general population (29) and in adults with asthma (30), and with compromised lung function even in early childhood (31). T-bet (TBX21 or T-box 21) on chromosome 17q21 regulates helper T-cell type 1 (Th1) lineage development by inducing IFN-{gamma} production and by inhibiting interleukin 4 (IL-4) and IL-5. Polymorphisms in T-bet were found to be associated with airway hyperresponsiveness in white children with asthma, but only the link between the c.–7947 variant and airway hyperresponsiveness was replicated in an independent cohort of adult males (13). Polymorphisms in the GPRA (G protein–related receptor for asthma) gene on chromosome 7p have now also been associated with asthma, airway hyperresponsiveness, and allergic predisposition in children (32, 33), confirming prior findings in adults of the gene's impact on asthma susceptibility and allergy (34).

ADULT ASTHMA AND MECHANISMS OF DISEASE

Biomarkers, Including Exhaled Nitric Oxide
In 2005 the use of FENO, both to aid in the diagnosis of asthma as well as to add to the tools used to monitor the course of asthma, continued to push closer to the mainstream. An update on the combined recommendations of the American Thoracic Society and the European Respiratory Society was published to standardize the approaches to its use (35). There are now studies that support the use of FENO to reduce ICS doses in mild–moderate asthma without increasing exacerbations. This approach allowed for greater reduction of ICS than when ICS was tapered in a more traditional fashion on the basis of clinical measures, without an increase in exacerbations (36). In addition to management of patients with asthma, FENO may also have a place in diagnosis of asthma (or at least the response to ICS therapy). In an article from the same group, 52 patients with new onset of respiratory symptoms were evaluated by FENO. The response to ICS was significantly higher in those subjects with an FENO exceeding 47 parts per billion, 15 of 17 of whom had a diagnosis of asthma (33).

The search for additional biomarkers for asthma and other respiratory conditions has produced potential candidates in sputum, exhaled breath, and blood. Lung (sputum/biopsy) eosinophils have been used to regulate ICS dose and decrease exacerbations as well as to define phenotypes (37, 38). Wood and colleagues reported that sputum 8-isoprostane levels (a marker of oxidative stress) increased with asthma severity, were elevated in acute asthma exacerbations, and decreased with recovery (and increased steroid therapy) (39). Interestingly, the Severe Asthma Research Program reported related findings in the serum of subjects with severe asthma (40). Superoxide dismutase activity was lower in the serum of subjects with asthma compared with that of control subjects. Although the activity was not lower in the severe asthma group compared with the nonsevere asthma group, lower activity levels were associated with lower FEV1. Both these studies support an increased oxidative process in asthma, with some indication that sputum activity may better differentiate severe asthma from less severe disease.

Brain-derived neurotrophic factor (serum, plasma, and platelets) appears to be increased in mild, untreated asthma, correlating with both airway obstruction and hyperresponsiveness (41). Although it appears to be effectively suppressed by ICS in vitro, the impact of ICS clinically and in relation to disease severity requires further study.

As noted above, using biomarkers to aid in asthma phenotyping, to improve therapeutic approaches, and to better link genetics to phenotypes is gaining interest. Individuals with asthma have been subdivided on the basis of eosinophils, neutrophils, and the absence of any obvious inflammatory cells (38, 42). These differing inflammatory cell patterns also appear to express differing injury and repair factors, such as matrix metalloproteinases (MMPs) and elastases. Eosinophilic asthma appears to have higher sputum quantities of MMP-9, including MMP-9 in the active form, than neutrophilic or "paucigranulocytic" asthma, whereas neutrophilic asthma appears to have higher amounts of neutrophil elastase than do the other two groups (43). The relationship of these different inflammatory patterns to immune processes remains to be determined, but sputum CD4+ and CD8+ cells from patients with allergic asthma (even those receiving ICS from 200 to 1,000 µg/d) were reported to produce a mix of Th2 and Th1 cytokines, suggesting that the actual balance of these mediators could influence the direction of the inflammatory process (44).

