Pediatric Pulmonology 14:18&186 (1992)
State of the Art Review Steroid Resistance in Asthma: Our Current Understanding Alan K. Kamada, Phartm,’ Donald Y.M. Leung, MD, INTRODUCTION
P ~ D , and ~ * ~ Stanley J.
Szefler, MD192’394
Turner-Warwick described a group of asthmatics with clinical characteristics consistent with steroid resistance Asthma has received heightened attention in recent in 1977.s In this report various patterns of airflow obyears due to an increase in its prevalence and apparent struction in chronic asthma were illustrated (Fig. 2). severity. With the recognition of inflammation as a priThey included “brittle” asthma, in which patients were mary contributing mechanism, treatment has been founresponsive to a variety of anti-asthma medications (incused on inhaled anti-inflammatory therapy, specifically cluding high-dose systemic glucocorticoids), and “irrecromolyn sodium and glucocorticoids.’.’ Oral glucocorversible” asthma, in which patients, although partially ticoids are reserved for acute exacerbations and mainteresponsive to bronchodilators, demonstrated a componance therapy for severe While glucocortinent that was persistent and irreversible by systemic glucoids have proved beneficial in the majority of cases of cocorticoid therapy. severe asthma, a subset of patients who fail to demonLater in 198 1, Carmichael and colleagues characterstrate a clinical response to high-dose systemic glucocorized the clinical features of steroid-resistant asthma.6 Steticoid therapy has been recognized. These patients have roid resistance was defined as a failure of forced expirabeen categorized as “steroid-resistant .” The purpose of tory volume in I second (FEV,) to increase by 15% this report is to review the clinical and immunologic during or at the end of a course of prednisolone, 3 2 0 mg characteristic features of steroid-resistant asthmatics, and daily for 7 days. A comparative study population of “steto provide practical recommendations for their manageroid-responsive” asthmatics demonstrated an increase in ment. FEV, by 230% with this treatment. Compared to the steroid-responsive asthmatics, several factors associated CLINICAL AND LABORATORY FEATURES with steroid resistance were recognized, including a more frequent family history of asthma, a longer duration of “Steroid-resistant” asthma was first described in 1968 by Schwartz and colleague^.^ The patients described had a poor clinical response to high-dose systemic glucocorticoid therapy, which was correlated to the eosinopenic From the Ira J . and Jacqueline Neimark Laboratory for Clinical Pharresponse to hydrocortisone. When 40 mg hydrocortisone macology in Pediatrics, Pharmacology Division, ’ and Allergy and was administered intravenously to these steroid-resistant Immunology Division,’ Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine; and Departments of asthmatics, a blunted eosinopenic response was observed Pediatrics3 and Pharmacology? University of Colorado Health Sciafter 2, 4, and 6 hours as compared to unselected asth- ences Center, Dcnver, Colorado. matics (Fig. 1 ). The reduction of peripheral blood eosinophils was 11% after 2 hours, 34%after 4 hours, and 3.6% Received May 7 , 1992; (revision) accepted for publication May 22. after 6 hours when compared to pre-hydrocortisone mea- 1992. surements. In contrast, the percent reduction of circulat- Supported in part by the American College of Clinical Pharmacying eosinophils in the unselected asthmatic controls was Sandoz Pharmaceuticals Research Fellowship in Immunology Thera35%, 77%, and 73%after 2,4, and 6 hours, respectively. peutics (A.K.K.)and National lnbtitutes of Health. Heart, Lung. and Further study demonstrated that accelerated plasma corti- Blood Institutc, grant HL-36577 (D.Y.M.L.,S.J.S.). sol clearance was, at least in part, responsible for the Address correspondence and rcprint requests to Dr. S.J. Szctler. Desteroid resistance observed. Mean plasma cortisol half- partment of Pediatrics (K-926), National Jewish Center for Immunollives were 86 minutes for the steroid-resistant asthmatics ogy and Respiratory Medicine, 1400 Jackson Street, Denver, CO and 128 minutes for the asthmatic controls (P < 0.001). 80206. 0 1992 Wiley-Liss, Inc.
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by skin blanching to increasing concentrations of beclomethasone dipropionate applied to the skin and occluded for 18 hours, the response was significantly lower in the steroid-resistant asthmatics in terms of blanching intensity and percentage of subjects demonstrating a positive response. This study suggests that steroid-resistant asthma is a manifestation of a generalized defect in the ability of tissues to respond to glucocorticoids. Asthmatics demonstrating an apparent steroid resistance are easily identified; however, this usually occurs 2 4 6 only after they fail to respond to a prolonged course of Hours Post-Dose systemic glucocorticoid therapy. These patients often beFig. 1. Percent change in circulating eosinophil counts after 40 come cushingoid in appearance, but have a localized lack mg intravenous hydrocortisone in control and steroid-resistant of response. Thus, steroid-resistant asthmatics may be at asthmatics. Open circles denote control asthmatics and solid risk for the adverse effects of glucocorticoid while receivcircles denote steroid-resistant asthmatics. (Reprinted from Schwartz HJ, et al., ref. 4, with permission from the American ing little therapeutic benefit. A definition of an adequate trial of systemic glucocorticoid therapy was put forth by College of Physicians.) Kamada and colleagues in 1992.'*Of asthmatic children whose morning pre-bronchodilator FEV, was < 70% symptoms, relatively lower morning peak expiratory predicted, 93% demonstrated a 2 15% improvement of flow rates, and increased bronchial hyperresponsiveness. the morning pre-bronchodilator FEV, within 10 days of These factors, however, may be more related to an in- initiating glucocorticoid burst therapy. From this it was creased severity of disease than specifically to steroid concluded that an adequate therapeutic trial was 10 days resistance. More importantly, the investigators recog- of high-dose systemic glucocorticoid administration (2 nized that patients exhibiting a poor response to systemic 15 mg twice daily) and that those asthmatics failing to glucocorticoids need to be identified at an early stage to respond within this time may need to be considered canallow withdrawal of unnecessary therapy and avoid sig- didates for alternative therapies. It remains essential that steroid-resistant asthmatics be nificant