Safety and clinical activity of atezolizumab plus erlotinib in patients with non-small-cell lung cancer.

BACKGROUND: Acquired resistance limits long-term epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) efficacy in patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) in whom anti-programmed death-ligand 1 (PD-L1) efficacy is also limited. We hypothesized that combining atezolizumab with erlotinib could enhance antitumor immunity and extend efficacy in these patients. PATIENTS AND METHODS: This open-label phase Ib trial was conducted in adults aged ≥18 years who had advanced, unresectable NSCLC. Stage 1 (safety evaluation) enrolled EGFR TKI-naive patients regardless of EGFR status. Stage 2 (expansion) enrolled patients with EGFR-mutant NSCLC treated with ≤1 prior non-EGFR TKI therapy. Patients received 150 mg erlotinib orally once daily. After a 7-day erlotinib run-in, atezolizumab 1200 mg was administered intravenously every 3 weeks. The primary endpoint was the safety and tolerability of the combination in all patients; secondary endpoints included antitumor activity per RECIST 1.1 in stage 2 patients. RESULTS: At the data cut-off on 7 May 2020, 28 patients (8 in stage 1, 20 in stage 2) were assessable for safety. No dose-limiting toxicities or grade 4 or 5 treatment-related adverse events occurred. Grade 3 treatment-related adverse events occurred in 46% of patients; the most common were increased alanine aminotransferase, diarrhea, pyrexia, and rash (each in 7% of patients). Serious adverse events occurred in 50% of patients. Pneumonitis (grade 1) was reported in a single patient (4%). The objective response rate was 75% [95% confidence interval (CI) 50.9% to 91.3%]), median response duration was 18.9 months (95% CI 9.5-40.5 months), median progression-free survival was 15.4 months (95% CI 8.4-39.0 months), and median overall survival was not estimable (NE) (95% CI 34.6-NE). CONCLUSIONS: Atezolizumab combined with erlotinib demonstrated a tolerable safety profile and encouraging, durable clinical activity in patients with advanced EGFR mutation-positive NSCLC.

Lung transplant acceptance is facilitated by early events in the graft and is associated with lymphoid neogenesis.

Early immune responses are important in shaping long-term outcomes of human lung transplants. To examine the role of early immune responses in lung rejection and acceptance, we developed a method to retransplant mouse lungs. Retransplantation into T-cell-deficient hosts showed that for lungs and hearts alloimmune responses occurring within 72 h of transplantation are reversible. In contrast to hearts, a 72-h period of immunosuppression with costimulation blockade in primary allogeneic recipients suffices to prevent rejection of lungs upon retransplantation into untreated allogeneic hosts. Long-term lung acceptance is associated with induction of bronchus-associated lymphoid tissue, where Foxp3(+) cells accumulate and recipient T cells interact with CD11c(+) dendritic cells. Acceptance of retransplanted lung allografts is abrogated by treatment of immunosuppressed primary recipients with anti-CD25 antibodies. Thus, events contributing to lung transplant acceptance are established early in the graft and induction of bronchus-associated lymphoid tissue can be associated with an immune quiescent state.

Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial.

