Targeting Biologic Markers in Asthma — Is Exhaled Nitric Oxide the Bull's-Eye?
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《新英格兰医药杂志》
Clinicians caring for patients with asthma need help. Asthma affects approximately 27 million persons in the United States. Despite the availability of effective therapies, asthma remains a source of significant morbidity and use of health care resources.1 National and international guidelines recommend that patients with persistent symptoms use inhaled corticosteroids as first-line therapy. On the basis of findings such as daytime or nighttime symptoms and impaired pulmonary function (as measured both at home and in the clinic), these guidelines also provide algorithms for increasing the doses of these medicines and adding other treatments.2,3,4 However, the practical application of these recommendations can be challenging because of the variable nature of the disease, the minimization of symptoms by patients, and poor compliance with home-based measurements. Thus, clinicians may find it difficult to determine the appropriate level of inhaled-corticosteroid treatment for an individual patient.
It is generally acknowledged that once control of asthma is achieved, a reduction of the inhaled corticosteroid to the lowest effective dose is in the patient's best interest. However, we have yet to establish the level and duration of asthma control that are needed before downward titration is undertaken and the mechanism by which such adjustments should be accomplished. Without specific and straightforward guidance, clinicians may opt to leave well enough alone and continue treatment in patients who appear to be doing well when, in fact, the dose of inhaled corticosteroid should either be increased or reduced. There is a need for clinically applicable ways to distinguish patients with asthma who require additional therapy from those who could have their medical regimen reduced.
Biologic markers associated with the presence of asthma that have commonly been used to judge asthma control include the degree of airway hyperresponsiveness to exogenous stimuli such as methacholine or histamine and eosinophil counts in sputum. A more recent addition to this list is the amount of nitric oxide in exhaled air (FENO). Although all of these measures are generally improved when inhaled corticosteroids are administered, the relationship between these markers and the basic pathology of asthma is uncertain.3 A previous study demonstrated that asthma outcomes improved when the dose of inhaled corticosteroid was titrated with the use of an algorithm that incorporated airway hyperresponsiveness in addition to other measures specified in standard treatment guidelines, as compared with guideline-based care alone. However, the improvement in control occurred in concert with the use of higher doses of inhaled corticosteroid.5 In contrast, other work has demonstrated that when inhaled-corticosteroid doses are adjusted according to the results of serial sputum eosinophil counts, improved clinical outcomes at similar corticosteroid doses, as compared with standard care, can be achieved.6 Although these studies support the plausibility of using biologic markers to help improve asthma treatment, the significant technical hurdles associated with performing airway challenges or sputum analysis have limited the use of these markers outside the laboratory.
An article by Smith et al. in this issue of the Journal moves us closer to a clinically useful yardstick for the adjustment of inhaled-corticosteroid doses in the treatment of asthma.7 In a single-blind, placebo-controlled, two-phase study of clinically stable patients with asthma who required moderate doses of inhaled corticosteroid, the investigators randomly assigned patients to have their inhaled-corticosteroid dose adjusted with the use of either an algorithm based on international guidelines — which comprised a composite of symptoms, pulmonary function, and use of supplemental medication — or measurements of FENO. In the first phase, the lowest dose of inhaled corticosteroid (fluticasone) that provided stability was determined according to either the conventional guideline-based algorithm or FENO measurements. In the second phase, patients maintained this baseline dose and were monitored at six clinic visits over one year. If the control of asthma deteriorated (as defined by the guideline-based algorithm in one group and by the FENO level in the other), the fluticasone dose was increased and then titrated downward after control had been maintained for at least four months. The researchers found that the adjustment of fluticasone therapy according to FENO measurements was associated with the control of symptoms, lung function, and freedom from exacerbations that was similar to the control achieved with therapy administered according to conventional guidelines. More important, this similar level of asthma control was achieved, at the conclusion of the study, at an average fluticasone dose that was approximately 40 percent lower than that required among patients in the conventional-management group (P=0.003).
This study sends a timely message about using biomarkers to improve asthma treatment for individual patients. However, more research in this area is needed, and the data require cautious interpretation and application. Although Smith et al. were careful to model the conventional-treatment algorithm on established guidelines, the average fluticasone dose in this control group at the end of the initial titration period was 567 μg per day, which is nearly double the dose needed to bring about the majority of the clinical benefits that can be achieved in most patients.8 Previous work has demonstrated that in patients similar to those studied by Smith et al., stability can be maintained with doses of inhaled corticosteroid adjusted to this level (or lower), without guidance from either conventional guidelines or biomarkers, through a standardized approach involving a uniform dose reduction of 50 percent.9 Therefore, the finding that FENO measurements provided similar control of asthma at a lower dose of fluticasone may reflect overtreatment in the control group rather than more appropriately targeted treatment in the FENO group.
