Update in Asthma 2007

American Journal of Respiratory and Critical Care Medicine

A major event in asthma was the publication of the third edition of the updated National Asthma Education and Prevention Program (NAEPP) ''Guidelines on the Diagnosis and Management of Asthma'' by the National, Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (1). The resource document for the guidelines has grown remarkably in length from 150 pages (1997) to more than 350 pages (2007), and is one indication of just how far our understanding of the clinical syndrome that is called asthma has progressed in the past decade. The guidelines are impressive, but it is important to remember that they are largely built on a solid background of studies that have led to our current insights into pathophysiologic mechanisms, clinical medicine, evidence-based treatment recommendations, and novel therapies.

Notable manuscripts published in the past year have included basic pathobiology in mice (2-22) and humans (23-35) as well as large randomized clinical trials exploring novel therapeutic options (36-39). Articles have advanced our understanding of the influence of genetics (40-45), early-life influences (46-48), and the environment on the development of asthma (49-55).New tools were developed to assess asthma control (56), predict risk (57), and monitor patients for comorbidities (58-60). Potential new biomarkers (61-64) and exhaled nitric oxide were evaluated as tools to diagnose and help manage asthma (65, 66). Monoclonal antibodies (67) and bronchial thermoplasty (68) were among the new therapies explored in asthma (69).

THE 2007 NAEPP GUIDELINES

The NAEPP guidelines have evolved over the years, but the basic structure of the algorithm has remained intact, with disease severity ''steps'' that correspond with evidence-based treatment recommendations. The long-awaited Expert Panel Report 3 addresses the important issues of clinical asthma care, how best to assess asthma severity, and the newer concept of asthma control as a different entity. These new patient-centric guidelines are focused on current impairment and future risk as markers of asthma control. Asthma severity steps 1-4 (intermittent and mild, moderate, and severe persistent asthma) remain intact from previous versions of the NAEPP guidelines and are determined by the usual markers of impairment (symptoms, rescue inhaler use, lung function), but the frequency of exacerbations requiring oral corticosteroids is now incorporated as an assessment of ''risk.'' Asthma control focuses on the state of asthma at the time the patient is seen and uses the same impairment criteria, but adds validated questionnaires to track impairment over the previous 1 to 4 weeks (Asthma Control Test, 4-wk recall; Asthma Control Questionnaire, 1-wk recall; or the Asthma Therapy Assessment Questionnaire) (1). Well-controlled asthma includes attempts to reduce future risks, including recurrent or severe exacerbations, and the possibilities of progressive loss of lung function or adverse effects related to long-term medication use.

The NAEPP guidelines address two new and important treatment issues in adult asthma: omalizumab (anti-IgE) therapy and the preferred approach to moderate persistent asthma. What was previously characterized as treatment step 4 has now been essentially split into steps 4-6 with an emphasis on a logical escalation of steroid doses and the incorporation of omalizumab (not available at the time of the older guidelines). It is important to stress that the U.S. Food and Drug Administration (FDA)-approved therapeutic indication for omalizumab is recurrent exacerbations in an allergic patient, not poor lung function or frequent symptoms. Also, the FDA issued a warning for omalizumab (Xolair) in 2007 after case reports of anaphylactic reactions that occurred at random time points postinjection and with various doses of exposure, not just the first dose (estimated to be 0.2% of all treated patients) (70). The FDA advises physicians administering Xolair to be prepared for this possible adverse effect, to advise patients of this serious potential reaction, and ways to react to such a possibility, including the use of epinephrine syringes in emergencies. Notably absent, however, is any clear recommendation for the length of time for monitoring of patients postinjection, which is still at the discretion of the physician. The second change in the treatment recommendations in the new NAEPP guidelines is a retraction of a preference for a low-dose inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) combination product over a doubling in ICS dose, in response to concerns of potential adverse effects (or risk) of LABAs (71, 72). The 2006 Global Initiative for Asthma (GINA) guidelines, however, continue to support low-dose ICS/LABA combination therapy over higher dose ICS based on a robust literature showing clinical superiority of the former treatment regimen (73).