CONTEXT: Inhaled long-acting beta(2)-agonists improve asthma control when added to inhaled corticosteroid (ICS) therapy. OBJECTIVE: To determine whether ICS therapy can be reduced or eliminated in patients with persistent asthma after adding a long-acting beta(2)-agonist to their treatment regimen. DESIGN AND SETTING: A 24-week randomized, controlled, blinded, double-dummy, parallel-group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 through January 1999. PARTICIPANTS: One hundred seventy-five patients aged 12 through 65 years with persistent asthma that was suboptimally controlled during a 6-week run-in period of treatment with inhaled triamcinolone acetonide (400 microg twice per day). INTERVENTION: Patients continued triamcinolone therapy and were randomly assigned to receive add-on therapy with either placebo (placebo-minus group, n = 21) or salmeterol xinafoate, 42 microg twice per day (n = 154) for 2 weeks. The entire placebo-minus group was assigned and half of the salmeterol group (salmeterol-minus group) was randomly assigned to reduce by 50% (for 8 weeks) then eliminate (for 8 weeks) triamcinolone treatment. The other half of the salmeterol group (salmeterol-plus group) was randomly assigned to continue both salmeterol and triamcinolone for the remaining 16 weeks (active control group). MAIN OUTCOME MEASURE: Time to asthma treatment failure in patients receiving salmeterol. RESULTS: Treatment failure occurred in 8.3% (95% confidence interval [CI], 2%-15%) of the salmeterol-minus group 8 weeks after triamcinolone treatment was reduced compared with 2.8% (95% CI, 0%-7%) of the salmeterol-plus group during the same period. Treatment failure occurred in 46.3% (95% CI, 34%-59%) of the salmeterol-minus group 8 weeks after triamcinolone therapy was eliminated compared with 13.7% (95% CI, 5%-22%) of the salmeterol-plus group. The relative risk (95% CI) of treatment failure at the end of the triamcinolone elimination phase in the salmeterol-minus group was 4.3 (2.0-9.2) compared with the salmeterol-plus group (P<.001). CONCLUSIONS: Our results indicate that in patients with persistent asthma suboptimally controlled by triamcinolone therapy alone but whose asthma symptoms improve after addition of salmeterol, a substantial reduction (50%) in triamcinolone dose can occur without a significant loss of asthma control. However, total elimination of triamcinolone therapy results in a significant deterioration in asthma control and, therefore, cannot be recommended.

Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial.

CONTEXT: Long-acting beta(2)-agonists are prescribed for patients with persistent asthma and are sometimes used without inhaled corticosteroids (ICSs). No evidence exists, however, to support their use as monotherapy in adults with persistent asthma. OBJECTIVE: To examine the effectiveness of salmeterol xinafoate, a long-acting beta(2)-agonist, as replacement therapy in patients whose asthma is well controlled by low-dose triamcinolone acetonide, an ICS. DESIGN AND SETTING: A 28-week, randomized, blinded, placebo-controlled, parallel group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 to January 1999. PARTICIPANTS: One hundred sixty-four patients aged 12 through 65 years with persistent asthma that was well controlled during a 6-week run-in period of treatment with inhaled triamcinolone (400 microg twice per day). INTERVENTIONS: Patients were randomly assigned to continue triamcinolone therapy (400 microg twice per day; n = 54) or switch to salmeterol (42 microg twice per day; n = 54) or to placebo (n = 56) for 16 weeks, after which all patients received placebo for an additional 6-week run-out period. MAIN OUTCOME MEASURES: Change in morning and evening peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV(1)), self-assessed asthma symptom scores, rescue albuterol use, asthma-specific quality-of-life scores, treatment failure, asthma exacerbation, bronchial reactivity, and markers of airway inflammation, compared among the 3 treatment groups. RESULTS: During the 16-week randomized treatment period, no significant differences between the salmeterol and triamcinolone groups were observed for conventional outcomes of clinical studies of asthma therapy-morning PEF, evening PEF, asthma symptom scores, rescue albuterol sulfate use, or quality of life. Both active treatments were superior to placebo. However, the salmeterol group had more treatment failures than the triamcinolone group (13/54 [24%] vs 3/54 [6%]; P =.004), as well as more asthma exacerbations (11/54 [20%] vs 4/54 [7%]; P =.04), greater increases in median (interquartile range) sputum eosinophils (2.4% [0.0% to 10.6%] vs -0.1% [-0.7% to 0.3%]; P<.001), eosinophil cationic protein (71 [-2 to 430] U/L vs -4 [-31 to 56] U/L; P =.005), and tryptase (3.1 [2.1 to 7.6] ng/mL vs 0.0 [0.0 to 0.7] ng/mL; P<.001). The duration of benefit when patients were switched from active treatment to placebo after 22 weeks of randomized treatment was not significantly longer in the triamcinolone group than in the salmeterol group. CONCLUSIONS: Patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control.