Furthermore, it is not clear that FENO is a specific or sensitive marker for asthma instability. Previous studies have demonstrated that measurements of sputum eosinophils, but not FENO, can allow clinicians to discriminate between persons in whom asthma will eventually deteriorate and those in whom it will not when treatment with inhaled corticosteroids is withdrawn.10,11,12 This may reflect the fact that in addition to suppressing other aspects of airway inflammation that are variably associated with FENO, corticosteroids directly inhibit the enzymatic production of nitric oxide.13 Thus, the FENO level in asthma that is treated with inhaled corticosteroids may be more closely correlated with the level of exposure to corticosteroids than with ongoing inflammation in the airway. In this regard, the current findings may not apply to the titration of other therapeutic agents, which suppress FENO through other mechanisms.
Finally, the current study involved patients with mild-to-moderate asthma, and we do not know whether the findings can be applied to patients with milder or more severe disease. A recent study has shown that in patients with mild, persistent asthma — a condition targeted, under current guidelines, for continuous therapy with inhaled corticosteroids — pulmonary function and overall stability are maintained with as-needed inhaled corticosteroids alone.14 It is unclear whether measurements of FENO could be additionally helpful in such a population. Similarly, we do not yet know whether it is appropriate to adjust inhaled-corticosteroid doses with the use of FENO measurements in patients with more severe disease, especially since these persons may be using multiple controller medications that may independently influence the relationship between asthma stability and FENO.
Although these concerns delineate areas for future study, the findings of Smith et al. underscore the importance of identifying the level of treatment that is appropriate for an individual patient. The authors strongly suggest that when it comes to establishing doses of inhaled corticosteroids in patients with mild-to-moderate asthma, we can do better than to adhere strictly to current guidelines. Whether through the matching of inhaled-corticosteroid doses to an individual patient's asthma activity or through the provision of an objective bioassay of inhaled-corticosteroid exposure, the use of FENO measurements appears to allow lower doses of inhaled corticosteroids to be used without compromising asthma control; this is a situation in which less is truly more.
The measurement of FENO is considerably less invasive and technically simpler than the assessment of airway responsiveness or of sputum eosinophil counts, but it remains unlikely that the use of FENO measurements will be adopted in the clinical setting until less expensive analytic techniques and standard reimbursement codes for the assay are developed. Nonetheless, it appears clear that the end is nearing for a de facto "one dose fits most" approach to the use of inhaled corticosteroids in asthma treatment. The next steps should involve double-blind studies of dose titration of asthma treatments with the use of various biomarkers as compared with standardized, uniform dose reductions and guideline-based care.
Source Information
From the Department of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston.
References
Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for asthma -- United States, 1980-1999. MMWR Surveill Summ 2002;51:1-13.
National Asthma Education and Prevention Program. Expert Panel report 2: guidelines for the diagnosis and management of asthma. Bethesda, Md.: National Institutes of Health, 1997. (NIH publication no. 97-4051.)
National Heart, Lung, and Blood Institute. Global strategy for asthma management and prevention: global initiative for asthma. Bethesda, Md.: National Institutes of Health, 2002. (NIH publication no. 02-3659.)
British guideline on the management of asthma. Thorax 2003;58:Suppl 1:i1-i94.
Sont JK, Willems LN, Bel EH, van Krieken JH, Vandenbroucke JP, Sterk PJ. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. Am J Respir Crit Care Med 1999;159:1043-1051.
Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002;360:1715-1721.
Smith AD, Cowan JO, Brassett KP, Herbison PG, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005;352:2163-2173.
Holt S, Suder A, Weatherall M, Cheng S, Shirtcliffe P, Beasley R. Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis. BMJ 2001;323:253-256.
Hawkins G, McMahon AD, Twaddle S, Wood SF, Ford I, Thomson NC. Stepping down inhaled corticosteroids in asthma: randomised controlled trial. BMJ 2003;326:1115-1115.
Leuppi JD, Salome CM, Jenkins CR, et al. Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med 2001;163:406-412.
