Severe Steroid-Dependent Asthma: Therapeutic Role of High-Dose Intravenous Immunoglobulin

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Abstract and Introduction


Steroid-resistant asthma continues to be a significant problem despite the availability of new high-potency inhaled steroids. Steroid-resistant asthmatic patients require oral glucocorticoid maintenance therapy to control their symptoms and to minimize exacerbations. Steroid resistance is related to increased levels of interleukin-2 (IL-2) and IL-4 in the airways of these patients. Because of severe adverse effects of steroids, these patients are in need of therapies that can minimize their steroid requirements and control their asthma. Intravenous immunoglobulin, which is known to decrease IL-2 and IL-4 production in vitro, has been shown to potentiate the inhibitory effects of glucocorticoids on cell proliferation and cytokine secretion. Open-label and placebo-controlled clinical studies in children with steroid-dependent asthma have demonstrated that intravenous immunoglobulin therapy can have significant steroid-sparing effects in these patients.


Glucocorticoids are a mainstay of therapy for a variety of chronic inflammatory diseases, including asthma. It is thought that glucocorticoids exert their therapeutic effects by inducing apoptosis and decreasing activation of the main effector cells in asthma--the eosinophil and the T lymphocyte.[1] In most patients with asthma, oral glucocorticoid bursts will quickly improve pulmonary function, and regular use of topical glucocorticoids will minimize exacerbations. However, some patients do not respond to what is considered adequate doses of glucocorticoids. Some of these patients are noncompliant or use poor inhaler techniques. Others are chronically exposed to allergens or have undertreated sinusitis -- conditions that cause persistent inflammation that may not be managed without oral steroids. Even after controlling for these variables, there is a subset of asthmatics that continue to be unresponsive to steroid therapy; these patients are termed "steroid resistant" (insensitive).[2]

Steroid resistance in these patients is dose dependent; if given in high enough doses, these patients will eventually respond, with improvement in their asthma symptoms and pulmonary function. Thus, the working definition of a steroid-resistant asthmatic patient is one who is at the lower end of the spectrum of responsiveness to treatment with glucocorticoids or takes longer to respond to glucocorticoids when experiencing an exacerbation. A clinical definition based on pulmonary function tests better defines these patients and is frequently used to identify them for clinical studies. These patients do not increase their initially low forced expiratory volume in 1 second (FEV1) by 15% after a 2-week burst of 40 mg/d of prednisone (93% of asthmatic patients will respond to this regimen).[3] A practical definition, useful for the clinician, is any patient who requires daily oral steroids (or very high doses of high-potency inhaled steroids) to minimize the frequency of asthma exacerbations. These patients are considered either steroid-dependent (normal pulmonary function maintained only if taking oral steroids) or steroid-resistant (poor pulmonary function despite treatment with oral steroids).


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