Clarithromycin potentiates glucocorticoid responsiveness in patients with asthma: results of a pilot study.

BACKGROUND: Selected macrolide antibiotics have steroid-sparing effects in patients with steroid-dependent asthma. In addition to inhibiting methylprednisolone clearance, macrolides may also display anti-inflammatory effects. OBJECTIVE: To determine whether clarithromycin, by virtue of its anti-inflammatory effects, enhances glucocorticoid sensitivity. DESIGN: Open-label, pilot study in a paired design (pre- and posttreatment). PARTICIPANTS: Seven patients, mean age 27 (range 15 to 42 years), with mild to moderate asthma under good control. METHODS: Clarithromycin (500 mg) was administered twice daily for 10 days with blood drawn for lymphocyte stimulation assays at baseline, and again upon completion of therapy. Lymphocytes were stimulated with phytohemagglutinin in the presence and absence of increasing concentrations of clarithromycin and dexamethasone (DEX). RESULTS: At baseline, clarithromycin alone did not cause a significant degree of suppression of T-lymphocyte activation, yet clarithromycin significantly enhanced the sensitivity of lymphocytes to suppression by DEX as measured by a shift in the DEX dose-response curve by at least 6-fold (P = 0.04). In addition, a 10-day course of clarithromycin resulted in: 1) a significant decrease in the inhibitory concentration which results in a 50% reduction in proliferation for DEX alone, thereby increasing glucocorticoid sensitivity (P = 0.04); 2) heightened inhibitory effect of clarithromycin alone (P = 0.03); and 3) a sustained suppressive effect with the combination of clarithromycin and DEX on the inhibition of lymphocyte stimulation (P = 0.01). CONCLUSIONS: Clarithromycin acts synergistically with DEX in suppressing lymphocyte activation. In addition, a 10-day course resulted in a significant treatment effect as evidenced by lower inhibitory concentration which results in a 50% reduction in proliferation value for DEX, a heightened response to clarithromycin alone, and a consistent degree of suppression of lymphocyte stimulation when clarithromycin and DEX were used together.

Risk factors associated with glucocorticoid-induced adverse effects in children with severe asthma.

BACKGROUND: Although high-dose inhaled glucocorticoids (GCs) with or without chronically administered oral GCs are often used in children with severe persistent asthma, the adverse effects associated with their use have not been well-described in this patient population. OBJECTIVE: We sought to determine the GC-induced adverse effects profile of older children with severe persistent asthma. METHODS: A chart review of 163 consecutive children 9 years of age or older admitted to National Jewish for difficult to control asthma was done. RESULTS: The population studied consisted mostly of adolescents (mean +/- SD age, 14.4 +/- 2.1 years) with severe asthma receiving high-dose inhaled GC therapy (1675 +/- 94 microg/d) and averaging 6 systemic GC bursts per year. 50% required chronic oral GC therapy. GC-associated adverse effects were common and included hypertension (88%), cushingoid features (66%), adrenal suppression (56%), myopathy (50%), osteopenia (46%), growth suppression (39%), obesity and hypercholesterolemia (30%), and cataracts (14%). Height standard deviation scores of -0.44, -1.22, and -0.93 for those receiving intermittent, alternate day, and daily oral GCs, respectively, were smaller (less suppressed) than published values from the same institution before inhaled GC therapy (standard deviation scores of -1.26, -1.91, and -1.95, respectively). Osteopenia was strongly associated with growth suppression (odds ratio, 5.6; confidence interval, 2.7-11.8; P <.0001) and was found to be more common in female than male subjects, even after correcting for short stature (42% vs 18%, P <.006). CONCLUSIONS: GC-associated adverse effects are still unacceptably common among children with severe asthma, even in those not receiving chronically administered oral GC therapy yet receiving high-dose inhaled GCs. Therefore close monitoring and proper intervention are warranted, especially in female subjects, who appear to be at greater risk for osteopenia. There is clearly a need to consider alternative therapy or earlier intervention. The magnitude of growth suppression, while still a problem, appeared to be less severe with the addition of inhaled GC therapy. This observation suggests that high-dose inhaled GC therapy, by affording better asthma control and allowing less use of systemic therapy, has attenuated the growth-suppressive effects of poorly controlled asthma.

