Update in Asthma 2007

By Moore, Wendy C

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 beta-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 yr) in whom only nebulized budesonide and cromolyn as well as an oral LTRA (montelukast) have FDA approval; LABAs do not. A randomized trial investigated the role of LTRAs as therapy for acute asthma exacerbations related to upper respiratory infections (URIs) in children with intermittent asthma (ages 2-14 yr) (39). Children enrolled in the trial (80% aged 2-5 yr) were asymptomatic between URI episodes, but were required to have a history of three to six asthma exacerbations in the prior 12 months requiring more than three visits to the doctor or a visit to the hospital or emergency room. Treatment with the first URI symptoms led to a modest decrease in urgent doctor visits, symptoms, and days of missed school time in children treated with an LTRA (montelukast) as compared with placebo. The children in this study, however, experienced frequent exacerbations and would not meet the criteria for intermittent asthma in the new NAEPP guidelines. Guideline-based therapy would recommend at least low-dose ICS for these patients, and the effect of ICS on the exacerbation rate would likely be superior to that seen with the LTRA. Although the concept of a steroid-sparing acute controller medication at the onset of an exacerbation is an intriguing idea, the studies discussed above would suggest this should be prospectively studied as add-on therapy to, not replacement of, corticosteroids in the acute setting.

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]-beta1 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 IL4Ralpha 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- gamma 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- alpha 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-beta 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)-kappaB 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 beta^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.

Conflict of Interest Statement: W.C.M. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Acknowledgment: The author acknowledges the invaluable and insightful editorial skills of Stephen Peters, M.D., Ph.D., with whom it is always a pleasure to collaborate.

References

1. National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and management of asthma [Internet]. Bethesda, MD: National Institutes of Health; National Heart, Lung, and Blood Institute; 2007. Publication No. 07-4051 [accessed 2007 Dec 30]. Available from: http://www.nhlbi.nih.gov/ guidelines/asthma/asthgdln.htm

2. Swaisgood CM, Aronica MA, Swaidani S, Plow EF. Plasminogen is an important regulator in the pathogenesis of a murine model of asthma. Am J Respir Crit Care Med 2007;176:333-342.

3. Shinagawa K, Martin JA, Ploplis VA, Castellino FJ. Coagulation factor Xa modulates airway remodeling in a murine model of asthma. Am J Respir Crit Care Med 2007;175:136-143.

4. Dillard P, Wetsel RA, Drouin SM. Complement C3a regulates Muc5ac expression by airway Clara cells independently of Th2 responses. Am J Respir Crit Care Med 2007;175:1250-1258.

5. Brown JP, Taube C, Miyahara N, Koya T, Pelanda R, Gelfand EW, Torres RM. Arhgef1 is required by T cells for the development of airway hyperreactivity and inflammation. Am J Respir Crit Care Med 2007;176:10-19.

6. Munitz A, Bachelet I, Finkelman FD, Rothenberg ME, Levi- Schaffer F. CD48 is critically involved in allergic eosinophilic airway inflammation. Am J Respir Crit Care Med 2007;175:911-918.

7. Katoh S, Ishii N, Nobumoto A, Takeshita K, Dai SY, Shinonaga R, Niki T, Nishi N, Tominaga A, Yamauchi A, et al. Galectin-9 inhibits CD44-hyaluronan interaction and suppresses a murine model of allergic asthma. Am J Respir Crit Care Med 2007;176:27-35.

8. Trujillo-Vargas CM, Werner-Klein M, Wohlleben G, Polte T, Hansen G, Ehlers S, Erb KJ. Helminth-derived products inhibit the development of allergic responses in mice. Am J Respir Crit Care Med 2007;175:336-344.

9. Gomes B, Cabral MD, Gallard A, Savignac M, Paulet P, Druet P, Mariame B, Moreau M, Leclerc C, Guery JC, et al. Calcium channel blocker prevents T helper type 2 cell-mediated airway inflammation. Am J Respir Crit Care Med 2007;175:1117-1124.

10. Horvat JC, Beagley KW, Wade MA, Preston JA, Hansbro NG, Hickey DK, Kaiko GE, Gibson PG, Foster PS, Hansbro PM. Neonatal chlamydial infection induces mixed T-cell responses that drive allergic airway disease. Am J Respir Crit Care Med 2007;176:556- 564.

11. Carey MA, Card JW, Bradbury JA, Moorman MP, Haykal-Coates N, Gavett SH, Graves JP, Walker VR, Flake GP, Voltz JW, et al. Spontaneous airway hyperresponsiveness in estrogen receptor-alpha- deficient mice. Am J Respir Crit Care Med 2007;175:126-135.