glucocorticoid-inducedadverse effects. A review by Lafdahl and colleagues in 1984 high- identified early so that unnecessary glucocorticoid therlighted drug interactions as a possible mechanism for apy can be discontinued, significant adverse effects apparent steroid resistance.' If glucocorticoid clearance avoided, and alternative therapies instituted in a more from the body is enhanced by another medication, the timely manner. However, perhaps more important, is the actual exposure to glucocorticoids is reduced, resulting in elucidation of the mechanisms of steroid-resistant athma. a diminished therapeutic response. In these cases, gluco- This would allow for institution of the appropriate altercorticoid-induced adverse effects would also be unex- native therapy and hopefully interruption of the inflampectedly absent or disproportionate to that expected for a matory process associated with the disease. The followspecific glucocorticoid dose. Supporting this principle is ing is a summary of the immunologic characteristics a report by Grandordy and colleagues demonstrating a associated with steroid-resistant asthma and the cellular greater increase of FEV, in asthmatics when betametha- mechanisms proposed thus far. sone was administered intramuscularly as compared to their response to oral prednisolone.' Complete bioavailIMMUNOLOGIC FEATURES AND ability by the intramuscular route or the longer half-life of POSSIBLE MECHANISMS betamethasone might account for this difference. In later Kay and colleagues reported in 1981 on investigations evaluations of steroid-resistant asthma by Corrigan and colleagues9 and Alvarez and colleagues,'" pharmacoki- related to the monocyte complement receptors and their netic abnormalities were considered and ruled out as eti- enhancement by a monocyte chemotactic factor in steologies for this phenomenon. Subjects underwent de- roid-resistant and steroid-responsive asthmatics.I 3 Monotailed pharmacokinetic studies to confirm that impaired cyte complement receptors and the enhanced rosetting oral absorption or rapid elimination were not contributing (complement receptor enhancement) when incubated to the observed steroid resistance. Thus it appears that a with a chemotactic factor (casein) were reduced in those subset of asthmatics resistant to glucocorticoid therapy patients who later responded to glucocorticoid treatment as compared to the steroid-resistant asthmatics. This sugdoes indeed exist. Brown and colleagues reported an abnormality in the gests that a reduced receptor number and low degree of cutaneous vasoconstrictor response to glucocorticoids in enhancement is a normal glucocorticoid response, and steroid-resistant asthmatics in 199 1 . ' I When evaluated that steroid-resistant asthmatics may have a defect in the
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expression and mobilization of complement receptors on the monocyte cell membrane. In 1984 Poznansky and colleagues reported on the immunophenotype and behavior of mononuclear cells from steroid-resistant asthmatics when incubated with phytohemagglutinin. In steroid-responsive and steroidresistant asthmatics there was no difference in the immunophenotype, specifically the proportion of T cells, T-inducer/CD4+ cells, Ia-positive cells, or cells reacting with the OKMl monocyte monoclonal antibody, nor in the number of cell colonies produced when incubated with phytohemagglutinin. A slightly lower, but not statistically significant, proportion of T-suppressorKD8S cells was found in steroid-resistant asthmatics. When mononuclear cells were co-incubated with methylprednisolone, a lesser degree of inhibition of proliferation was observed in the cells from the steroid-resistant asthmatics. This study demonstrated a functional abnormality, specifically mononuclear cell responsiveness to glucocorticoids, rather than a difference in immunophenotype in steroid-resistant asthma.
An interesting model for steroid resistance in renal transplants was suggested by Walker and colleagues in 1987.I s These investigators measured interleukin-2 (IL-2) synthesis by human lymphocytes in response to phytohemagglutinin in the presence and absence of prednisolone. In the three subjects termed steroid-resistant. a significantly higher IL-2 activity was found in the supernatants of both prednisolone and non-prednisolonetreated lymphocyte cultures. In addition, exogenous IL-2, added to lymphocyte cultures from normal subjects, reduced the suppressive effects of prednisolone, suggesting that a high 1L-2 activity plays a role in steroid resistance. In 1989 Wilkinson and colleagues identified a 3 kDa ncutrophil-activating factor, derived from monocytes. I' When hydrocortisone was incubated with peripheral blood mononuclear cells from steroid-responsive asthmatics, leukotriene B, production from calcium ionophore-activated neutrophils primed by the supernatants of thc peripheral blood mononuclear cells was supprcssed. In steroid-resistant asthmatics no suppression was ob-
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served. The authors suggest that a monocyte-derived factor in steroid-resistant asthmatics enhances the pro-inflammatory potential of infiltrating neutrophils despite the presence of inhibitory concentrations of glucocorticoids. Later in 1991, Lane and Lee characterized the glucocorticoid receptor of monocytes in steroid-resistant asthmatics. l 7 No significant difference in the binding affinity or receptor number was observed in monocytes from steroid-resistant and steroid-responsive asthmatics. In fact, the receptor characteristics from these asthmatics were similar to those previously reported for normal individuals. This suggests that the glucocorticoid receptor, at least in monocytes, does not play a role and that intracellular events may be more important in the mechanism of steroid resistance. Corrigan and colleagues followed with two reports characterizing the T cells of steroid-resistant asthmatics in 1991.".Ix In the first report,9 it was demonstrated that phytohemagglutinin-induced proliferation of peripheral blood T cells was inhibited by dexamethasone in steroidresponsive asthmatics, but not in steroid-resistant asthmatics. The steroid resistance observed could not be accounted for by differences in plasma prednisolone clearance or peripheral blood mononuclear cell glucocorticoid receptors, although a reduced receptor binding affinity (higher Kd value) was found in the steroid-resistant asthmatics (Fig. 3). This report suggests that lymphocyte insensitivity to glucocorticoids contributes to steroid resistance. In their second report, I' Corrigan and colleagues demonstrated an increased expression of activation molecules 1L-2R and HLA-DR on T cells of steroid-resistant asth-