Clinical outcomes of steroid-insensitive asthma.

BACKGROUND: Steroid insensitivity increasingly is being recognized in patients with severe, chronic asthma. Virtually no data exist regarding the clinical outcomes of steroid insensitive (SI) asthma despite clear expectations of poorer longitudinal course for this condition. METHODS: We obtained 2-year follow-up data from 34 pediatric patients who had been evaluated for steroid insensitivity at a national asthma referral center. Outcomes evaluated included current oral glucocorticoid (GC) dose; number of GC bursts, emergency room visits, and hospitalizations for asthma in the prior 12 months; Asthma Functional Severity; Pediatric Asthma Quality of Life; and Pediatric Asthma Caregiver's Quality of Life. RESULTS: At follow-up, patients with SI asthma and their caregiving parent both reported poorer quality of life (QOL) compared with those with steroid sensitive (SS) asthma (adolescent: 4.6 +/- 0.4 versus 5.6 +/- 0.3; P < .05; caregiver: 5.1 +/- 0.4 versus 6.2 +/- 0.2; P < .05). Steroid-insensitive patients showed no significant difference in GC dose, number of GC bursts, emergency room visits or hospitalizations, or Asthma Functional Severity compared with SS patients. CONCLUSIONS: Steroid insensitivity was associated with significantly poorer QOL at 2-year follow-up. Steroid insensitive patients did not show poorer clinical outcomes compared with SS patients as assessed by current steroid requirements and health care utilization. Overall, the observed pattern of results suggests that SI asthma may be a worse form of asthma because a more fixed pattern of lung obstruction has developed. Further longitudinal study of the clinical and cellular outcomes of SI asthma is needed to more fully characterize the types and magnitude of risks associated with SI status.

Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy.

BACKGROUND: Macrolide antibiotics have long been used as steroid-sparing agents in patients with severe steroid-dependent asthma. Their efficacy and their propensity to potentiate glucocorticoid adverse effects have been attributed in part to their ability to delay glucocorticoid clearance. OBJECTIVE: We sought to determine whether clarithromycin, a newer macrolide antibiotic, can alter the pharmacokinetic profile of oral glucocorticoids and thereby increase the risk of steroid-induced adverse effects. METHODS: An open-label study in a paired design (before and after treatment) was conducted in a hospital-based outpatient clinic. Participants were 6 adult patients (mean age, 30 years) with mild-to-moderate asthma. Prednisone (40 mg/1.73 m2) and methylprednisolone (40 mg/1.73 m2) were given as single randomized doses on consecutive study days before and on days 8 and 9 of a clarithromycin (500 mg twice daily) course. Twelve-hour pharmacokinetic profiles with measurement of plasma methylprednisolone and prednisolone levels were taken before and after clarithromycin therapy. RESULTS: Clarithromycin therapy resulted in a 65% reduction of methylprednisolone clearance and significantly higher mean plasma methylprednisolone concentrations compared with preclarithromycin concentrations but had no significant effect on prednisolone clearance or mean prednisolone plasma concentrations. CONCLUSIONS: Clinicians must be aware of potential drug interactions that could place patients at increased risk for steroid-induced adverse effects. Such an effect has been demonstrated between clarithromycin and methylprednisolone, two drugs that may be administered concomitantly in asthma. To avoid potential steroid-enhancing effects, prednisone should be substituted for methylprednisolone during prolonged courses of clarithromycin therapy.

Immunologic basis and management of steroid-resistant asthma.