CHALLENGING CONCEPTS IN THE TREATMENT OF ASTHMA

How Best to Step Down Therapy

In May 2007, the New England Journal of Medicine posed a clinical vignette focused on the best way to de-escalate therapy (step-down) in a patient with mild persistent asthma who was well controlled on medium-dose ICS (74). Readers were invited to select one of three options: (1) prescribe as-needed ICS/albuterol in a single inhaler for asthma symptoms, (2) discontinue ICS and substitute a leukotriene receptor antagonist (LTRA), or (3) prescribe once-daily ICS/LABAcombination product. In the United States, all three options were selected equally (75). This was somewhat surprising in that the guidelines note that ''data are insufficient'' to recommend intermittent or once-daily use of steroids (options 1 or 3) or the use of LABAs in mild persistent asthma (option 3), and the complete discontinuation of ICS in favor of LTRA monotherapy replaces the ''recommended treatment'' with an ''alternate, but not preferred'' drug (option 2). All parties believed that therapy should be stepped down, but how should we best step down therapy within the same step?

Two studies contrasted different treatment regimens for asthma with surprising results (76, 77). The American Lung Association-Asthma Clinical Research Centers (ALA-ACRC) conducted a large clinical trial (n = 500) in which patients with mild persistent asthma that was well controlled on low-dose ICS were randomized to continue on twice-daily low-dose ICS, stepdown to an LTRA alone (montelukast), or step-down to a lowdose ICS/LABA combination product given once daily (76). Treatment failure (primarily a >20% decrease in FEV^sub 1^) was greatest (60% increase in hazard ratio) in subjects who received an LTRA, but there was no difference in the other arms, suggesting that twice-daily ICS could be stepped down to oncedaily ICS/LABA, effectively halving the ICS dose. The second study was also a large randomized clinical trial (n = 455) comparing different step-down strategies in mild persistent asthma using a new ICS/albuterol combination product. Subjects who were well controlled on twice-daily low-dose ICS were stepped down to one of four treatment arms, two as-needed arms (albuterol only [no ICS] or low-dose ICS/albuterol only), or two twice-daily arms (low-dose ICS twice daily or low-dose ICS/ albuterol twice daily). There were no differences in primary endpoints between the three ICS arms, but the as-needed lowdose ICS/albuterol arm achieved these endpoints with a fourfold lower dose of ICS (77). The latter study extends the ALA-ACRC study results, suggesting that less than daily low-dose ICS alone may be sufficient to achieve good asthma control in mild persistent asthma.

The Role of the ''Alternate, but Not Preferred'' LTRAs

LTRAs continue to be second-line therapy for persistent asthma (step 2 and above) in the new NAEPP guidelines. Several trials investigated the role of LTRAs as potential ''steroid-sparing'' agents in asthma (36-39). The Asthma Clinical Research Network (ACRN) performed a randomized crossover trial to evaluate whether an LTRA (montelukast) with an LABA (salmeterol) could replace low-dose ICS with an LABA in subjects who were well controlled after a run-in period on low-dose ICS with an LTRA (36). The study was terminated after only 3 months when the primary efficacy variable (treatment failure) was reached, with clear inferiority of the LTRA with LABA combination (9% failed on ICS with LABA vs. 26% who failed on LTRA with LABA). This result was true for subjects with normal or abnormal baseline lung function and suggests that LTRAs cannot replace ICS in patients already receiving an LABA (step 3).

The ALA-ACRC performed a large randomized clinical trial (n = 480) comparing the addition of an LTRA (montelukast) or theophylline (Theo) to the existing treatment regimens of patients with poorly controlled asthma (37). Although the Asthma Control Questionnaire scores and baseline lung function suggest that these subjects were less controlled (more severe) than those studied in the ACRN study, the result is the same: an LTRA (or Theo) did not improve primary outcomes (lung function, rescue inhaler use, exacerbations) when added to existing therapy. A subgroup analysis of the 20-25% of subjects not receiving ICS showed that the addition of Theo (but not an LTRA) improved markers of impairment (lung function, rescue inhaler use), but not exacerbation rates, suggesting a possible role for low-dose Theo in very mild asthma that would need to be studied in a prospective manner. The ALA-ACRC trial also provided some alarming insights into the state of guideline therapy today. Despite evidence of poor asthma control, only 74-79% of subjects were receiving ICS and 14-20% were on monotherapy with an LABA without an ICS. Furthermore, compliance with oral drug therapy (measured by serum drug levels) eroded over the course of the study, with79%compliance falling to60%by the end of the 24-week treatment period. Adherence to treatment regimens is believed to be at its best in clinical trials and oral drugs are frequently considered to have better patient compliance; both of these statements seem to be unfounded based on this trial.