Asthma and Environmental Exposures
Although an underlying immunologic component of atopy, and perhaps asthma, includes activation of Th2 pathways, it is also likely that clinical asthma, especially in adults, is associated, if not driven by, interactions with numerous other environmental/infectious and immune signals (45, 46). These interactions have received increasing attention as it becomes clear that Th2 activation (alone) does not appear to explain clinical asthma, and perhaps more specifically, severe asthma (47).

In asthma, two of the environmental factors believed to play the largest roles are viral infections and endotoxin exposure, either through general environmental conditions or tobacco smoke. Although respiratory viral infections are generally linked to upper airway symptoms, a report demonstrated that rhinovirus could be detected in the lower airways (48). This report did not detect differences between the amount of virus, or the duration of time virus was detectable, in subjects with asthma versus control subjects. However, other studies have suggested that the immune response to an acute virus in asthma may differ from that seen in nonasthmatic subjects and prolong the presence of the virus in the lower airways (49). Mechanistically, studies have shown a more robust IL-10 response in subjects with asthma, as well as reductions in epithelial cell IFN-beta production (50, 51). These blunted immune responses could perpetuate virus in the lower airways or at least lead to a more prolonged/low-grade response to it. Whether similar mechanisms contribute to the newly described predisposition of patients with asthma to pneumococcal disease is not clear, but a large Medicaid database study identified a two- to fourfold increased risk for pneumococcal disease, which was dependent on the severity of underlying asthma (52).

Exposure to endotoxin and its relationship to asthma continues to be of interest. In contrast to the hygiene hypothesis, which suggests endotoxin exposure in childhood protects against atopy and asthma, adults exposed to high levels of endotoxin appear to be at higher risk for asthma and asthma-related symptoms (53). However, the effect was not seen in children, nor was there a greater effect on atopic asthma, as might be suggested from studies that combined short-term cigarette smoke exposure with an ovalbumin-sensitized/challenged mouse system. In that case, cigarette smoke, known to contain high amounts of endotoxin, enhanced allergic inflammation (but, interestingly, not airway responsiveness) (54). However, continued cigarette smoking in humans appeared to increase the risk for bronchial hyperresponsiveness irrespective of atopy or allergy (55).

It is also conceivable that some of the increased risk of endotoxin/ETS exposure could be modified by genetic variants, such as those found in CD14 (a component of the LPS–endotoxin receptor complex). In a study of Latinos by Choudhry and colleagues, specific mutations in the CD14 gene (single-nucleotide polymorphisms at positions +1437 and –159) were associated with lower lung function and higher IgE levels than in control subjects without the same degree of ETS exposure, supporting gene-by-environment interactions in the endotoxin pathways (56). Similar gene-by-environment interactions may explain the findings that Mexican Americans born in the United States are at greater risk for asthma than Mexican Americans born in Mexico (57).

As suggested by the dramatically different impact of endotoxin exposure on asthma in childhood and adulthood, the immune/inflammatory response in asthma is likely to be complex and plastic. However, in most model systems, exposure to endotoxin/LPS activates an inflammatory process. In classic studies using a chimeric mouse system targeting specific expression of Toll-like receptor (TLR)-4, the classic LPS receptor, Hollingsworth and coworkers were able to prove that hematopoietic-derived cells, including alveolar macrophages, were critical for neutrophil recruitment into the airways after LPS challenge (58). In contrast, TLR-9, the receptor for bacterial CpG oligonucleotides, does not appear to be functional in alveolar macrophages, at least in mice (59). In addition to primary stimulation of hematopoietic cells by endotoxin, however, an amplification of the response can involve resident cells, such as smooth muscle cells (60). Although TLR-2 and TLR-4 were found to be expressed on airway smooth muscle cells, these receptors did not appear to be functional. In contrast, when mononuclear cells were added to the system and challenged with LPS, there was a marked synergistic up-regulation of both IL-6 and IL-8 production that appeared to be dependent on generation of IL-1beta and close contact with the non–T-cell mononuclear cell fraction (60). These data suggest that a cascade of events occurs in tissue after initial stimulation of hematopoietic cells by LPS, and that it involves activation of resident cells as well.