12. Alcorn JF, Rinaldi LM, Jaffe EF, van Loon M, Bates JHT, Janssen-Heininger YMW, Irvin CG. Transforming growth factor-1 suppresses airway hyperresponsiveness in allergic airway disease. Am J Respir Crit Care Med 2007;176:974-982.

13. Whitehead GS, Wang T, DeGraff LM, Card JW, Lira SA, Graham GJ, Cook DN. The chemokine receptor D6 has opposing effects on allergic inflammation and airway reactivity. Am J Respir Crit Care Med 2007;175:243-249.

14. Bao Z, Lim S, Liao W, Lin Y, Thiemermann C, Leung BP, Wong WSF. Glycogen synthase kinase-3 inhibition attenuates asthma in mice. Am J Respir Crit Care Med 2007;176:431-438. 15. Camateros P, Tamaoka M, Hassan M, Marino R, Moisan J, Marion D, Guiot MC, Martin JG, Radzioch D. Chronic asthma-induced airway remodeling is prevented by toll-like receptor-7/8 ligand S28463. Am J Respir Crit Care Med 2007;175:1241-1249.

16. Ma Y, HayGlass KT, Becker AB, Fan Y, Yang X, Basu S, Srinivasan G, Simons FER, Halayko AJ, Peng Z. Novel recombinant interleukin-13 peptide-based vaccine reduces airway allergic inflammatory responses in mice. Am J Respir Crit Care Med 2007;176:439-445.

17. Forsythe P, Inman MD, Bienenstock J. Oral treatment with live lactobacillus reuteri inhibits the allergic airway response in mice. Am J Respir Crit Care Med 2007;175:561-569.

18. Lundblad LKA, Thompson-Figueroa J, Allen GB, Rinaldi L, Norton RJ, Irvin CG, Bates JHT. Airway hyperresponsiveness in allergically inflamed mice: the role of airway closure. Am J Respir Crit Care Med 2007;175:768-774.

19. Chida Y, Sudo N, Sonoda J, Hiramoto T, Kubo C. Early-life psychological stress exacerbates adult mouse asthma via the hypothalamus-pituitary-adrenal axis. Am J Respir Crit Care Med 2007;175:316-322.

20. Chimenti L, Morici G, Paterno A, Bonanno A, Siena L, Licciardi A, Veca M, Guccione W, Macaluso F, Bonsignore G, et al. Endurance training damages small airway epithelium in mice. Am J Respir Crit Care Med 2007;175:442-449.

21. Johnston RA, Zhu M, Rivera-Sanchez YM, Lu FL, Theman TA, Flynt L, Shore SA. Allergic airway responses in obese mice. Am J Respir Crit Care Med 2007;176:650-658.

22. Vieira RP, Claudino RC, Duarte ACS, Santos ABG, Perini A, Neto HCCF, Mauad T, Martins MA, Dolhnikoff M, Carvalho CRF. Aerobic exercise decreases chronic allergic lung inflammation and airway remodeling in mice. Am J Respir Crit Care Med 2007;176:871-877.

23. Singh D, Richards D, Knowles RG, Schwartz S, Woodcock A, Langley S, O’Connor BJ. Selective inducible nitric oxide synthase inhibition has no effect on allergen challenge in asthma. Am J Respir Crit Care Med 2007;176:988-993.

24. Cohen L, Xueping E, Tarsi J, Ramkumar T, Horiuchi TK, Cochran R, DeMartino S, Schechtman KB, Hussain I, Holtzman MJ, et al.; NHLBI Severe Asthma Research Program. Epithelial cell proliferation contributes to airway remodeling in severe asthma. Am J Respir Crit Care Med 2007;176:138-145.

25. Wenzel SE, Balzar S, Ampleford E, Hawkins GA, Busse WW, Calhoun WJ, Castro M, Chung KF, Erzurum S, Gaston B, et al. IL4R mutations are associated with asthma exacerbations and mast cell/ IgE expression. Am J Respir Crit Care Med 2007;175:570-576.

26. Hallstrand TS, Chi EY, Singer AG, Gelb MH, Henderson WR Jr. Secreted phospholipase A^sub 2^ group x overexpression in asthma and bronchial hyperresponsiveness. Am J Respir Crit Care Med 2007;176: 1072-1078.

27. Tsoumakidou M, Elston W, Zhu J, Wang Z, Gamble E, Siafakas NM, Barnes NC, Jeffery PK. Cigarette smoking alters bronchial mucosal immunity in asthma. Am J Respir Crit Care Med 2007;175:919- 925.