Although the majority of patients with asthma respond favorably to inhaled and systemic glucocorticoids, up to 25% of patients with difficult-to-control asthma have poor clinical responses to high doses of systemic glucocorticoids. Early identification of these patients is required to minimize serious side effects from long-term systemic glucocorticoid therapy in patients who are insensitive to such therapy. Recent studies indicate that these individuals have developed diminished glucocorticoid receptor ligand and DNA binding affinity as the result of poorly controlled immune activation potentially triggered by allergens or infection. The current review will examine the immune mechanisms underlying glucocorticoid resistance and discuss the management of this challenging group of patients.

Mechanisms of glucocorticoid reduction in asthmatic subjects treated with intravenous immunoglobulin.

BACKGROUND: Intravenous immunoglobulin (IVIG) has been used as an oral glucocorticoid (GC)-sparing agent in patients with steroid-dependent asthma. Despite its use, little is known regarding its mechanism of action. OBJECTIVE: We sought to determine whether the GC-sparing effects of IVIG in severe asthma are related to improved GC receptor (GCR)-binding affinity and subsequent enhanced GC sensitivity. METHODS: In an open-label study, 11 steroid-dependent asthmatic subjects (6 GC-insensitive, 5 GC-sensitive) received monthly infusions of IVIG (2 g/kg) for 6 months. Peak expiratory flow rates and oral GC dose were recorded daily, and spirometry was performed monthly. Blood was drawn for lymphocyte stimulation assays and GCR assays at baseline and after 3 and 6 months of therapy. Lymphocytes were stimulated ex vivo with PHA in the presence and absence of IVIG and increasing concentrations of dexamethasone (DEX). RESULTS: IVIG resulted in significant reductions in oral GC dose (P <.02), number of GC bursts (P =.033), and hospitalizations (P =.001) after 6 months of IVIG. Those with GC-insensitive asthma responded equally well to IVIG as those with GC-sensitive asthma. Associated with the improved clinical efficacy, IVIG acted synergistically with DEX in suppressing lymphocyte activation as measured by a shift in the DEX dose-response curve by 1 log-fold (P =.03). IVIG therapy was also associated with significantly improved GCR-binding affinity (P =.01). CONCLUSIONS: IVIG resulted in significant reductions in oral GC requirements and hospitalizations in a group of patients with severe asthma, with IVIG being as effective in patients with GC-insensitive asthma as in patients with GC-sensitive asthma. IVIG therapy acted synergistically with DEX in suppressing lymphocyte activation and significantly improved GCR-binding affinity after 3 and 6 months of therapy.

Fluticasone propionate results in improved glucocorticoid receptor binding affinity and reduced oral glucocorticoid requirements in severe asthma.

BACKGROUND: Inhaled glucocorticoids (iGC) have become important first line agents in the management of moderate-to-severe asthma. Severe asthma is associated with reduced glucocorticoid receptor (GCR) binding affinity. METHODS: To evaluate the potential impact of inhaled fluticasone propionate on markers of airway inflammation [GCR binding affinity (Kd) and eosinophil cationic protein (ECP)] and oral GC requirements in steroid-dependent asthmatics, we examined the effects of fluticasone propionate (FP) 500 microg or 1000 microg BID and placebo in a double-blind, randomized study of 13 steroid-dependent asthmatics at a single center. Glucocorticoid receptor binding affinity and ECP values were obtained at baseline, 4, 6, 26, and 52 weeks after patients were enrolled into the study. Oral GC dose and FEV1 values were also recorded at each visit. RESULTS: Inhaled FP resulted in large reductions in oral GC requirement by 6 weeks of therapy while no reduction was seen in the placebo group. All patients in the FP 2000 microg/d group who continued double-blind therapy at 52 weeks were able to eliminate oral prednisone use. In contrast, every patient in the placebo group had to be withdrawn from the study due to poor asthma control. Associated with the oral GC dose reduction on high dose FP therapy, were improvements in GCR binding affinity with the GCR Kd falling from 42.5 nM at baseline to 19.5 nM at 6 weeks (P=.08). The GCR KD values remained stable thereafter with values of 23.5 nM at 26 weeks (P=.02) and 19.5 nM at 52 weeks (P=.01). In addition, high dose FP therapy resulted in reductions in serum ECP values. CONCLUSION: This study suggests that high dose FP therapy results in significant oral GC sparing effects associated with improved GCR binding affinity and reductions in serum ECP levels in patients with steroid-dependent asthma.