A role for LTRAs (as opposed to guideline-based ICS treatment) in the treatment of smokers with asthma was explored in the ACRN's SMOG (Smoking Modulates Outcomes of Glucocorticoid therapy) trial (38). This randomized crossover study enrolled 83 subjects with mild-moderate asthma subjects (47% current ''light'' smokers), evaluated resistance to ICS in smokers, and explored treatment with anLTRA(montelukast) as an alternative nonsteroidal antiinflammatory drug. As expected, moderate doses of ICS improved lung function (FEV^sub 1^) and reduced bronchial hyperresponsiveness (BHR), asthma symptoms, and sputum eosinophilia in the nonsmokers. Although there were similar trends toward improved outcomes with ICS in the smokers, these changes were smaller in magnitude and, in general, did not meet statistical significance. Treatment with an LTRA, however, improved outcomes (peak flow, quality of life) in the smokers, but not the nonsmokers. These results imply that active smoking does impair therapeutic response to ICS treatment and suggest further studies are needed to investigate a possible role for LTRAs as alternative (or additive) antiinflammatory drugs that may have increased efficacy in smokers with asthma.

The other attractive arena for LTRAs has been childhood asthma, especially in young children (<4>

DEVELOPING BIOMARKERS

Exhaled Nitric Oxide

The use of exhaled nitric oxide (FE^sub NO^) as a biomarker to diagnose asthma and/or guide clinical decision making in asthma care continues to be controversial. A large community study in New Zealand (n = 528) explored possible reference ranges for FE^sub NO^ and found that FE^sub NO^ levels were influenced by sex, atopy, and smoking status, with higher FE^sub NO^ levels reported in males, allergic subjects and nonsmokers (65). Overall, there was a wide range of FE^sub NO^ levels in even normal subjects. The test performed poorly as a diagnostic ''screen'' for asthma in subjects who met a diagnosis of asthma but were not receiving ICS, with low sensitivity and specificity at a 20-ppb cutoff (sensitivity, 49%; specificity, 61%), although the specificity improved as the ''bar'' was raised to 50 ppb (96%), but at the expense of sensitivity (19%).

It is perhaps more likely that biomarkers such as FE^sub NO^ might have utility in managing asthma more so than in diagnosing the disease. Two previous trials have evaluated FE^sub NO^ concentrations in milder asthma as an accessible biomarker (78, 79). Both studies failed to show a reduction in exacerbation rates, although the overall annualized dose of ICS was lower in the biomarker-driven algorithm in one study (78). A large randomized 12-month clinical trial (n = 118) further explored the utility of FE^sub NO^ levels (26-ppb cutoff) to guide asthma treatment and again failed to show reductions in exacerbation rates or, in this study, any difference in annualized ICS dose at the end of the study (66). Of interest, 16% of subjects in the FE^sub NO^ management group had persistent elevation in FE^sub NO^ on high-dose ICS, but did not have airway eosinophilia on sputum induction. ICS dose was decreased in these subjects without adverse outcomes, suggesting a ''disconnect'' between these two biomarkers. An intensive, randomized, placebo-controlled bronchoscopy study (n = 28) evaluating the effect of inhibition of inducible NO synthase in an allergen challenge model of asthma reported a similar disconnect between FE^sub NO^ and airway inflammation; although the drug decreased FE^sub NO^ levels to 25% of preallergen levels, there was no effect on allergen-induced airway inflammation in bronchoalveolar lavage specimens (23).

THE ROLE OF ENVIRONMENT IN ASTHMA

Several recent studies have evaluated the effect of environment on risk to develop asthma. These studies ranged from prebirth and childhood (genetics, in utero tobacco exposure, breastfeeding) (46-49) to the home (outdoor and indoor air pollutants) (49-52, 55) and workplace (health care workers) (53, 54). The overall bottom line is to be careful what you breathe because it might give you asthma.