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matics, with no differences in phenotypic markers. It was also shown that dexamethasone inhibits phytohemagglutinin-induced lymphocyte proliferation and IL-2 and interferon-? production in cells from steroid-responsive asthmatics and not in cells from steroid-resistant asthmatics (Fig. 4). Interestingly, cyclosporin A inhibited proliferation and cytokine production in lymphocytes from both steroid-resistant and steroid-responsive asthmatics. These data support the concept that ongoing or persistent T cell activation may be a mechanism for steroid resistance, and that cyclosporin A may be of therapeutic benefit in asthmatics exhibiting unresponsiveness to glucocorticoid therapy. Similar results were recently reported by Alvarez and colleagues. l o Steroid-resistant asthmatics demonstrated no abnormalities in plasma glucocorticoid clearance and their lymphocytes showed a reduced inhibition of phytohemagglutinin-induced proliferation when incubated with methylprednisolone. Also, when co-incubated with troleandomycin, a macrolide antibiotic that inhibits methylprednisolone but not prednisolone metabolism,"' proliferation was reduced in a dose-dependent fashion in lymphocytes from both steroid-resistant and steroid-responsive asthmatics. Further inhibition was observed when methylprednisolone was added to the cultures (Fig. 5). This suggests that troleandomycin has some immunomodulatory properties of its own and that steroid resistance is a reversible phenomenon. Sher and colleagues recently reported an abnormality of glucocorticoid receptor binding and increased activation markers in steroid-resistant asthmatics."' Steroidresistant asthmatics had a higher percentage of activated T cells in both peripheral blood and bronchoalveolar lavage fluid, which persisted despite a course of high-dose glucocorticoid therapy. It was also demonstrated that there was a lower nuclear glucocorticoid receptor binding affinity in steroid-resistant asthmatics, as compared to normals and steroid-responsive asthmatics. These data support the hypothesis that steroid resistance is associated with persistent inflammation. The mechanisms of the abnormal glucocorticoid receptor was studied by Kam and colleagues." These investigators demonstrated that the abnormalities observed in steroid resistance can be induced in peripheral blood mononuclear cells from normal donors by co-incubation with IL-2 and IL-4. Furthermore, these changes were prevented by addition of interferon-?. This suggests that TH2cells, the predominant T lymphocyte subpopulation in the bronchoalveolar lavage fluid of atopic asthmatics reported by Robinson and colleagues,'* may play a role in the pathogenesis of steroidresistance in asthma. Lane and colleagues'" and Vecchiarelli and coworke r ~ simultaneously * ~ reported the effects of glucocorticoid treatment on the lipopolysaccharide-induced secretion of IL-l and tumor necrosis factor (TNF) by
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peripheral blood monocytes from steroid-resistant and steriod-responsive asthmatics. The first group reported no change in cytokine production between the two groups of asthmatics when cells were cultured with and without varying concentrations of hydrocortisone and dexamethasone. The second publication also demonstrated no difference in 1L-1 production before and after systemic glucocorticoid treatment. However, TNF production was significantly reduced after treatment in the steroid-responsive asthmatics and was unchanged in the steroidresistant ones (Fig. 6). This study suggests that the inflammatory mediator TNF may play an important role in steroid-resistant asthma. These inimunologic characteristics of steroid-resistant asthma shed light on its possible etiologies. Thus far. the cells implicated in having an abnormal response to glucocorticoids in steroid-resistant asthma include monocytes.
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esophageal reflux, vocal cord dysfunction, congcstive heart failure, anatomic abnormalities and foreign bodies, immunodeficiency, interstitial lung disease, bronchopul150 monary dysplasia, bronchiolitis obliterans, allergic bronchopulmonary aspergillosis, and pulmonary hemosiderosis (Table 1). Other factors that need consideration are poor compliance with the medical regimen including patient technique with metered-dose inhalers, drug interactions with glucocorticoids, abnormal absorption or elimination of glucocorticoids, food sensitivity, environmental factors (i.e., allergens and other triggers), and psychosocial factors. While these should be part of any complete asthma heroid-responsive steroid-resistant ' work-up, they are especially important in the evaluation Fig. 6. LPSinduced production of tumor necrosis factor (TNF) of the severe asthmatic. by monocytes from steroid-resistant and steroid-responsive Poor absorption or rapid elimination can be detected by asthmatics. Open bars indicate before glucocorticoid therapy performing detailed pharmcokinetic studies ." If abnorand solid bars indicate after glucocorticoid therapy. There is a statistically significant difference between before and after malities are detected, manipulation of the dosing regimen glucocorticoid therapy for steroid-responsive asthmatics (either timing of the dose, split dosing regimens, or an (P = 0.031) and between steroid-responsive and steroid-resis- alternative glucocorticoid) can be made to promote a tant asthmatics after glucocorticoid therapy (P = 0.035). (Reprinted from Vecchiarelli et al., ref. 24), with permission from response to glucocorticoid therapy. Only after these abnormalities are ruled out should alternative therapies be Blackwell Scientific Publishers, Ltd.) considered. While never specifically studied in steroidresistant asthmatics, these alternatives include troleandoneutrophils, and lymphocytes. The most recent research mycin, methotrexate, gold, intravenous gamma globulin, has focused on lymphocytes, with persistent activation hydroxychloroquine, dapsone, cyclosporin A, and interdespite glucocorticoid therapy, as being the current hy- feron-y." The choice of such alternatives should be pothesis for the etiology of steroid-resistant a~thma.'-"'~'~ based on the risk-versus-benefit ratio, cost, and perhaps Specific cellular mechanisms, however, remain poorly the patient's history of response. understood. Nevertheless, a number of interventions can be made to facilitate a response to glucocorticoid therapy. SUMMARY