28. Brown NJ, Salome CM, Berend N, Thorpe CW, King GG. Airway distensibility in adults with asthma and healthy adults, measured by forced oscillation technique. Am J Respir Crit Care Med 2007;176: 129-137.

29. Eikermann M, Vogt F, Herbstreit FM, Vahid-Dastgerdi M, Zenge MO, Ochterbeck C, de Greiff A, Peters J. The predisposition to inspiratory upper airway collapse during partial neuromuscular blockade. Am J Respir Crit Care Med 2007;175:9-15.

30. Kariyawasam HH, Aizen M, Barkans J, Robinson DS, Kay AB. Remodeling and airway hyperresponsiveness but not cellular inflammation persist after allergen challenge in asthma. Am J Respir Crit Care Med 2007;175:896-904.

31. Mazzone SB, McLennan L, McGovern AE, Egan GF, Farrell MJ. Representation of capsaicin-evoked urge-to-cough in the human brain using functional magnetic resonance imaging. Am J Respir Crit Care Med 2007;176:327-332.

32. Saglani S, Payne DN, Zhu J, Wang Z, Nicholson AG, Bush A, Jeffery PK. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med 2007;176:858-864.

33. Sharafkhaneh A, Babb TG, Officer TM, Hanania NA, Sharafkhaneh H, Boriek AM. The confounding effects of thoracic gas compression on measurement of acute bronchodilator response. Am J Respir Crit Care Med 2007;175:330-335.

34. Simcock DE, Kanabar V, Clarke GW, O’Connor BJ, Lee TH, Hirst SJ. Proangiogenic activity in bronchoalveolar lavage fluid from patients with asthma. Am J Respir Crit Care Med 2007;176:146-153.

35. Slats AM, Janssen K, van Schadewijk A, van der Plas DT, Schot R, van den Aardweg JG, de Jongste JC, Hiemstra PS, Mauad T, Rabe KF, et al. Bronchial inflammation and airway responses to deep inspiration in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:121-128.

36. Deykin A, Wechsler ME, Boushey HA, Chinchilli VM, Kunselman SJ, Craig TJ, DiMango E, Fahy JV, Kraft M, Leone F, et al.; National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. Combination therapy with a long-acting -agonist and a leukotriene antagonist in moderate asthma. Am J Respir Crit Care Med 2007; 175:228-234.

37. American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. Am J Respir Crit Care Med 2007;175:235-242.

38. Lazarus SC, Chinchilli VM, Rollings NJ, Boushey HA, Cherniack R, Craig TJ, Deykin A, DiMango E, Fish JE, Ford JG, et al.; National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. Smoking affects a response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med 2007;175:783-790.

39. Robertson CF, Price D, Henry R, Mellis C, Glasgow N, Fitzgerald D, Lee AJ, Turner J, Sant M. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med 2007;175:323-329.

40. Battle NC, Choudhry S, Tsai HJ, Eng C, Kumar G, Beckman KB, Naqvi M, Meade K, Watson HG, LeNoir M; SAGE (Study of African Americans, Asthma, Genes, and Environments) Investigators. Ethnicity- specific gene-gene interaction between IL-13 and IL-4Ra among African Americans with asthma. Am J Respir Crit Care Med 2007;175:881-887.

41. Begin P, Tremblay K, Daley D, Lemire M, Claveau S, Salesse C, Kacel S, Montpetit A, Becker A, Chan-Yeung M, et al. Association of urokinase-type plasminogen activator with asthma and atopy. Am J Respir Crit Care Med 2007;175:1109-1116.

42. Chen E, Chim LS, Strunk RC, Miller GE. The role of the social environment in children and adolescents with asthma. Am J Respir Crit Care Med 2007;176:644-649.

43. Hersh CP, Raby BA, Soto-Quiros ME, Murphy AJ, Avila L, Lasky- Su J, Sylvia JS, Klanderman BJ, Lange C, Weiss ST, et al. Comprehensive testing of positionally cloned asthma genes in two populations. Am J Respir Crit Care Med 2007;176:849-857.

44. Park JH, Chang HS, Park CS, Jang AS, Park BL, Rhim TY, Uh ST, Kim YH, Chung IY, Shin HD. Association analysis of CD40 polymorphisms with asthma and the level of serum total IgE. Am J Respir Crit Care Med 2007;175:775-782.

45. Wilk JB, Herbert A, Shoemaker CM, Gottlieb DJ, Karamohamed S. Secreted modular calcium-binding protein 2 haplotypes are associated with pulmonary function. Am J Respir Crit Care Med 2007;175:554- 560.

