Correspondence
Treatment of Mild Asthma
N Engl J Med 2005; 353:424-427July 28, 2005
- Article
To the Editor:
Boushey et al. (April 14 issue)1 report that regularly scheduled treatment with budesonide for mild persistent asthma has no significant advantage over intermittent short-course treatment. We compared data from a large pediatric survey of prescriptions for antiasthma drugs,2,3 involving seven Italian regions, with the same kind of information from our region, Friuli-Venezia Giulia. In our region, ours is the regional referral center for pediatric asthma, and we suggest that short courses of controller therapies are preferable to prolonged treatments.4 In our region, the number of prescriptions for inhaled corticosteroids in one year (2003) for children up to 13 years of age was one third as high as in other Italian regions (0.47 vs. 1.46 packets per child, respectively), and the number of prescriptions for montelukast was less than half as high (0.11 vs. 0.26 packet per child, respectively). Nevertheless, the amount of reliever drugs (albuterol) dispensed to each child with asthma (i.e., the major indicator of asthma exacerbations) in our region was similar to that in the other regions (1.42 vs. 1.44 packets per child, respectively). These findings in 88,736 children with asthma seem to support the conclusions of Boushey et al. in a study of adult patients.
4 ReferencesIrene Berti, M.D.
Giorgio Longo, M.D.
Institute of Child Health Burlo Garofolo, 34100 Trieste, Italy
berti@burlo.trieste. it Stefano Visintin, Ph.D.
Pharmacy Service ASS 2 Isontina, 34074 Monfalcone, Italy1
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
Full Text | Web of Science | Medline2
Clavenna A ,Rossi E ,Berti A ,Pedrazzi G ,De Rosa M ,Bonati M . Inappropriate use of anti-asthmatic drugs in the Italian paediatric population. Eur J Clin Pharmacol 2003;59:565-569
CrossRef | Web of Science | Medline3
Clavenna A ,Bonati M ,Rossi E ,Berti A ,De Rosa M . Il profilo prescrittivo della popolazione pediatrica italiana nelle cure primarie. Ric Prat 2004;20:224-2444
Travan L ,Berti I ,Longo G . Quando iniziare e quando sospendere i farmaci antiasmatici: per un razionale oltre le linee guida. Med Bambino 2005;24:157-163
To the Editor:
Boushey et al. conclude that as-needed corticosteroids may be adequate to treat mild persistent asthma on the basis of a study in which daily budesonide, daily zafirlukast, or intermittent treatment failed to show a difference in morning peak expiratory flow (PEF), the primary efficacy variable, and in asthma exacerbation. A conclusion based on failure to show a difference in a study not designed as a noninferiority study has limitations.1 The study did not have a concurrent control group that could validate the sensitivity of morning PEF. Such a control group would have been useful because prebronchodilator forced expiratory volume in one second (FEV1), which is another surrogate for asthma control, and some results with respect to patient-reported outcomes and markers of disease activity were significantly superior with daily budesonide as compared with other treatments. In this study, the pretreatment PEF and FEV1 results were not similar — in contrast to many clinical studies with corticosteroids in which results for these two related measures of lung function were similar.2 It is possible that daily budesonide was better than the other treatments, but morning PEF was not sufficiently sensitive to show the difference.
2 ReferencesBadrul A. Chowdhury, M.D., Ph.D.
Food and Drug Administration, Rockville, MD 20857
chowdhuryb@cder.fda. gov 1
Altman DG ,Bland JM . Absence of evidence is not evidence of absence. BMJ 1995;311:485-485
CrossRef | Web of Science | Medline2
Physicians' desk reference. Montvale, N.J.: Thomson PDR, 2005:629, 1494, 1722.
To the Editor:
We welcome Boushey and colleagues' contribution to evidence on the management of mild persistent asthma, which occurs in a large patient population in Westernized countries. However, we urge caution in interpreting these data. The study intervention was not simply intermittent inhaled corticosteroids; it also included regular medical review, written action plans, immediate availability of medication for exacerbations, and prior assessment of suitability for this approach. Furthermore, given that the aim of the study was to examine the effects of 12 months of treatment on asthma control, the change in the morning PEF between two short periods was not the ideal primary outcome variable, and the importance of improvement in the number of symptom-free days appears to have been undervalued. Finally, without regular monitoring, it would be unwise to assume that exacerbations were not underreported, when they were diagnosed only on the basis of the patient's implementation of a complex, high-dose, symptom-based action plan and acknowledged untreated symptomatic episodes. Further studies are needed to identify the circumstances in which intermittent inhaled corticosteroids can achieve optimal outcomes in mild asthma.