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CLINICAL CONSIDERATIONS
Obviously, the evaluation of an apparently steroidresistant asthmatic should include confirmation of the diagnosis of asthma and identification of any contributing factors. A number of diagnoses, some unresponsive to glucocorticoid therapy, may present as asthma or may contribute to its severity. These include sinusitis, gastroTABLE 1-Factors
While much information has recently been obtained regarding the features of steroid-resistant asthma, it continues to be a dilemma for practitioners, and investigation into its mechanisms will remain an important part of asthma research. Until a clear marker defining steroidresistant asthmatics is found, the principle first put forth by Carmichael and colleagues" should be adhered to: that is, asthmatics resistant to glucocorticoid therapy need to
in the Evaluation of Steroid-Resistant Asthma
Differential diagnosis Sinusitis Gastroesophagedl reflux Vocal cord dysfunction Congestive heart failure Anatomic abnormalities Foreign bodics Immunodeficiency Interstitial lung disease Bronchopulmonary dysplasia Bronchiolitis obliterans Allergic bronchopulmonary aspergillosis Pulmonarv hemosiderosis
Patient factors Poor compliance Drug interactions with glucocorticoids Abnormal absorption or elimination of glucocorticoids Food sensitivity Environmental factors ( i . e . , allergens, smoke, danders. and other triggers) Psychosocial factors
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be identified at an early stage so that unnecessary and perhaps harmful therapy can be discontinued. A 10 day course of high-dose (230 mg/day) systemic glucocorticoid therapy, as suggested by Kamada and colleagues," may constitute an adequate trial and may sufficiently identify asthmatics who may require alternative treatments. A more rational approach to the selection of alternative asthma treatments will be gained when the mechanisms of steroid resistance are identified. REFERENCES 1. Asthma-United States, 198C-1987. MMWR 1990: 39:49-497. 2. Barnes PJ. A new approch to the treatment of asthma. N Engl J Med. 1989; 312:1517-1527. 3. Expert Panel Report, National Heart, Lung, and Blood Institute, National Asthma Mucation Program. Guidelines lor the diagnosis and treatment of asthma. J Allergy Clin lmmunol. I99 I ; 88:425534. 4. Schwartz HJ. Lowell FC, Melby JC. Steroid resistance in bronchial asthma. Ann Intern Med. 1968; 69:493499. 5. Turner-Warwick M.On observing patterns of airflow obstruction in chronic asthma. Br J Dis Chest. 1977; 71:73-86. 6. Carmichael J, Paterson IC. Diaz P, Cromptom GK, Kay AB, Grant IWB. Corticostcroid resistance in chronic asthma. Br Med J. 1981; 282:1419-)-1422. 7. Liifdahl C-G, Mellstrand T, Svedmyr N. Glucocorticoids and asthma. Studics of resistance and systemic effects of glucocorticoids. Eur J Respir Dis. 1984; 65(Suppl 136):69-77. 8. Grandordy B, Belmatoug N, Morclle A. De Lauture D, Marsac J. Effect of betamethasone on airway obstruction and bronchial response to salbutamol in prednisolonc rcsistant asthma. Thorax. 1987; 42:65-7 I . 9. Corrigan CJ. Brown PH, Barnes NC, Szcfler SJ, Tsai J-J. Frew AJ. Kay AB. Glucocorticoid resistance in chronic asthma. Glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitm. Am Rev Respir Dis. 1991; 144:101& 1025. 10. AlvarezJ, Surs W, Lcung DYM, lklC D, Gelfand EW, Szcllcr SJ. Steroid-resistant asthma: Immunologic and pharmacologic features. J Akrgy Clin Inimunol. 1992; 89:714-721. I I . Brown P, Tcclucksingh S , Matusiewicz SP. Grccning AP, Crompton GK, Edwards CR. Cutaneous vasoconstrictor response to glucocorticoids in asthma. Lancet 1992; 337576-580. 12. Kamada A K , Leung DYM, Hill MR, Szefler SJ. Glucocorticoid burst therapy in chronic, severe asthmatic children: The time course of response [abstractl. J Allergy Clin Irnmunol. 1992; 89:366.
13. Kay AB, Diaz P. Carmichael J , Grant IWB. Corticosteroid-resistant chronic asthma and monocyte complement rcccptors. Clin Exp lmniunol 1981; 44:57&580. 14. Poznanzky MC. Gordon ACH. Douglas JG, Krajewski AS, Wyllie AH, Grant IWB. Resistance to niethylprcdnisolone in cultures of blood mononuclcar cells from glucocorticoid-resistantasthmatic patients. Clin Sci. 1984; 67:630-645. 15. Walker KB, Potter JM, Housc AK. lntcrleukin 2 synthesis in the presence of steroids: A model of steroid resistance. Clin Exp lmmunol. 1987; 68:162-167. 16. Wilkinson JR, Crea AEG, Clark TJH, Lcc TH. Identification and characterization of a monocyte-derived neutrophil-activating factor in corticosteroid-resistant bronchial asthma. J Clin Invest. 1989; 84:1930-1941. 17. Lane SJ, Lee TH. Glucocorticoid receptor characteristics in monocytes of patients with corticostcroid-resist;lnt bronchial asthma. A m Rev Respir Dis. IYYI; 143:102&1024. 18. Corrigan CJ, Brown PH, Barnes NC. Tsai J-J. Frew AJ. Kay AB. ncc in chronic asthma. Peripheral blood T and comparison of the T lymphocyte inhibitory effects of glucocorticoids and cyclosporin A. Am Rev Kespir Dis. 1991; 144:1026--1032. 19. Szefler SJ. Ellis EF, Brenner M, Rose JQ. Spcctor SL. Yurchak A , Andrews F, Jusko WJ. Steroid-specific and anticonvulsant aspect of troleandoniycin-steroid therapy. J Allergy Clin [inmunol. 1982; 69:455460. 20. Shcr ER, Surs W, Kam JC, Kamada AK, Harbeck R, Leung DYM, Szefler SJ. Charactcrization of T lymphocytes and glucocorticoid receptors in stcroid resistant asthma [abstract]. J Allergy Clin Imrnunol. 1992: X9:285. 21. Kam JC, Surs W, Trumble A, SLcllcr SJ, h u n g DYM. The combined effects of IL-2 and IL-4 alter the binding affinity of the glucocorticoid receptor [abstract]. J Allergy Clin Imrnunol. 1992; 89:340. 22. Robinson DS, Hamid Q, Ying S, Tsicopoulos A. Barkans J. Bentley AM, Corrigan C, Durham S , Kay AB. Predominant T,,?likc bronchoalveolar lavage T-lymphocyte population in atopic asthma. N Engl J Med 1992; 326:298-304. 23. Lane SJ, Arm JP. Lce TH. Steroids and cytokines in asthma [abstract]. J Allergy Clin lmmunol. 1992; 89: 146. 24. Vecchiarelli A, Siracusa A , Ccnci E. Puliti M, Abbritti G. Effect of corticosteroid treatment o n interleukin- I and tumor nccrosis factor secretion by monocytes from subjects with asthma. Clin Exp Allcrgy. 1992; 22365-370. 25. Hill MR. Szefler SJ. Ball BD, Bartoszek M, Brenner AM. Monitoring glucocorticoid therapy: A pharmacokinetic approach. Clin Pharmacol Ther. 1990;48:39&398. 26. Szefler SJ. Alternative therapy in severe asthma: Rationale and guidclines for applications. In: Middlcton E. Reed CE, Ellis EF. Adkinson NF. Yuninger JW. eds. Update No. I I lor Allergy. Principles and Practice. ed 3. St. Louis: CV Mosby. 1991: 1-14.