Difficult-to-control asthma: clinical characteristics of steroid-insensitive asthma.

BACKGROUND: Although widely used, little is known regarding the patterns of response that subjects with severe asthma exhibit to oral glucocorticoid (GC) therapy. METHODS: We retrospectively reviewed the charts of 164 consecutive adolescents admitted to the National Jewish Medical and Research Center for difficult-to-control asthma. Data collected included medical history, pulmonary function measures by plethysmography, methacholine challenge results, AM cortisol levels, serum IgE, total eosinophil counts (TEC), serum eosinophil cationic protein (ECP), soluble IL-2 receptor (sIL-2R), and spirometry. RESULTS: Eighty-seven patients (53%) required a GC burst during the hospitalization secondary to poor asthma control. Those requiring a GC burst had a significantly longer history of asthma, a greater degree of bronchial hyperresponsiveness, and lower pulmonary function. Twenty-one patients (24%) failed to respond with a greater than 15% improvement in their AM prebronchodilator FEV1 after the GC burst and were termed steroid insensitive (SI). Although those with SI asthma had a similar duration of asthma, they required oral GC therapy at a younger age, required a larger maintenance oral GC dose on admission, and were more likely to be African-American, compared with those with steroid-sensitive asthma. Furthermore, two distinct spirometry patterns were noted among the SI asthmatic subjects: "chaotic" and "nonchaotic." Patients with the chaotic pattern were characterized by a significant degree of variability (greater than 30%) in daily pulmonary function, whereas those with nonchaotic, SI asthma were characterized by less than 15% variability in daily lung function. Those with nonchaotic SI were diagnosed with asthma and treated with oral GCs at a later age. CONCLUSIONS: This retrospective study suggests that SI asthma is quite common (25%) among adolescents with severe asthma evaluated at a national referral center. In addition, two distinct patterns of SI asthma have been identified that may constitute different pathophysiologic processes. Finally, the overrepresentation of African-Americans in the SI group supports the need for further epidemiologic studies investigating the prevalence of SI asthma and the impact early asthma intervention may have on this severe form of asthma.

Allergen exposure decreases glucocorticoid receptor binding affinity and steroid responsiveness in atopic asthmatics.

Allergen exposure can confound the management of asthma. To understand the potential mechanisms by which allergens increase the steroid requirements in atopic asthmatics, we examined the effects of allergens on glucocorticoid receptor (GCR) binding affinity and glucocorticoid (GC) responsiveness of peripheral blood mononuclear cells (PBMC) from atopic asthmatics. A significant reduction (p < 0.001) in the GCR binding affinity (Kd) was observed in ragweed-allergic asthmatics during ragweed pollen season compared with PBMC obtained before and after ragweed season. In vitro effects of allergen on PBMC GCR Kd were also examined by incubating PBMC from atopic asthmatics with allergen (ragweed and cat) versus Candida albicans. GCR binding affinity was significantly reduced after incubation with ragweed (p < 0.001) or cat allergen (p < 0.001) compared with baseline or C. albicans stimulation. This effect was limited to atopic asthmatics in that in vitro cat allergen incubation for 48 h failed to significantly alter GCR binding affinity in nonasthmatic, atopic individuals. These allergen-induced reductions in GCR binding affinity also rendered the PBMC less sensitive to the inhibitory effects of hydrocortisone and dexamethasone on allergen-induced proliferation (p < 0.01). To test the hypothesis that allergen-induced alterations in GCR binding affinity were cytokine-induced, we examined the effects of interleukin-2 (IL-2)and IL-4 neutralization using anticytokine antibodies. Addition of both anti-lL-2 and anti-lL-4 antibodies resulted in a significant (p < 0.001) inhibition of allergen-induced alterations in GCR binding affinity. Furthermore incubation with cat allergen induced significantly higher concentrations of IL-2 (p = 0.03) and IL-4 (p = 0.02) by PBMC from atopic as compared with nonatopic subjects. Our current observations suggest that allergen exposure may contribute to poor asthma control by reducing GCR binding affinity in mononuclear cells. This appears to be mediated through IL-2 and IL-4. These findings may have important implications for novel approaches to the treatment of poorly controlled asthma.