Christine R. Jenkins, M.D.
Guy B. Marks, Ph.D.
Helen K. Reddel, Ph.D.
Woolcock Institute of Medical Research, Sydney NSW 2050, Australia
crj@med.usyd. edu. au Dr. Jenkins reports having received honoraria for educational presentations, funding for clinical research, travel expenses, and payment for service on advisory boards from AstraZeneca and GlaxoSmithKline. Dr. Marks reports having received honoraria for educational presentations from AstraZeneca and GlaxoSmithKline and research funding from GlaxoSmithKline. Dr. Reddel reports having received funding for clinical research from AstraZeneca and funding to attend conferences from AstraZeneca and GlaxoSmithKline. The Woolcock Institute of Medical Research receives educational grants and research funding from AstraZeneca and GlaxoSmithKline.
To the Editor:
The study by Boushey and colleagues serves to highlight further the disconnection between airway caliber and airway inflammation. Although no apparent change in airway caliber was demonstrated in the three treatment groups, patients who did not have the benefit of regular inhaled corticosteroids had significantly higher levels of exhaled nitric oxide, more eosinophils in sputum, and greater bronchial reactivity, indicating underlying ongoing untreated airway inflammation. No one is certain of the long-term consequences of leaving persistent airway inflammation unchecked, especially when inflammation itself forms the very basis of asthma and contributes to airway remodeling. This study should therefore act as a catalyst for further research, rather than as a source of definitive support for pro re nata use of corticosteroids in mild asthma with persistent airway inflammation.
Daniel K.C. Lee, M.B., B.Ch., M.D.
Ipswich Hospital, Ipswich IP4 5PD, United Kingdom
dkclee@doctors.org. uk To the Editor:
When comparing the efficacy of different treatment strategies in asthma, it is important to choose the appropriate end points that are more likely to influence decision making in clinical practice. Boushey et al. chose morning PEF as the primary end point in a comparison of the efficacy of regular and intermittent inhaled corticosteroid therapy. We do not believe that morning PEF is the most important measure that influences decision making. Lung function does not always correlate well with clinical outcomes.1 Johansson et al.2 recently reported that patients with asthma ranked symptom-free days as the most important attribute of asthma treatment. Boushey et al. report that regular inhaled steroids increased symptom-free days by almost a month, as compared with intermittent therapy. In addition, they report significant improvements in airway hyperresponsiveness and reduction in underlying airway inflammation. Had these variables — which we believe are more relevant in decision making in clinical practice — been chosen as primary end points, Boushey et al. would have concluded that regular treatment with inhaled corticosteroids is better than intermittent treatment.
Anchala Raghupathy, D.T.C.D.
Bill Brashier, D.T.C.D.
Sundeep Salvi, M.D., Ph.D.
Chest Research Foundation, Pune 411014, India
sundeepsalvi@yahoo.com Drs. Raghupathy, Brashier, and Salvi report involvement in clinical trials for Cipla (India).
2 References1
Bateman ED ,Frith LF ,Braunstein GL . Achieving guideline-based asthma control: does the patient benefit? Eur Respir J 2002;20:588-595
CrossRef | Web of Science | Medline2
Johansson G ,Stallberg B ,Tornling G , et al. Asthma treatment preference study: a conjoint analysis of preferred drug treatments. Chest 2004;125:916-923
CrossRef | Web of Science | Medline
Author/Editor Response
We appreciate the comments of Dr. Berti and colleagues. If confirmed, their findings would suggest that intermittent therapy may be an acceptable strategy for a subgroup of children with asthma. Dr. Chowdhury is correct that our study was not designed as a noninferiority trial. However, we found that even at the limits of the confidence intervals, the between-group differences in exacerbation rates may not have been great enough to justify advocating regular therapy in the population studied. Although morning PEF was selected as the primary outcome variable, other indexes of asthma control were included a priori in our analysis plan. The change in post-bronchodilator FEV1 was selected as a possible indicator of permanent or, at least, poorly reversible change in airway caliber.
Several correspondents refer to the potential value of an increase in symptom-free days. In the absence of important differences in exacerbation rates or in the change in post-bronchodilator FEV1, this increase means simply that patients may be allowed to decide whether the gain in symptom-free days justifies taking daily therapy. This decision will no doubt be influenced by the patient's perception of the importance of fewer days of symptoms as compared with the inconvenience, cost, and perceived toxicity of treatment.