The interaction of genes (transforming growth factor [TGF]-β1 C-509T polymorphisms) and environment (traffic-related pollution and tobacco exposure) was explored in the Children's Health Study of fourth, seventh, and tenth graders (49). In this cohort, the presence of the risk genotype (-509TT) was associated with asthma before the age of 3 years (odds ratio [OR], 1.8) and the effect was amplified in those children with exposure in utero to tobacco smoking (OR, 3.4) and traffic-related pollutants as measured by distance from freeway (OR, 5.5), although the latter two associations did not meet statistical significance due to the small number of subjects with asthma and the TT genotype. This study suggests that genetic background influences the effect of environment exposures on disease expression.

Several studies explored the role of allergen exposure to mites (Der p1) and cats (Fel d1) in the development of allergen sensitization (specific IgE or skin prick tests), BHR, and clinical asthma (50-52). The Asthma Multicenter Infant Cohort Study (>1,000 newborns) measured allergen in the homes of 3-monthold babies and then performed skin prick testing at 6 years of age (50). Cat allergen exposure, but not dust mite, increased sensitization to skin testing (OR, 4.4) and asthma (OR, 2.6). Two subanalyses from the European Community Respiratory Health Survey (ECRHS) examined the effect of dust and cat allergen exposure on the development and magnitude of BHR (51, 52). In the first, subjects with allergic rhinitis that were sensitized to cat and dust allergens were shown to be at increased risk to develop BHR(OR, 7.9 cat; OR, 2.8 mites) (51). In the second, the authors extended their findings and reported a shift toward more severe BHR in atopic individuals with cat exposure at moderate levels; this effect was not limited to those who were sensitized to cats by specific IgE testing (52). Together, these studies imply that cat exposure (but not to mites) leads to increased risk of cat sensitization, BHR, and asthma; this effect is most marked in patients with atopy, with or without asthma.

The effect of cleaning solutions and sprays used in the home on the development of asthma was also studied in theECRHScohort (53). Frequent exposure to cleaning sprays (number of times per week) and the number of sprays being used (1 to >3) was associated with a relative risk of developing asthma as high as 2.4 for those using more than three different sprays more than 1 day per week. An analysis of the work environment of health care professionals likewise found increased odds of developing asthma based on exposure to aerosolized irritants such as cleaning solvents (ORs as high as 2.2), nebulized medications (OR, 1.7), and powdered latex gloves (OR, 2.2), although the latter risk dissipated after 2000 with the change in glove materials (54). Nurses appeared to be at highest risk (OR, 1.9), and there was a dose-response relationship between reported asthma and length of time on the job (OR, 4.1 for those >27 yr). Children living on farms have previously been reported to have a low incidence of asthma; these reports of an increased incidence of asthma in adults exposed to cleaning materials reiterates that being overly clean can make you wheeze.

PATHOBIOLOGIC MECHANISMS IN ASTHMA

Human Studies

Several studies examined bronchial biopsies and induced sputum specimens focusing on components of airway remodeling (24-27, 30, 32, 34, 35). Two of these studies were from investigators in the NHLBI-sponsored Severe Asthma Research Program and involved bronchial biopsies from subjects with severe asthma (24, 25). In the first, biopsies from subjects with severe asthma showed dysregulation of the epithelial layer, with increased cell proliferation and cell death with concurrent increased airway epithelial and lamina reticularis thickness despite higher doses of ICS (24). In the second, polymorphisms in the IL4Rα gene and mast cells in bronchial biopsies were evaluated in two cohorts of subjects with severe asthma (25). Two polymorphisms were associated with severe exacerbations and poor lung function (one of these with increased tissue mast cells and bound IgE) despite higher doses of ICS and, in half of the patients, chronic oral steroids. Together, these studies highlight changes in the airways that likely contribute to persistent airflow obstruction and exacerbations, important characteristics of severe asthma.

Two studies published in 2007 looked at less mainstream areas in asthma pathobiology (26, 27). In the first, an important enzyme in the arachadonic acid pathway, phospholipase A^sub 2^ (PLA^sub 2^), was measured in induced sputum from subjects with mild asthma, both before and after exercise challenge (26). Although PLA^sub 2^ had been previously reported to increase after allergen challenge (80), the current study reports preferential overexpression of group X secretory PLA^sub 2^ after exercise challenge, suggesting a possible mechanism that could lead to dysregulation of eicosanoid biosynthesis. In the second study, investigative bronchoscopy was performed in a group of subjects with asthma who have not been intensively studied (i.e., those who smoke) (27). Staining of multiple cellular markers in bronchial mucosal biopsies revealed reduced numbers of mature dendritic cells (CD83^sup +^) and B cells (CD20^sup +^) in smoker subjects with asthma. In neversmoker subjects with asthma, treatment with ICS resulted in fewer Langerhans cells (CD11) and decreased IFN-γ staining, but there were no differences seen in smokers with asthma when stratified by treatment with ICS. These findings suggest possible mechanisms for decreased cellular immunity and diminished responsiveness to steroid treatment in smokers.