Similar to endotoxin/ETS exposures, ozone, a prime component of air pollution, has also been linked to worsening asthma, inflammation, and exacerbations. Interestingly, human alveolar macrophages appear to be involved in inflammatory responses to ozone (61). Whether a newly discovered cytokine, IL-17F, which augments goblet cell formation and neutrophil influx in a murine allergen/ovalbumin model, could contribute to the greater degree of inflammation seen in combined challenges, such as ozone/endotoxin, with allergen, remains to be determined (62).

Allergen sensitization and exposure itself could contribute to an enhanced response to a second allergen. This appeared to be true for sensitization and exposure to house dust mite extract. The initial exposure dramatically enhanced the immunologic and inflammatory response to the much less immunogenic ovalbumin (63). Thus, allergen exposure itself may enhance the response to other allergens, at least in murine lungs.

Remodeling in Asthma
Although remodeling continues to be extensively discussed, defining its role in relation to asthma remains problematic. In an innovative study using fractal analyses of autopsied lungs from individuals with fatal and nonfatal asthma as well as control nonasthma lungs, marked differences in the airways were observed. Such changes correlated with a decreased overall structural complexity highlighted by increased airway truncation, longitudinal ridges, and horizontal corrugations. These remodeling alterations corresponded to mucus plugging and smooth muscle hypertrophy (64). Whether some of these cast images can be used to enhance our ability to understand other imaging techniques, such as those using positron emission tomography scanning to identify regions of bronchoconstriction and altered blood flow, remains to be seen (65).

Further investigations of airway-remodeling changes included several studies investigating the mechanisms behind the hyperplasia/hypertrophy of the airway smooth muscle. ADAM33 has received considerable attention because of its genetic link to asthma and its specific localization to fibroblasts and airway smooth muscle. In further studies of ADAM33 expression in the airways, Haitchi and colleagues identified several protein isoforms in developed and developing lung, suggesting that it may play a role in both initial modeling and remodeling (66).

Fibronectin, and collagen, both of which have been reported in increased quantities in tissue and lavage fluid in asthma, have been shown to increase the proliferation of airway smooth muscle cells in response to mitogens, such as thrombin and platelet-derived growth factor. It now appears that this enhanced proliferation requires the engagement of a variety of beta1-integrins, and it has been suggested that blocking these integrins might decrease proliferation (67). Interestingly, airway smooth muscle cells may also serve as a source of chemoattractants, such as CXCL10, which serve to attract mast cells specifically to the smooth muscle through CXCR3 (68). As mast cell tryptase has been reported to enhance smooth muscle proliferation, this specific attraction of mast cells could also contribute to smooth muscle remodeling in asthma.

The role of the epithelium, in particular the regulation of mucus and its clearance, in asthma and other airway diseases remains an area of considerable focus (69–71). As one of several gene array studies done on various cells of interest in asthma, Lilly and colleagues evaluated the epithelial cell response following an allergen challenge. In this study, 141 up-regulated genes and 8 down-regulated genes were identified, including those associated with allergic responses, such as IL-4 receptor {alpha}, monocyte chemotactic protein-1, and IL-8, as well as genes related to proliferation and differentiation (72). Activation of IL-4 receptor {alpha} by IL-4 in airway epithelial cells was shown to increase the production of gelsolin, an enzyme that breaks down actin (71). It is conceivable that this enzyme enhances the fluidity of mucus in asthma and, at least in the chronic, noninfected state where it was observed to be present in high amounts, may prevent the development of the thicker, more tenacious sputum associated with chronic bronchitis (71). Whether gelsolin production changes in exacerbations is not known. An additional antagonist, a brevetoxin produced by the dinoflagellate causing red tides in Florida, also appears to increase mucus clearance through increasing its velocity, and thus could also potentially serve as a future therapeutic agent (73).

Although it was perhaps surprising that MUC5AC, the primary mucin gene in airway epithelial cells, was not up-regulated directly by allergen, it is conceivable that the up-regulation of MUC5AC occurs secondary to other events (neutrophil influx or change in the oxidation status of the cells). The up-regulation in HS-292 cells appears to occur through activation of the epidermal growth factor receptor and involves activation by proteases such as ADAM17 and/or MMP-9 (74). Studies in sinus (as opposed to bronchial) tissues from patients undergoing sinus surgery suggest that L-selectins may play a role in the migration of inflammatory cells into the tissue, which then activates mucus production through mechanisms as outlined above (75).