State of the Art Review Steroid Resistance in Asthma: Our Current Understanding Alan K. Kamada, Phartm,’ Donald Y.M. Leung, MD, INTRODUCTION
P ~ D , and ~ * ~ Stanley J.
Szefler, MD192’394
Turner-Warwick described a group of asthmatics with clinical characteristics consistent with steroid resistance Asthma has received heightened attention in recent in 1977.s In this report various patterns of airflow obyears due to an increase in its prevalence and apparent struction in chronic asthma were illustrated (Fig. 2). severity. With the recognition of inflammation as a priThey included “brittle” asthma, in which patients were mary contributing mechanism, treatment has been founresponsive to a variety of anti-asthma medications (incused on inhaled anti-inflammatory therapy, specifically cluding high-dose systemic glucocorticoids), and “irrecromolyn sodium and glucocorticoids.’.’ Oral glucocorversible” asthma, in which patients, although partially ticoids are reserved for acute exacerbations and mainteresponsive to bronchodilators, demonstrated a componance therapy for severe While glucocortinent that was persistent and irreversible by systemic glucoids have proved beneficial in the majority of cases of cocorticoid therapy. severe asthma, a subset of patients who fail to demonLater in 198 1, Carmichael and colleagues characterstrate a clinical response to high-dose systemic glucocorized the clinical features of steroid-resistant asthma.6 Steticoid therapy has been recognized. These patients have roid resistance was defined as a failure of forced expirabeen categorized as “steroid-resistant .” The purpose of tory volume in I second (FEV,) to increase by 15% this report is to review the clinical and immunologic during or at the end of a course of prednisolone, 3 2 0 mg characteristic features of steroid-resistant asthmatics, and daily for 7 days. A comparative study population of “steto provide practical recommendations for their manageroid-responsive” asthmatics demonstrated an increase in ment. FEV, by 230% with this treatment. Compared to the steroid-responsive asthmatics, several factors associated CLINICAL AND LABORATORY FEATURES with steroid resistance were recognized, including a more frequent family history of asthma, a longer duration of “Steroid-resistant” asthma was first described in 1968 by Schwartz and colleague^.^ The patients described had a poor clinical response to high-dose systemic glucocorticoid therapy, which was correlated to the eosinopenic From the Ira J . and Jacqueline Neimark Laboratory for Clinical Pharresponse to hydrocortisone. When 40 mg hydrocortisone macology in Pediatrics, Pharmacology Division, ’ and Allergy and was administered intravenously to these steroid-resistant Immunology Division,’ Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine; and Departments of asthmatics, a blunted eosinopenic response was observed Pediatrics3 and Pharmacology? University of Colorado Health Sciafter 2, 4, and 6 hours as compared to unselected asth- ences Center, Dcnver, Colorado. matics (Fig. 1 ). The reduction of peripheral blood eosinophils was 11% after 2 hours, 34%after 4 hours, and 3.6% Received May 7 , 1992; (revision) accepted for publication May 22. after 6 hours when compared to pre-hydrocortisone mea- 1992. surements. In contrast, the percent reduction of circulat- Supported in part by the American College of Clinical Pharmacying eosinophils in the unselected asthmatic controls was Sandoz Pharmaceuticals Research Fellowship in Immunology Thera35%, 77%, and 73%after 2,4, and 6 hours, respectively. peutics (A.K.K.)and National lnbtitutes of Health. Heart, Lung. and Further study demonstrated that accelerated plasma corti- Blood Institutc, grant HL-36577 (D.Y.M.L.,S.J.S.). sol clearance was, at least in part, responsible for the Address correspondence and rcprint requests to Dr. S.J. Szctler. Desteroid resistance observed. Mean plasma cortisol half- partment of Pediatrics (K-926), National Jewish Center for Immunollives were 86 minutes for the steroid-resistant asthmatics ogy and Respiratory Medicine, 1400 Jackson Street, Denver, CO and 128 minutes for the asthmatic controls (P < 0.001). 80206. 0 1992 Wiley-Liss, Inc.
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by skin blanching to increasing concentrations of beclomethasone dipropionate applied to the skin and occluded for 18 hours, the response was significantly lower in the steroid-resistant asthmatics in terms of blanching intensity and percentage of subjects demonstrating a positive response. This study suggests that steroid-resistant asthma is a manifestation of a generalized defect in the ability of tissues to respond to glucocorticoids. Asthmatics demonstrating an apparent steroid resistance are easily identified; however, this usually occurs 2 4 6 only after they fail to respond to a prolonged course of Hours Post-Dose systemic glucocorticoid therapy. These patients often beFig. 1. Percent change in circulating eosinophil counts after 40 come cushingoid in appearance, but have a localized lack mg intravenous hydrocortisone in control and steroid-resistant of response. Thus, steroid-resistant asthmatics may be at asthmatics. Open circles denote control asthmatics and solid risk for the adverse effects of glucocorticoid while receivcircles denote steroid-resistant asthmatics. (Reprinted from Schwartz HJ, et al., ref. 4, with permission from the American ing little therapeutic benefit. A definition of an adequate trial of systemic glucocorticoid therapy was put forth by College of Physicians.) Kamada and colleagues in 1992.'*Of asthmatic children whose morning pre-bronchodilator FEV, was < 70% symptoms, relatively lower morning peak expiratory predicted, 93% demonstrated a 2 15% improvement of flow rates, and increased bronchial hyperresponsiveness. the morning pre-bronchodilator FEV, within 10 days of These factors, however, may be more related to an in- initiating glucocorticoid burst therapy. From this it was creased severity of disease than specifically to steroid concluded that an adequate therapeutic trial was 10 days resistance. More importantly, the investigators recog- of high-dose systemic glucocorticoid administration (2 nized that patients exhibiting a poor response to systemic 15 mg twice daily) and that those asthmatics failing to glucocorticoids need to be identified at an early stage to respond within this time may need to be considered canallow withdrawal of unnecessary therapy and avoid sig- didates for alternative therapies. It remains essential that steroid-resistant asthmatics be nificant glucocorticoid-inducedadverse