Jones SL, Kittelson J, Cowan JO, et al. The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 2001;164:738-743.
Deykin A, Lazarus SC, Fahy JV, et al. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids. J Allergy Clin Immunol 2005;115:720-727.
Gaston B, Drazen JM, Loscalzo J, Stamler JS. The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 1994;149:538-551.
Boushey HA, Sorkness CA, King TS, et al. Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005;352:1519-1528.(Aaron Deykin, M.D.)
It is generally acknowledged that once control of asthma is achieved, a reduction of the inhaled corticosteroid to the lowest effective dose is in the patient's best interest. However, we have yet to establish the level and duration of asthma control that are needed before downward titration is undertaken and the mechanism by which such adjustments should be accomplished. Without specific and straightforward guidance, clinicians may opt to leave well enough alone and continue treatment in patients who appear to be doing well when, in fact, the dose of inhaled corticosteroid should either be increased or reduced. There is a need for clinically applicable ways to distinguish patients with asthma who require additional therapy from those who could have their medical regimen reduced.
Biologic markers associated with the presence of asthma that have commonly been used to judge asthma control include the degree of airway hyperresponsiveness to exogenous stimuli such as methacholine or histamine and eosinophil counts in sputum. A more recent addition to this list is the amount of nitric oxide in exhaled air (FENO). Although all of these measures are generally improved when inhaled corticosteroids are administered, the relationship between these markers and the basic pathology of asthma is uncertain.3 A previous study demonstrated that asthma outcomes improved when the dose of inhaled corticosteroid was titrated with the use of an algorithm that incorporated airway hyperresponsiveness in addition to other measures specified in standard treatment guidelines, as compared with guideline-based care alone. However, the improvement in control occurred in concert with the use of higher doses of inhaled corticosteroid.5 In contrast, other work has demonstrated that when inhaled-corticosteroid doses are adjusted according to the results of serial sputum eosinophil counts, improved clinical outcomes at similar corticosteroid doses, as compared with standard care, can be achieved.6 Although these studies support the plausibility of using biologic markers to help improve asthma treatment, the significant technical hurdles associated with performing airway challenges or sputum analysis have limited the use of these markers outside the laboratory.
An article by Smith et al. in this issue of the Journal moves us closer to a clinically useful yardstick for the adjustment of inhaled-corticosteroid doses in the treatment of asthma.7 In a single-blind, placebo-controlled, two-phase study of clinically stable patients with asthma who required moderate doses of inhaled corticosteroid, the investigators randomly assigned patients to have their inhaled-corticosteroid dose adjusted with the use of either an algorithm based on international guidelines — which comprised a composite of symptoms, pulmonary function, and use of supplemental medication — or measurements of FENO. In the first phase, the lowest dose of inhaled corticosteroid (fluticasone) that provided stability was determined according to either the conventional guideline-based algorithm or FENO measurements. In the second phase, patients maintained this baseline dose and were monitored at six clinic visits over one year. If the control of asthma deteriorated (as defined by the guideline-based algorithm in one group and by the FENO level in the other), the fluticasone dose was increased and then titrated downward after control had been maintained for at least four months. The researchers found that the adjustment of fluticasone therapy according to FENO measurements was associated with the control of symptoms, lung function, and freedom from exacerbations that was similar to the control achieved with therapy administered according to conventional guidelines. More important, this similar level of asthma control was achieved, at the conclusion of the study, at an average fluticasone dose that was approximately 40 percent lower than that required among patients in the conventional-management group (P=0.003).
This study sends a timely message about using biomarkers to improve asthma treatment for individual patients. However, more research in this area is needed, and the data require cautious interpretation and application. Although Smith et al. were careful to model the conventional-treatment algorithm on established guidelines, the average fluticasone dose in this control group at the end of the initial titration period was 567 μg per day, which is nearly double the dose needed to bring about the majority of the clinical benefits that can be achieved in most patients.8 Previous work has demonstrated that in patients similar to those studied by Smith et al., stability can be maintained with doses of inhaled corticosteroid adjusted to this level (or lower), without guidance from either conventional guidelines or biomarkers, through a standardized approach involving a uniform dose reduction of 50 percent.9 Therefore, the finding that FENO measurements provided similar control of asthma at a lower dose of fluticasone may reflect overtreatment in the control group rather than more appropriately targeted treatment in the FENO group.