Dr. Jenkins and colleagues urge that care be taken in generalizing our findings to settings in which patients are not seen regularly, instructed in an action plan, or provided with medication to use when their asthma symptoms flare. We agree. We do not agree that exacerbations were underreported, since inquiry was made about such events every six weeks. We do agree, however, that further studies to examine the applicability of our findings would be useful.
Dr. Raghupathy and colleagues claim that reduction in markers of airway inflammation is a more relevant end point for guiding clinical decision making. As we reported, markers of inflammation are increased in patients with sustained spontaneous clinical remission of asthma.1,2 We would question the relevance to clinical practice of aiming treatment at normalizing a laboratory test if that normalization were not associated with improvements in the quality of life in the present or a reduction of risk in the future. We thus agree with Dr. Lee that additional research is needed on the long-term consequences of checking the very mild inflammation found in patients such as those enrolled in our study.
Homer A. Boushey, M.D.
University of California, San Francisco, San Francisco, CA 94143-0130Elliot Israel, M.D.
Brigham and Women's Hospital, Boston, MA 02115Since publication of his April 14 article, Dr. Boushey reports having received consulting fees from Altana.
2 References1
van Den Toorn LM ,Prins JB ,Overbeek SE ,Hoogsteden HC ,de Jongste JC . Adolescents in clinical remission of atopic asthma have elevated exhaled nitric oxide levels and bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000;162:953-957
Web of Science | Medline2
van den Toorn LM ,Overbeek SE ,de Jongste JC ,Leman K ,Hoogsteden HC ,Prins JB . Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med 2001;164:2107-2113[Erratum, Am J Respir Crit Care Med 2002;166:1143.]
Web of Science | Medline
Author/Editor Response
The provocative article by Boushey et al. challenges the “politically correct” doctrine of current guidelines recommending continuous treatment of mild persistent asthma with inhaled steroids. Thus, it is no surprise that it has generated discussion. Three letters addressed to Boushey et al. have also been sent to me for comment, as they touch on issues discussed in my accompanying editorial.1 Jenkins et al. suggest that the selection of patients and the management plan may have contributed to a masking of differences among treatments. I agree that the careful selection of persons with mild persistent asthma — so mild that it did not require regular treatment after almost 20 years — and the management plan offered to all subjects may have contributed to an inability to detect differences among treatments for many of the outcomes examined.
Jenkins et al., Raghupathy et al., and Lee criticize the selection of morning PEF as the primary outcome, suggesting that the use of patient-centered outcomes (e.g., symptom-free days) would have led to different conclusions and a different clinical message. Although I, too, would have preferred a patient-centered outcome as the primary outcome, I believe that the clinical message of this report would not have changed. The only difference would have been the order of description of the results: more days of symptoms but no difference in PEF and other relevant secondary outcomes.
Dr. Lee is concerned that leaving persistent inflammation uncontrolled with intermittent treatment, rather than regular treatment, may be associated with adverse long-term events, particularly airway remodeling. As I stated in my editorial, there is no evidence that mild chronic asthmatic inflammation is responsible for the progression of the disease. We still do not know whether chronic persistent inflammation, which is present not only in persons with mild asthma but also in those with nonasthmatic rhinitis,2 including very young children,3 represents an offensive abnormality that needs to be suppressed even in asymptomatic persons.
One point we all agree on is that we need a properly designed and powered study that is comprehensive enough to answer the fundamental questions raised by Boushey et al. Until we have the results of such a study, any clinical recommendation is necessarily based on limited evidence.
3 ReferencesLeonardo M. Fabbri, M.D.
University of Modena and Reggio Emilia, Modena I-41100, Italy1
Fabbri LM . Does mild persistent asthma require regular treatment? N Engl J Med 2005;352:1589-1591
Full Text | Web of Science | Medline2
Crimi E ,Milanese M ,Oddera S , et al. Inflammatory and mechanical factors of allergen-induced bronchoconstriction in mild asthma and rhinitis. J Appl Physiol 2001;91:1029-1034
Web of Science | Medline3
Barbato A ,Turato G ,Baraldo S , et al. Airway inflammation in childhood asthma. Am J Respir Crit Care Med 2003;168:798-803
CrossRef | Web of Science | Medline
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