effects. A review by Lafdahl and colleagues in 1984 high- identified early so that unnecessary glucocorticoid therlighted drug interactions as a possible mechanism for apy can be discontinued, significant adverse effects apparent steroid resistance.' If glucocorticoid clearance avoided, and alternative therapies instituted in a more from the body is enhanced by another medication, the timely manner. However, perhaps more important, is the actual exposure to glucocorticoids is reduced, resulting in elucidation of the mechanisms of steroid-resistant athma. a diminished therapeutic response. In these cases, gluco- This would allow for institution of the appropriate altercorticoid-induced adverse effects would also be unex- native therapy and hopefully interruption of the inflampectedly absent or disproportionate to that expected for a matory process associated with the disease. The followspecific glucocorticoid dose. Supporting this principle is ing is a summary of the immunologic characteristics a report by Grandordy and colleagues demonstrating a associated with steroid-resistant asthma and the cellular greater increase of FEV, in asthmatics when betametha- mechanisms proposed thus far. sone was administered intramuscularly as compared to their response to oral prednisolone.' Complete bioavailIMMUNOLOGIC FEATURES AND ability by the intramuscular route or the longer half-life of POSSIBLE MECHANISMS betamethasone might account for this difference. In later Kay and colleagues reported in 1981 on investigations evaluations of steroid-resistant asthma by Corrigan and colleagues9 and Alvarez and colleagues,'" pharmacoki- related to the monocyte complement receptors and their netic abnormalities were considered and ruled out as eti- enhancement by a monocyte chemotactic factor in steologies for this phenomenon. Subjects underwent de- roid-resistant and steroid-responsive asthmatics.I 3 Monotailed pharmacokinetic studies to confirm that impaired cyte complement receptors and the enhanced rosetting oral absorption or rapid elimination were not contributing (complement receptor enhancement) when incubated to the observed steroid resistance. Thus it appears that a with a chemotactic factor (casein) were reduced in those subset of asthmatics resistant to glucocorticoid therapy patients who later responded to glucocorticoid treatment as compared to the steroid-resistant asthmatics. This sugdoes indeed exist. Brown and colleagues reported an abnormality in the gests that a reduced receptor number and low degree of cutaneous vasoconstrictor response to glucocorticoids in enhancement is a normal glucocorticoid response, and steroid-resistant asthmatics in 199 1 . ' I When evaluated that steroid-resistant asthmatics may have a defect in the
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expression and mobilization of complement receptors on the monocyte cell membrane. In 1984 Poznansky and colleagues reported on the immunophenotype and behavior of mononuclear cells from steroid-resistant asthmatics when incubated with phytohemagglutinin. In steroid-responsive and steroidresistant asthmatics there was no difference in the immunophenotype, specifically the proportion of T cells, T-inducer/CD4+ cells, Ia-positive cells, or cells reacting with the OKMl monocyte monoclonal antibody, nor in the number of cell colonies produced when incubated with phytohemagglutinin. A slightly lower, but not statistically significant, proportion of T-suppressorKD8S cells was found in steroid-resistant asthmatics. When mononuclear cells were co-incubated with methylprednisolone, a lesser degree of inhibition of proliferation was observed in the cells from the steroid-resistant asthmatics. This study demonstrated a functional abnormality, specifically mononuclear cell responsiveness to glucocorticoids, rather than a difference in immunophenotype in steroid-resistant asthma.
An interesting model for steroid resistance in renal transplants was suggested by Walker and colleagues in 1987.I s These investigators measured interleukin-2 (IL-2) synthesis by human lymphocytes in response to phytohemagglutinin in the presence and absence of prednisolone. In the three subjects termed steroid-resistant. a significantly higher IL-2 activity was found in the supernatants of both prednisolone and non-prednisolonetreated lymphocyte cultures. In addition, exogenous IL-2, added to lymphocyte cultures from normal subjects, reduced the suppressive effects of prednisolone, suggesting that a high 1L-2 activity plays a role in steroid resistance. In 1989 Wilkinson and colleagues identified a 3 kDa ncutrophil-activating factor, derived from monocytes. I' When hydrocortisone was incubated with peripheral blood mononuclear cells from steroid-responsive asthmatics, leukotriene B, production from calcium ionophore-activated neutrophils primed by the supernatants of thc peripheral blood mononuclear cells was supprcssed. In steroid-resistant asthmatics no suppression was ob-
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served. The authors suggest that a monocyte-derived factor in steroid-resistant asthmatics enhances the pro-inflammatory potential of infiltrating neutrophils despite the presence of inhibitory concentrations of glucocorticoids. Later in 1991, Lane and Lee characterized the glucocorticoid receptor of monocytes in steroid-resistant asthmatics. l 7 No significant difference in the binding affinity or receptor number was observed in monocytes from steroid-resistant and steroid-responsive asthmatics. In fact, the receptor characteristics from these asthmatics were similar to those previously reported for normal individuals. This suggests that the glucocorticoid receptor, at least in monocytes, does not play a role and that intracellular events may be more important in the mechanism of steroid resistance. Corrigan and colleagues followed with two reports characterizing the T cells of steroid-resistant asthmatics in 1991.".Ix In the first report,9 it was demonstrated that phytohemagglutinin-induced proliferation of peripheral blood T cells was inhibited by dexamethasone in steroidresponsive asthmatics, but not in steroid-resistant asthmatics. The steroid resistance observed could not be accounted for by differences in plasma prednisolone clearance or peripheral blood mononuclear cell glucocorticoid receptors, although a reduced receptor binding affinity (higher Kd value) was found in the steroid-resistant asthmatics (Fig. 3). This report suggests that lymphocyte insensitivity to glucocorticoids contributes to steroid resistance. In their second report, I' Corrigan and colleagues demonstrated an increased expression of activation molecules 1L-2R and HLA-DR on T cells of steroid-resistant asth-