Furthermore, it is not clear that FENO is a specific or sensitive marker for asthma instability. Previous studies have demonstrated that measurements of sputum eosinophils, but not FENO, can allow clinicians to discriminate between persons in whom asthma will eventually deteriorate and those in whom it will not when treatment with inhaled corticosteroids is withdrawn.10,11,12 This may reflect the fact that in addition to suppressing other aspects of airway inflammation that are variably associated with FENO, corticosteroids directly inhibit the enzymatic production of nitric oxide.13 Thus, the FENO level in asthma that is treated with inhaled corticosteroids may be more closely correlated with the level of exposure to corticosteroids than with ongoing inflammation in the airway. In this regard, the current findings may not apply to the titration of other therapeutic agents, which suppress FENO through other mechanisms.
Finally, the current study involved patients with mild-to-moderate asthma, and we do not know whether the findings can be applied to patients with milder or more severe disease. A recent study has shown that in patients with mild, persistent asthma — a condition targeted, under current guidelines, for continuous therapy with inhaled corticosteroids — pulmonary function and overall stability are maintained with as-needed inhaled corticosteroids alone.14 It is unclear whether measurements of FENO could be additionally helpful in such a population. Similarly, we do not yet know whether it is appropriate to adjust inhaled-corticosteroid doses with the use of FENO measurements in patients with more severe disease, especially since these persons may be using multiple controller medications that may independently influence the relationship between asthma stability and FENO.
Although these concerns delineate areas for future study, the findings of Smith et al. underscore the importance of identifying the level of treatment that is appropriate for an individual patient. The authors strongly suggest that when it comes to establishing doses of inhaled corticosteroids in patients with mild-to-moderate asthma, we can do better than to adhere strictly to current guidelines. Whether through the matching of inhaled-corticosteroid doses to an individual patient's asthma activity or through the provision of an objective bioassay of inhaled-corticosteroid exposure, the use of FENO measurements appears to allow lower doses of inhaled corticosteroids to be used without compromising asthma control; this is a situation in which less is truly more.
The measurement of FENO is considerably less invasive and technically simpler than the assessment of airway responsiveness or of sputum eosinophil counts, but it remains unlikely that the use of FENO measurements will be adopted in the clinical setting until less expensive analytic techniques and standard reimbursement codes for the assay are developed. Nonetheless, it appears clear that the end is nearing for a de facto "one dose fits most" approach to the use of inhaled corticosteroids in asthma treatment. The next steps should involve double-blind studies of dose titration of asthma treatments with the use of various biomarkers as compared with standardized, uniform dose reductions and guideline-based care.
Source Information
From the Department of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston.
References
Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for asthma -- United States, 1980-1999. MMWR Surveill Summ 2002;51:1-13.
National Asthma Education and Prevention Program. Expert Panel report 2: guidelines for the diagnosis and management of asthma. Bethesda, Md.: National Institutes of Health, 1997. (NIH publication no. 97-4051.)
National Heart, Lung, and Blood Institute. Global strategy for asthma management and prevention: global initiative for asthma. Bethesda, Md.: National Institutes of Health, 2002. (NIH publication no. 02-3659.)
British guideline on the management of asthma. Thorax 2003;58:Suppl 1:i1-i94.
Sont JK, Willems LN, Bel EH, van Krieken JH, Vandenbroucke JP, Sterk PJ. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. Am J Respir Crit Care Med 1999;159:1043-1051.
Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002;360:1715-1721.
Smith AD, Cowan JO, Brassett KP, Herbison PG, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005;352:2163-2173.
Holt S, Suder A, Weatherall M, Cheng S, Shirtcliffe P, Beasley R. Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis. BMJ 2001;323:253-256.
Hawkins G, McMahon AD, Twaddle S, Wood SF, Ford I, Thomson NC. Stepping down inhaled corticosteroids in asthma: randomised controlled trial. BMJ 2003;326:1115-1115.
Leuppi JD, Salome CM, Jenkins CR, et al. Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med 2001;163:406-412.
Jones SL, Kittelson J, Cowan JO, et al. The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 2001;164:738-743.
Deykin A, Lazarus SC, Fahy JV, et al. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids. J Allergy Clin Immunol 2005;115:720-727.
Gaston B, Drazen JM, Loscalzo J, Stamler JS. The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 1994;149:538-551.
Boushey HA, Sorkness CA, King TS, et al. Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005;352:1519-1528.(Aaron Deykin, M.D.)