Airway remodeling may alter neurogenic responses, as well. Myers and coworkers were the first to describe a role for neurokinin-3 receptors in selected subsegments of airways (76). It was suggested that the localization of this pathway to specific regions of the airways could control airflow distribution. Whether alterations in this pathway could contribute to the recognized heterogeneity of the bronchoconstrictive pattern in asthma remains to be determined (77). However, studies in various diseases involving the upper airway (acute sinusitis, allergic rhinitis, and nonallergic rhinitis) suggest that differences in these and other neurogenic pathways could control mucus production as well as bronchial tone (78).

Severe Asthma and Natural Progression of the Disease
The ultimate clinical manifestation of remodeling is the development of severe disease, either progressively or after an initial insult. Severe asthma remains a heterogeneous disease where both mechanisms for its development could be operative at different times or in different populations (79, 80). For instance, a 12- to 15-yr follow-up study of subjects with childhood asthma suggested that the more severe the disease in childhood, the more severe the disease would be in early adulthood, supporting the concept that processes that occur early in the course of the disease determine its longer term outcome (7). In contrast, a follow-up study of young adults with asthma suggested that the inflammatory profile in endobronchial biopsies, specifically the presence of CD8+ lymphocytes, predicted a progressive decline in FEV1 (81). What is not clear is whether these are distinct processes or overlapping processes, or even whether the decline in lung function is greater in individuals with more severe disease early on.

Whatever the mechanism for the development or presence of severe asthma, several studies addressed potential biologic mechanisms associated with this entity. Interest in lipoxins, metabolic downstream interactive products of lipoxygenase pathways, has increased because of their potential antiinflammatory effects. In the serum of patients with severe asthma, levels of lipoxins appeared to be decreased and correlated with FEV1 (82). There was a lower ratio of lipoxins to cysteinyl leukotrienes as well, suggesting that some of the protective effects of these compounds might be diminished in severe asthma. A second study addressed the inability of alveolar macrophages from subjects with severe asthma to clear apoptotic cells (83). Reduced clearance of apoptotic cells in response to LPS was associated with a decrease in the production of lipid mediators, particularly prostaglandin E2 and 15-hydroxyeicosatraenoic acid, both at baseline and in response to LPS. This is noteworthy as one of the parent compounds for lipoxins is 15-hydroxyeicosatraenoic acid, a product of the 15-lipoxygenase pathway, suggesting a mechanism by which lipoxin levels may be reduced in severe asthma.

Little is understood regarding the pathology of severe asthma, with even less understood regarding the distal lung in asthma. In studies of transbronchial (distal) and endobronchial (proximal) biopsies from subjects with severe asthma, mast cells, specifically chymase-positive mast cells, dominated in the distal airways and were present in higher quantities in severe asthma than in distal airways from "normal" autopsy control subjects (84). Of note, there was little evidence of increased inflammatory cells in the parenchyma of these patients with severe asthma as compared with other compartments or the postmortem lungs. This lack of abundant parenchymal inflammation is in sharp contrast to the large amount of parenchymal inflammation and remodeling described in many murine allergic response models, bringing into question their utility in the study of human asthma (85). It may also help explain why beta-agonists with larger particle size, delivered to airways as opposed to parenchyma, are more effective as asthma therapy (86).

There is increasing interest in differences between males and females in both the presence of severe asthma, as well as differences in the phenotypes related to sex. Several studies have now suggested that severe asthma is made up of a higher proportion of women than men (87, 88). However, when focusing specifically on FEV1 (as opposed to symptoms), the decline in FEV1 over time appears to be steeper in males than females (79, 89). In contrast to the large proportion of males with asthma in childhood, the ratios appear to reverse in adolescence or shortly thereafter, with women becoming the majority. Therefore, there is increased interest in life events occurring around the time of menarche. The study by Varraso and colleagues suggesting that the combination of early menarche and high body mass index is associated with more severe asthma in women (89). Whether increased body mass index is one of the contributors to the high incidence of gastroesophageal reflux in severe asthma is not clear, but a study of the use of proton pump inhibitors in this population did not appear to improve asthma symptoms in this population (90).