46. Guilbert TW, Stern DA, Morgan WJ, Martinez FD, Wright AL. Effect of breastfeeding on lung function in childhood and modulation by maternal asthma and atopy. Am J Respir Crit Care Med 2007;176: 843-848.

47. Tata LJ, Lewis SA, McKeever TM, Smith CJP, Doyle P, Smeeth L, West J, Hubbard RB. A comprehensive analysis of adverse obstetric and pediatric complications in women with asthma. Am J Respir Crit Care Med 2007;175:991-997.

48. Rusconi F, Galassi C, Forastiere F, Bellasio M, De Sario M, Ciccone G, Brunetti L, Chellini E, Corbo G, La Grutta S, et al.; SIDRIA-2 Collaborative Group. Maternal complications and procedures in pregnancy and at birth and wheezing phenotypes in children. Am J Respir Crit Care Med 2007;175:16-21.

49. Salam MT, Gauderman WJ, McConnell R, Lin PC, Gilliland FD. Transforming growth factor-beta1 C-509T polymorphism, oxidant stress, and early-onset childhood asthma. Am J Respir Crit Care Med 2007; 176:1192-1199.

50. Torrent M, Sunyer J, Garcia R, Harris J, Iturriaga MV, Puig C, Vall O, Anto JM, Taylor AJN, Cullinan P. Early-life allergen exposure and atopy, asthma, and wheeze up to 6 years of age. Am J Respir Crit Care Med 2007;176:446-453.

51. Shaaban R, Zureik M, Soussan D, Anto JM, Heinrich J, Janson C, Kunzli N, Sunyer J, Wjst M, Burney PG, et al. Allergic rhinitis and onset of bronchial hyperresponsiveness: a population-based study. Am J Respir Crit Care Med 2007;176:659-666.

52. Chinn S, Heinrich J, Anto JM, Janson C, Norback D, Olivieri M, Svanes C, Sunyer J, Verlato G, Wjst M, et al. Bronchial responsiveness in atopic adults increases with exposure to cat allergen. Am J Respir Crit Care Med 2007;176:20-26.

53. Zock JP, Plana E, Jarvis D, Anto JM, Kromhout H, Kennedy SM, Kunzli N, Villani S, Olivieri M, Toren K, et al. The use of household cleaning sprays and adult asthma: an international longitudinal study. Am J Respir Crit Care Med 2007;176:735-741.

54. Delclos GL, Gimeno D, Arif AA, Burau KD, Carson A, Lusk C, Stock T, Symanski E, Whitehead LW, Zock JP, et al. Occupational risk factors and asthma among health care professionals. Am J Respir Crit Care Med 2007;175:667-675.

55. Weinmayr G, Weiland SK, Bjorksten B, Brunekreef B, Buchele G, Cookson WOC, Garcia-Marcos L, Gotua M, Gratziou C, van Hage M, et al.; ISAAC Phase Two Study Group. Atopic sensitization and the international variation of asthma symptom prevalence in children. Am J Respir Crit Care Med 2007;176:565-574.

56. Joseph CLM, Peterson E, Havstad S, Johnson CC, Hoerauf S, Stringer S, Gibson-Scipio W, Ownby DR, Elston-Lafata J, Pallonen U, et al.: Asthma in Adolescents Research Team. A we-based, tailored asthma management program for urban African-American high school students. Am J Respir Crit Care Med 2007;175:888-895. 57. Teerlink CC, Hegewald MJ, Cannon-Albright LA. A genealogical assessment of heritable predisposition to asthma mortality. Am J Respir Crit Care Med 2007;176:865-870.

58. Barr RG, Kurth T, Stampfer MJ, Buring JE, Hennekens CH, Gaziano JM. Aspirin and decreased adult-onset asthma: randomized comparisons from the Physicians’ Health Study. Am J Respir Crit Care Med 2007;175:120-125.

59. Beuther DA, Sutherland ER. Overweight, obesity, and incident asthma: a meta-analysis of prospective epidemiologic studies. Am J Respir Crit Care Med 2007;175:661-666.

60. Goodwin RD, Fisher M, Goldberg J. A twin study of post- traumatic stress disorder symptoms and asthma. Am J Respir Crit Care Med 2007;176:983-987.

61. Carraro S, Rezzi S, Reniero F, Heberger K, Giordano G, Zanconato S, Guillou C, Baraldi E. Metabolomics applied to exhaled breath condensate in childhood asthma. Am J Respir Crit Care Med 2007; 175:986-990.

62. Kodric M, Shah AN, Fabbri LM, Confalonieri M. An investigation of airway acidification in asthma using induced sputum: a study of feasibility and correlation. Am J Respir Crit Care Med 2007;175:905-910.