Mouse Models of Allergic Asthma

Several studies explored the basic pathobiology of asthma using an ovalbumin-challenge murine model of asthma (2-18, 21, 22). The scope of the articles ranged from the role of the coagulation (2, 3) and complement pathways (4) in asthma to determinants of the Th1/Th2 milieu (5-7) and alteration of the lymphocyte population through treatment with helmith-derived products (8) or calcium channel blockers (9) to infection with Chlamydia (10). Estrogen receptor-α knockout mice showed increased airway hyperresponsiveness (AHR) and reduced M2 muscarinic receptor expression (11). Studies investigating the effect of the inhibition of asthma phenotypes through focused blockade reported some disconnects in therapeutic effect: inhibition of TGF-β improved airway remodeling, but worsened AHR (12), whereas the absence of the D6 chemokine receptor increased airway inflammation but reducedAHR(13). Down-regulation of nuclear factor (NF)-κB activity by glycogen synthase kinase-3b had wide-ranging effects, reducing both AHR and eosinophilic airway inflammation (14). Treatment with Toll-like receptor 7/8 ligand inhibited smooth muscle proliferation and goblet cell hyperplasia typical of chronic asthma (15). A recombinant IL-13 peptide-based vaccine (16) and oral treatment with a probiotic (17) were both able to suppress airway inflammation andAHRin mice. These studies exemplify how far we have traveled from the original articles on the basic pathobiology of asthma. The differential pathophysiologic effects seen with modulation of any one mediator, however, reinforce the complexity of asthma and the challenge of finding novel therapeutic targets.

CONCLUSIONS

The past year has seen striking developments in clinical asthma research. The new 2007 NAEPP guidelines reflect our uncertainty in the treatment of mild to moderate asthma. Several large clinical trials challenged the paradigm of twice-daily dosing of ICS, suggesting that once-daily dosing is the potential future of the ''how low you can go'' goal with ICS. The quest for a steroidsparing asthma medication continues with several clinical trials that hoped to find a role for leukotriene modifiers; all were unable to even show equivalency. Most of these clinical trials showed inferiority to the gold standard of ICS. At this juncture, it appears that decreasing the frequency of ICS dosing to diminish the daily dose may be the best option for steroid sparing.

Exhaled nitric oxide had a difficult year. Interpretation of this potential biomarker is complicated by sex, atopy, and smoking, with poor sensitivity and specificity when used as a screening tool to diagnose asthma. FE^sub NO^ also performed poorly in a clinical trial using yet another different cutoff point to titrate asthma care, bringing into focus the question of what is the right cutoff point to use? Perhaps the most disturbing finding in this clinical trial is that there were patients with high FE^sub NO^ who did not have sputum eosinophils. This result challenges the basic premise that FE^sub NO^ is a surrogate measure of ongoing eosinophilic airway inflammation that should support a step-up to a higher dose of ICS. There remain many questions associated with FE^sub NO^ in the management of asthma. It is clearly still a research tool and not ready for mainstream use despite the availability of an FDA-approved device for use in any clinic.

What will 2008 bring? Among the most interesting topics that will be revisited in 2008 are questions as to whether genetic variation in the β^sub 2^-adrenergic receptor will be shown to be associated with adverse asthma outcomes in large prospective trials conducted by both the NHLBI-sponsoredACRN(LARGE trial) and the pharmaceutical industry. We expect further studies from the NHLBI Severe Asthma Research Program to increase our understanding of pathobiologic mechanisms at this spectrum of the disease. We eagerly await clinical trials of immunomodulators and novel therapies (bronchial thermoplasty) that have been designed to target specific subphenotypes of patients with severe asthma; several recent monoclonal antibody studies have proven that biologic therapy does not work unless the correct patients are studied. Finally, we expect incremental progress in the areas of both asthma biomarkers and asthma pharmacogenetics.