Treatment of Asthma
ICSs remain the "gold standard" for asthma therapy. However, several studies have explored aspects of ICS therapy that may modify our use of this class of medications in certain individuals or phenotypes. Perhaps the most controversial study, from the Asthma Clinical Research Network, suggested that daily ICS treatment of patients with truly mild persistent asthma was only marginally better than intermittent treatment, with no differences observed in postbronchodilator FEV1 or exacerbations, but significant (although numerically small) differences in asthma control scores and symptom-free days (91). This study suggested that a population of adults with mild asthma may exist for which daily ICS offers only marginal benefit. Similarly, it has become increasingly appreciated that not all individuals with asthma at every severity level exhibit a robust response to ICS. Therefore, identifying phenotypes of subjects with asthma who are more or less responsive to ICS is desirable. This was the objective of a study from the Childhood Asthma Research and Education Network in which baseline characteristics of children who responded to ICS versus the leukotriene receptor antagonist montelukast were identified (25). Of interest, only 40% of children exhibited a 7.5% or greater improvement in FEV1 in response to fluticasone. Perhaps not surprisingly, airway obstruction and evidence of active inflammation were the best predictors for response to ICS in this study. In contrast, the ability of ICS to improve the beneficial response to deep inspiration appeared to be more prominent in subjects with mild asthma (92). Finally, tobacco use was further identified as a factor that altered the dose response to ICS such that substantially higher amounts of ICS were required to produce an effect (93).

It is conceivable that acute asthma is a "phenotype" that responds well to ICS. The second study on the use of high-dose ICSs suggested that repeated and high doses of inhaled fluticasone were more effective in the treatment of acute asthma than intravenous hydrocortisone, with a more rapid onset of action and a greater response than the intravenous formulation (94). Independent confirmation of these studies by another group, as well as further studies of the mechanisms behind these observations, are required.

Given the relatively common lack of response to ICS, it is not surprising that combination therapy (long-acting beta-agonist [LABA] and ICS) has become an increasingly popular approach to asthma therapy, including (and dependent on the LABA) its use as both a controller and reliever medication (95). Although much of the benefit of the combination likely is through the differing mechanisms of action (bronchodilation versus antiinflammatory), some of the additive effects may be due to the ability of LABAs to enhance the translocation of the glucocorticoid receptor to the nucleus, where most of the antiinflammatory effects of corticosteroids are believed to occur (96).

In addition to the benefits of LABAs, concerns continue regarding possible problems with their use, at least in a subset of patients with a specific genetic variant of the beta receptor-2 gene (97). Some of these concerns have contributed to the U.S. Food and Drug Administration changes to the label regarding the use of LABA in asthma. However, this area remains highly controversial, with some studies suggesting that polymorphisms, such as the Arg-16 polymorphism, are related to asthma severity (98) and others suggesting the opposite (99, 100). Clearly, further prospective clinical studies of potentially "at risk" genotypes are required.

With these concerns regarding LABA in asthma, studies evaluating alternative bronchodilators in asthma are of considerable interest. Anticholinergics are widely used in chronic obstructive pulmonary disease, but their effectiveness in asthma has not been well studied. A guinea pig model of allergic inflammation suggested that smooth muscle remodeling may be dependent on cholinergic pathways (101). Unfortunately, confirmation of these effects in humans is difficult. Phosphodiesterase-4 inhibitors, being developed for use in human asthma, also appear to have an impact on airway resistance in an ovalbumin rat model of allergic inflammation (67). Whether drugs impacting either of these pathways could replace beta-agonists in "at risk" genotypes awaits further study.

Underlying the effective use of any asthma medication is the requirement for patient understanding of the disease and its treatment. In an emergency room discharge study of "asthma literacy," 22% of patients with asthma were found to have inadequate understanding of the asthma medications and their use, which improved with education (102). Whether this improved understanding translates to better outcomes requires further study.