63. Jackson A, Sandrini A, Campbell C, Chow S, Thomas P, Yates D. Comparison of biomarkers in exhaled breath condensate and bronchoalveolar lavage. Am J Respir Crit Care Med 2007;175:222-227.

64. Schuster DP. The opportunities and challenges of developing imaging biomarkers to study lung function and disease. Am J Respir Crit Care Med 2007;176:224-230.

65. Travers J, Marsh S, Aldington S, Williams M, Shirtcliffe P, Pritchard A, Weatherall M, Beasley R. Reference ranges for exhaled nitric oxide derived from a random community survey of adults. Am J Respir Crit Care Med 2007;176:238-242.

66. Shaw DE, Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ, Pavord ID. The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. Am J Respir Crit Care Med 2007;176:231-237.

67. Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, Robinson D, Wenzel S, Busse W, Hansel TT, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 2007;176: 1062- 1071.

68. Pavord ID, Cox G, Thomson NC, Rubin AS, Corris PA, Niven RM, Chung KF, Laviolette M. Safety and efficacy of bronchial thermoplasty in symptomatic severe asthma. Am J Respir Crit Care Med 2007;176:1185-1191.

69. Boot JD, de Haas S, Tarasevych S, Roy C, Wang L, Amin D, Cohen J, Sterk PJ, Miller B, Paccaly A, et al. Effect of an NK^sub 1^/NK^sub 2^ receptor antagonist on airway responses and inflammation to allergen in asthma. Am J Respir Crit Care Med 2007;175:450-457.

70. U.S. Food and Drug Administration. FDA alert: omalizumab (marketed as Xolair) information [Internet]. 2007 Feb 21 [updated 2007 Jul 5; accessed 2008 Jan 7]. Available from: http:// www.fda.gov/cder/drug/ infopage/omalizumab/default.htm

71. U.S. Food and Drug Administration. FDA public health advisory: Serevent, Diskus, Advair Diskus, Foradil Aerolizer [Internet]. 2005 Nov 18 [updated 2006 May 15, accessed 2008 Jan 7]. Available from: http:// www.fda.gov/cder/drug/advisory/LABA.htm

72. Nelson HS. Is there a problem with inhaled long-acting B- adrenergic agonists? J Allergy Clin Immunol 2006;117:3-16.

73. National Heart, Lung, and Blood Institute; National Institutes of Health. Global strategy for asthma management and prevention: Global Initiative for Asthma (GINA): 2006 update [Internet]. [accessed 2008 Jan 10]. Available from: http:// www.ginasthma.org

74. Kraft M, Israel E, O’Connor GT. Treatment of mild persistent asthma [clinical vignette]. N Engl J Med 2007;356:2096-2100.

75. Fredenburgh LE, Campion EW, Drazen JM. Mild persistent asthmapolling results. N Engl J Med 2007;357:179-180.

76. American Lung Association Asthma Clinical Research Centers. Randomized comparison of strategies for reducing treatment in mild persistent asthma. N Engl J Med 2007;356:2027-2039.

77. Papi A, Canonica GW, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E, Crimi N, Vignola AM, Morelli P, Nicolini G, et al.; BEST Study Group. Rescue use of beclomethasone and albuterol in a single inhaler. N Engl J Med 2007;356:2040-2052.

78. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide therapy in chronic asthma. N Engl J Med 2005;352:2163-2173.

79. Pijnenburg MW, Bakker EM, Hop WC, De Jongste JC. Titrating steroids on exhaled nitric oxide in asthmatic children: a randomized controlled trial. Am J Respir Crit Care Med 2005;172:831-836.

80. Bowton DL, Seeds MC, Fasano MB, Goldsmith B, Bass DA. Phospholipase A2 and arachidonate increase in bronchoalveolar lavage fluid after inhaled allergen challenge in asthmatics. Am J Respir Crit Care Med 1997;155:421-425.

Wendy C. Moore1

1Section on Pulmonary, Critical Care, Allergy, and Immunologic Disease, and the Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina

(Received in original form February 22, 2008; accepted in final form February 22, 2008)

Correspondence and requests for reprints should be addressed to Wendy C. Moore, M.D., Center for Human Genomics and Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: wmoore@wfubmc.edu

Am J Respir Crit Care Med Vol 177. pp 1068-1073, 2008

DOI: 10.1164/rccm.200802-315UP

Internet address: www.atsjournals.org

Copyright American Thoracic Society May 15, 2008

(c) 2008 American Journal of Respiratory and Critical Care Medicine. Provided by ProQuest Information and Learning. All rights Reserved.