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matics, with no differences in phenotypic markers. It was also shown that dexamethasone inhibits phytohemagglutinin-induced lymphocyte proliferation and IL-2 and interferon-? production in cells from steroid-responsive asthmatics and not in cells from steroid-resistant asthmatics (Fig. 4). Interestingly, cyclosporin A inhibited proliferation and cytokine production in lymphocytes from both steroid-resistant and steroid-responsive asthmatics. These data support the concept that ongoing or persistent T cell activation may be a mechanism for steroid resistance, and that cyclosporin A may be of therapeutic benefit in asthmatics exhibiting unresponsiveness to glucocorticoid therapy. Similar results were recently reported by Alvarez and colleagues. l o Steroid-resistant asthmatics demonstrated no abnormalities in plasma glucocorticoid clearance and their lymphocytes showed a reduced inhibition of phytohemagglutinin-induced proliferation when incubated with methylprednisolone. Also, when co-incubated with troleandomycin, a macrolide antibiotic that inhibits methylprednisolone but not prednisolone metabolism,"' proliferation was reduced in a dose-dependent fashion in lymphocytes from both steroid-resistant and steroid-responsive asthmatics. Further inhibition was observed when methylprednisolone was added to the cultures (Fig. 5). This suggests that troleandomycin has some immunomodulatory properties of its own and that steroid resistance is a reversible phenomenon. Sher and colleagues recently reported an abnormality of glucocorticoid receptor binding and increased activation markers in steroid-resistant asthmatics."' Steroidresistant asthmatics had a higher percentage of activated T cells in both peripheral blood and bronchoalveolar lavage fluid, which persisted despite a course of high-dose glucocorticoid therapy. It was also demonstrated that there was a lower nuclear glucocorticoid receptor binding affinity in steroid-resistant asthmatics, as compared to normals and steroid-responsive asthmatics. These data support the hypothesis that steroid resistance is associated with persistent inflammation. The mechanisms of the abnormal glucocorticoid receptor was studied by Kam and colleagues." These investigators demonstrated that the abnormalities observed in steroid resistance can be induced in peripheral blood mononuclear cells from normal donors by co-incubation with IL-2 and IL-4. Furthermore, these changes were prevented by addition of interferon-?. This suggests that TH2cells, the predominant T lymphocyte subpopulation in the bronchoalveolar lavage fluid of atopic asthmatics reported by Robinson and colleagues,'* may play a role in the pathogenesis of steroidresistance in asthma. Lane and colleagues'" and Vecchiarelli and coworke r ~ simultaneously * ~ reported the effects of glucocorticoid treatment on the lipopolysaccharide-induced secretion of IL-l and tumor necrosis factor (TNF) by
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peripheral blood monocytes from steroid-resistant and steriod-responsive asthmatics. The first group reported no change in cytokine production between the two groups of asthmatics when cells were cultured with and without varying concentrations of hydrocortisone and dexamethasone. The second publication also demonstrated no difference in 1L-1 production before and after systemic glucocorticoid treatment. However, TNF production was significantly reduced after treatment in the steroid-responsive asthmatics and was unchanged in the steroidresistant ones (Fig. 6). This study suggests that the inflammatory mediator TNF may play an important role in steroid-resistant asthma. These inimunologic characteristics of steroid-resistant asthma shed light on its possible etiologies. Thus far. the cells implicated in having an abnormal response to glucocorticoids in steroid-resistant asthma include monocytes.
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esophageal reflux, vocal cord dysfunction, congcstive heart failure, anatomic abnormalities and foreign bodies, immunodeficiency, interstitial lung disease, bronchopul150 monary dysplasia, bronchiolitis obliterans, allergic bronchopulmonary aspergillosis, and pulmonary hemosiderosis (Table 1). Other factors that need consideration are poor compliance with the medical regimen including patient technique with metered-dose inhalers, drug interactions with glucocorticoids, abnormal absorption or elimination of glucocorticoids, food sensitivity, environmental factors (i.e., allergens and other triggers), and psychosocial factors. While these should be part of any complete asthma heroid-responsive steroid-resistant ' work-up, they are especially important in the evaluation Fig. 6. LPSinduced production of tumor necrosis factor (TNF) of the severe asthmatic. by monocytes from steroid-resistant and steroid-responsive Poor absorption or rapid elimination can be detected by asthmatics. Open bars indicate before glucocorticoid therapy performing detailed pharmcokinetic studies ." If abnorand solid bars indicate after glucocorticoid therapy. There is a statistically significant difference between before and after malities are detected, manipulation of the dosing regimen glucocorticoid therapy for steroid-responsive asthmatics (either timing of the dose, split dosing regimens, or an (P = 0.031) and between steroid-responsive and steroid-resis- alternative glucocorticoid) can be made to promote a tant asthmatics after glucocorticoid therapy (P = 0.035). (Reprinted from Vecchiarelli et al., ref. 24), with permission from response to glucocorticoid therapy. Only after these abnormalities are ruled out should alternative therapies be Blackwell Scientific Publishers, Ltd.) considered. While never specifically studied in steroidresistant asthmatics, these alternatives include troleandoneutrophils, and lymphocytes. The most recent research mycin, methotrexate, gold, intravenous gamma globulin, has focused on lymphocytes, with persistent activation hydroxychloroquine, dapsone, cyclosporin A, and interdespite glucocorticoid therapy, as being the current hy- feron-y." The choice of such alternatives should be pothesis for the etiology of steroid-resistant a~thma.'-"'~'~ based on the risk-versus-benefit ratio, cost, and perhaps Specific cellular mechanisms, however, remain poorly the patient's history of response. understood. Nevertheless, a number of interventions can be made to facilitate a response to glucocorticoid therapy. SUMMARY