Animal Models and Development of New Asthma Therapies
Two studies in mice support the use of currently available therapies for asthma. In the first, Miyahara and colleagues demonstrated that leukotriene B4 (acting through the BLT1 receptor) was critical for airway hyperresponsiveness and was associated with IL-13 production by lymphocytes (103). These studies would support further investigation of five lipoxygenase inhibitors in asthma, which not only block cysteinyl leukotrienes (as leukotriene receptor antagonists do), but also prevent the production of leukotriene B4. The second study, of imatinib (Gleevec), suggested that it strongly suppressed inflammation and reactivity in a mouse model of allergic inflammation (104). Whether this effect is through effects on platelet-derived growth factor or c-Kit, or whether efficacy in human asthma will be demonstrated, remains to be determined.

In addition to these available medications, mouse models have suggested additional targets for development in human disease. These include I{kappa}-B kinase-2 inhibition, which diminishes activation of nuclear factor-{kappa}B; inhibition of p38 mitogen-activated protein kinase through an inhaled antisense oligonucleotide approach; and decoy-mediated inhibition of the transcription factor–activating protein-1 (AP-1) (105–107). In a "combination therapy" approach, Weigt and colleagues suggested that macrophage-activating lipopeptide-2, when combined with IFN-{gamma}, markedly reduced airway hyperresponsiveness and allergic inflammation (108). In contrast to other models, treatment with IFN-{gamma} had no effect on airway hyperresponsiveness. Further studies of these agents in human disease are needed to determine whether any of these approaches has applicability to human asthma.

Asthma Genetics
In addition to the utility of mouse models to develop new targets for asthma therapy, genomic studies of asthma are also helpful in that regard. Genomewide screens have suggested that multiple genes on chromosome 2q may be important in asthma, particularly as related to airflow limitation (109). Positional cloning identified an additional potential asthma susceptibility gene on chromosome 5q33, that is, cytoplasmic fragile X mental retardation protein-interacting protein-2, which was associated with the development of asthma, although verification in a second cohort is still required (110). Interestingly, two studies identified genes related to allergic responses both to molds and cockroaches, common triggers of asthma. In the first, Weiss and colleagues identified single-nucleotide polymorphisms in the beta3-integrin gene in association with mold hypersensitivity and bronchial hyperresponsiveness (111). In the second follow-up study to the 2004 paper in Science (112), polymorphisms and haplotypes in the human acid mammalian chitinase gene, likely to be involved in the regulatory responses to cockroaches and other chitin-containing allergens, were associated with bronchial asthma (113). Whether individuals with susceptible polymorphisms will be more responsive to environmental controls awaits additional study.

Studies have supported new targets for genetic abnormalities in asthma and supported the necessity of evaluating polymorphisms in one gene in relation to another. Targeted analyses of the G protein–coupled receptor for asthma gene on chromosome 7p have confirmed results from a previous study (32, 34). In addition, a study from Randolph and colleagues supported the approach that combines genetic abnormalities in two different, but likely linked, gene clusters, those impacting tumor necrosis factor-{alpha} and lymphotoxin. Although neither genetic abnormality was significantly associated with asthma in isolation, an impact was observed when they were evaluated together (114). For complex diseases such as asthma, the necessity for these gene–gene interactions is not surprising.

CONCLUSIONS
Substantial advances in our understanding of asthma, the associated inflammation and remodeling, and appropriate therapy have occurred in 2005. Perhaps the most significant observations have been those related to the heterogeneity of the disease from a phenotype/genotype perspective, but also as related to natural history and response to therapy. Investigations into underlying mechanisms of these phenotypes are essential, but noninvasive/more accessible tools need to be developed, especially for children, and, in the case of sputum eosinophils and FENO, further validated. Understanding the heterogeneous nature of asthma, its course, and therapeutic approaches will likely improve outcomes.

FOOTNOTES

DOI: 10.1164/rccm.2601007

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form January 9, 2006; accepted in final form January 9, 2006

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