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"Refractory" Eosinophilic Airway Inflammation in Severe Asthma

Posted on: Saturday, 1 January 2005, 03:00 CST

To the Editor.

The recent study by ten Brinke and colleagues (1) should make us pause to consider the direction in which research into the mechanisms of refractory asthma is heading. Their data demonstrate that use of intramuscular triamcinolone, in patients with refractory asthma, leads to a reduction in sputum eosinophils and rescue medication score and an increase in FEV^sub 1^. The authors suggest that a possible explanation for their findings is that triamcinolone may reach areas of the lung, as well as the bone marrow, that are inaccessible to inhaled corticosteroids. However, this does not explain why intramuscular treatment should be superior to oral, unless there is a problem with gastrointestinal absorption. The authors also acknowledge, albeit without much conviction, that poor adherence to maintenance corticosteroids might play a role.

Many believe that poor treatment adherence is an important cause of refractory asthma. However, there are surprisingly few published data to support this view, and compared with the advances made in understanding the cellular and molecular basis of refractory asthma, the assessment of adherence remains a neglected area. All the currently available methods for assessing adherence to inhaled therapy, including electronic monitors, have their limitations (2), which may explain why only one of several recent descriptive studies of patients with refractory asthma has attempted to provide objective data on adherence to inhaled therapy (3). Several groups have measured serum prednisolone and cortisol to assess adherence to oral prednisolone (1, 3-6), although this method also has drawbacks. Detectable prednisolone only reflects short-term adherence, whereas measurement of cortisol is an indirect method, which assumes that demonstration of adrenal suppression reflects corticosteroid use. However, a single cortisol measurement only reliably reflects adrenal suppression when the level is low (< 100 nM) (4). Levels greater than 100 nM are harder to interpret.

These difficulties most likely explain the paucity of published data. One of the advantages of administering intramuscular triamcinolone is that adherence is assured. In their study, ten Brinke and colleagues (1) have demonstrated that significant improvements are possible, even in adults with refractory, eosinophilic asthma, providing patients receive an adequate corticosteroid dose. This highlights the need to establish what proportion of those with refractory asthma really are receiving the corticosteroid dose they are prescribed and to develop ways of improving adherence, where appropriate. Our own practice is to diagnose steroid-insensitive asthma only after a failed trial of intramuscular triamcinolone, and we suggest that this be incorporated into the definition of this problem.

Conflict of Interest Statement: A.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter; D.N.R.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter.

DONALD N. R. PAYNE

ANDREW BUSH

Royal Brompton Hospital

London, United Kingdom

References

1. ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. "Refractory" eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am J Respir Crit Care Med 2004;170:601-605.

2. Cochrane MG, Bala MV, Downs KE, Mauskopf J, Ben-Joseph RH. Inhaled corticosteroids for asthma therapy: patient compliance, devices, and inhalation technique. Chest 2000;117:542-550.

3. Ranganathan SC, Payne DN, Jaffe A, McKenzie SA. Difficult asthma: defining the problems. Pediatr Pulmonol 2001;31:114-120.

4. Payne D. Adrenal response to glucocorticoid treatment [letter]. Lancet 2000;355:1458.

5. Robinson DS, Campbell DA, Durham SR, Pfeffer J, Barnes PJ, Chung KF. Systematic assessment of difficult-to-treat asthma. Eur Respir J 2003; 22:478-483.

6. Wenzel SE, Szefler SJ, Leung DY, Sloan SI, Rex MD, Martin RJ. Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997;156: 737-743.

From the Authors:

We thank Drs. Payne and Bush for their critical comments on our article (1). We do agree that a diagnosis of "steroid-insensitive asthma" should be made with caution, in particular because of the possibility of noncompliance with therapy, which is probably an underestimated problem in this category of patients. We also sympathize in principle with their proposition to incorporate a failed trial with intramuscular triamcinolone into the diagnosis of steroid-insensitive asthma, although it must be kept in mind that in case of an unforeseen steroid-induced complication such as diabetes, hypertension, or psychiatric disturbances, there is no possibility to discontinue the treatment. In our clinic, we rather prefer a trial with intravenous corticosteroids in a hospital setting, where allergen avoidance can be guaranteed at the same time.

Although difficult to prove, we do not think that noncompliance was the major cause of the lack of sufficient response to therapy in our patients. These patients were intensively managed by a chest physician, repeatedly informed about the importance of regular treatment, and were highly motivated to participate in the study. In six out of seven patients on regular oral corticosteroids, cortisol levels were adequately suppressed (< 100 nM), while sputum eosinophil percentages were still elevated. This means either that the patients had poor perception of dyspnea and were relatively undertreated, or that the patients (and their doctors) accepted a certain level of symptoms to avoid the side effects of higher doses of systemic corticosteroids. In our view, such patients represent a specific subgroup of patients with severe asthma who cannot be controlled with inhaled medication or low dose oral corticosteroids alone rather than patients who are noncompliant with prescribed therapy. The observation that patients on regular oral corticosteroids further improved after intramuscular triamcinolone is probably due to the extremely high doses of triamcinolone (120 mg) that were administered in this study. Obviously, such high doses of regular systemic corticosteroids are not recommended in clinical practice!

On the basis of the results of our study, we are convinced that a subgroup of patients with severe asthma needs potent systemic antiinflammatory therapy for optimal control of their disease, which should preferably be associated with less serious side effects than high dose oral or intramuscular corticosteroids.

Conflict of Interest Statement: A.t.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.H.Z. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; P.J.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.F.R. has been consulting, participated in Advisory Board meetings and received lecture fees from AltanaPharma, Novartis, AstraZeneca, GlaxoSmithKline, Pfizer, Boehringer, and Merck Sharp & Dohme; E.H.B. has participated in Advisory Board meetings of Merck Sharp & Dohme from 2001 until 2004.

The Department of Pulmonology at Leiden University Medical Center has received grants from AltanaPharma, Novartis, Bayer, AstraZeneca, Pfizer, Merck Sharp & Dohme, Exhale Therapeutics, and GlaxoSmithKline in the years 2001 until 2004.

ANNEKE TEN BRINKE

Medisch Centrum Leeuwarden

Leeuwarden, the Netherlands

AEILKO H. ZWINDERMAN

Academic Medical Center

Amsterdam, the Netherlands

PETER J. STERK

KLAUS F. RABE

ELISABETH H. BEL

Leiden University Medical Center

Leiden, the Netherlands

References

1. ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. "Refractory" eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am J Respir Crit Care Med 2004;170:601-605.

Copyright American Thoracic Society Dec 15, 2004

Source: American Journal of Respiratory and Critical Care Medicine

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