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Obviously, the evaluation of an apparently steroidresistant asthmatic should include confirmation of the diagnosis of asthma and identification of any contributing factors. A number of diagnoses, some unresponsive to glucocorticoid therapy, may present as asthma or may contribute to its severity. These include sinusitis, gastroTABLE 1-Factors
While much information has recently been obtained regarding the features of steroid-resistant asthma, it continues to be a dilemma for practitioners, and investigation into its mechanisms will remain an important part of asthma research. Until a clear marker defining steroidresistant asthmatics is found, the principle first put forth by Carmichael and colleagues" should be adhered to: that is, asthmatics resistant to glucocorticoid therapy need to
in the Evaluation of Steroid-Resistant Asthma
Differential diagnosis Sinusitis Gastroesophagedl reflux Vocal cord dysfunction Congestive heart failure Anatomic abnormalities Foreign bodics Immunodeficiency Interstitial lung disease Bronchopulmonary dysplasia Bronchiolitis obliterans Allergic bronchopulmonary aspergillosis Pulmonarv hemosiderosis
Patient factors Poor compliance Drug interactions with glucocorticoids Abnormal absorption or elimination of glucocorticoids Food sensitivity Environmental factors ( i . e . , allergens, smoke, danders. and other triggers) Psychosocial factors
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be identified at an early stage so that unnecessary and perhaps harmful therapy can be discontinued. A 10 day course of high-dose (230 mg/day) systemic glucocorticoid therapy, as suggested by Kamada and colleagues," may constitute an adequate trial and may sufficiently identify asthmatics who may require alternative treatments. A more rational approach to the selection of alternative asthma treatments will be gained when the mechanisms of steroid resistance are identified. REFERENCES 1. Asthma-United States, 198C-1987. MMWR 1990: 39:49-497. 2. Barnes PJ. A new approch to the treatment of asthma. N Engl J Med. 1989; 312:1517-1527. 3. Expert Panel Report, National Heart, Lung, and Blood Institute, National Asthma Mucation Program. Guidelines lor the diagnosis and treatment of asthma. J Allergy Clin lmmunol. I99 I ; 88:425534. 4. Schwartz HJ. Lowell FC, Melby JC. Steroid resistance in bronchial asthma. Ann Intern Med. 1968; 69:493499. 5. Turner-Warwick M.On observing patterns of airflow obstruction in chronic asthma. Br J Dis Chest. 1977; 71:73-86. 6. Carmichael J, Paterson IC. Diaz P, Cromptom GK, Kay AB, Grant IWB. Corticostcroid resistance in chronic asthma. Br Med J. 1981; 282:1419-)-1422. 7. Liifdahl C-G, Mellstrand T, Svedmyr N. Glucocorticoids and asthma. Studics of resistance and systemic effects of glucocorticoids. Eur J Respir Dis. 1984; 65(Suppl 136):69-77. 8. Grandordy B, Belmatoug N, Morclle A. De Lauture D, Marsac J. Effect of betamethasone on airway obstruction and bronchial response to salbutamol in prednisolonc rcsistant asthma. Thorax. 1987; 42:65-7 I . 9. Corrigan CJ. Brown PH, Barnes NC, Szcfler SJ, Tsai J-J. Frew AJ. Kay AB. Glucocorticoid resistance in chronic asthma. Glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitm. Am Rev Respir Dis. 1991; 144:101& 1025. 10. AlvarezJ, Surs W, Lcung DYM, lklC D, Gelfand EW, Szcllcr SJ. Steroid-resistant asthma: Immunologic and pharmacologic features. J Akrgy Clin Inimunol. 1992; 89:714-721. I I . Brown P, Tcclucksingh S , Matusiewicz SP. Grccning AP, Crompton GK, Edwards CR. Cutaneous vasoconstrictor response to glucocorticoids in asthma. Lancet 1992; 337576-580. 12. Kamada A K , Leung DYM, Hill MR, Szefler SJ. Glucocorticoid burst therapy in chronic, severe asthmatic children: The time course of response [abstractl. J Allergy Clin Irnmunol. 1992; 89:366.
13. Kay AB, Diaz P. Carmichael J , Grant IWB. Corticosteroid-resistant chronic asthma and monocyte complement rcccptors. Clin Exp lmniunol 1981; 44:57&580. 14. Poznanzky MC. Gordon ACH. Douglas JG, Krajewski AS, Wyllie AH, Grant IWB. Resistance to niethylprcdnisolone in cultures of blood mononuclcar cells from glucocorticoid-resistantasthmatic patients. Clin Sci. 1984; 67:630-645. 15. Walker KB, Potter JM, Housc AK. lntcrleukin 2 synthesis in the presence of steroids: A model of steroid resistance. Clin Exp lmmunol. 1987; 68:162-167. 16. Wilkinson JR, Crea AEG, Clark TJH, Lcc TH. Identification and characterization of a monocyte-derived neutrophil-activating factor in corticosteroid-resistant bronchial asthma. J Clin Invest. 1989; 84:1930-1941. 17. Lane SJ, Lee TH. Glucocorticoid receptor characteristics in monocytes of patients with corticostcroid-resist;lnt bronchial asthma. A m Rev Respir Dis. IYYI; 143:102&1024. 18. Corrigan CJ, Brown PH, Barnes NC. Tsai J-J. Frew AJ. Kay AB. ncc in chronic asthma. Peripheral blood T and comparison of the T lymphocyte inhibitory effects of glucocorticoids and cyclosporin A. Am Rev Kespir Dis. 1991; 144:1026--1032. 19. Szefler SJ. Ellis EF, Brenner M, Rose JQ. Spcctor SL. Yurchak A , Andrews F, Jusko WJ. Steroid-specific and anticonvulsant aspect of troleandoniycin-steroid therapy. J Allergy Clin [inmunol. 1982; 69:455460. 20. Shcr ER, Surs W, Kam JC, Kamada AK, Harbeck R, Leung DYM, Szefler SJ. Charactcrization of T lymphocytes and glucocorticoid receptors in stcroid resistant asthma [abstract]. J Allergy Clin Imrnunol. 1992: X9:285. 21. Kam JC, Surs W, Trumble A, SLcllcr SJ, h u n g DYM. The combined effects of IL-2 and IL-4 alter the binding affinity of the glucocorticoid receptor [abstract]. J Allergy Clin Imrnunol. 1992; 89:340. 22. Robinson DS, Hamid Q, Ying S, Tsicopoulos A. Barkans J. Bentley AM, Corrigan C, Durham S , Kay AB. Predominant T,,?likc bronchoalveolar lavage T-lymphocyte population in atopic asthma. N Engl J Med 1992; 326:298-304. 23. Lane SJ, Arm JP. Lce TH. Steroids and cytokines in asthma [abstract]. J Allergy Clin lmmunol. 1992; 89: 146. 24. Vecchiarelli A, Siracusa A , Ccnci E. Puliti M, Abbritti G. Effect of corticosteroid treatment o n interleukin- I and tumor nccrosis factor secretion by monocytes from subjects with asthma. Clin Exp Allcrgy. 1992; 22365-370. 25. Hill MR. Szefler SJ. Ball BD, Bartoszek M, Brenner AM. Monitoring glucocorticoid therapy: A pharmacokinetic approach. Clin Pharmacol Ther. 1990;48:39&398. 26. Szefler SJ. Alternative therapy in severe asthma: Rationale and guidclines for applications. In: Middlcton E. Reed CE, Ellis EF. Adkinson NF. Yuninger JW. eds. Update No. I I lor Allergy. Principles and Practice. ed 3. St. Louis: CV Mosby. 1991: 1-14.