New insights into the pathogenesis and management of steroid-resistant asthma.

A population of difficult-to-control asthmatics exists who, despite high-dose daily GC therapy, continue to display evidence for active disease. This group has been termed steroid resistant since they fail to adequately respond to aggressive courses of high-dose oral and inhaled GC therapy. Persistent immune activation and airway inflammation which to varying degrees is resistant to GC therapy appears to define the immunological abnormality underlying SR asthma. Recent studies utilizing molecular biological techniques have identified both ligand- and DNA-binding defects that could possibly account for steroid resistance at a molecular level. The evaluation of the SR asthmatic must be comprehensive in its scope as several confounding factors can contribute to this symptom complex. Among others, these include poor compliance, improper medication technique, inadequate anti-inflammatory therapy, unrecognized contributing diseases, incorrect diagnoses, environmental factors, and psychosocial disturbances. The management of the SR asthmatic is challenging, and every attempt should be made to maximize conventional therapy in these patients prior to embarking on alternative therapies as all of the alternative anti-inflammatory/immunomodulatory modalities are associated with significant toxicity or cost. Second-generation inhaled GC therapy, methotrexate, cyclosporine, IVIG, and leukotriene antagonists are potential alternative therapies, and although they remain viable options, they have been used in small numbers, and for short periods of time, and fail to result in long-term remissions. Although much insight into the pathogenesis of SR asthma has been gained, several issues remain unresolved. Ongoing airway inflammation is thought to contribute to steroid resistance, but at present, we have no standard method of determining the degree of inflammation. The incorporation of bronchoscopy with transbronchial biopsy has the potential to provide the greatest amount of information regarding the presence or absence of ongoing airway inflammation, but the invasive nature of the procedure precludes its use in pediatric patients and the most severe adult asthmatics. Large multicenter, placebo-controlled studies evaluating the available alternative therapies that incorporate markers of airway inflammation are needed, as are studies that evaluate these therapies over longer periods of time. It is hoped that by better understanding the mechanisms involved and the natural history of the SR asthmatic, specific treatment modalities will be developed for this challenging group of severe asthmatics.

Effects of glucocorticoids on lymphocyte activation in patients with steroid-sensitive and steroid-resistant asthma.

BACKGROUND: Glucocorticoids are important medications used to control the airway inflammation associated with asthma. Synthetic glucocorticoids vary in their binding affinity for the glucocorticoid receptor (GCR). METHODS: We compared hydrocortisone, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, and budesonide with regard to their capacity to inhibit phytohemagglutinin-induced peripheral blood mononuclear cell proliferation from six patients with steroid-sensitive asthma and seven patients with steroid-resistant asthma. Peripheral blood mononuclear cell GCR binding affinities for dexamethasone and budesonide were also determined for both patient groups by using a radioligand binding assay and Scatchard analysis. RESULTS: Dose-dependent inhibition was demonstrated for all glucocorticoids in both patient groups, with the steroid-resistant group requiring approximately 2 log-fold more glucocorticoids for an equivalent degree of inhibition. The mean concentrations necessary to cause 50% inhibition of lymphocyte proliferation (IC50s) for the steroid-sensitive group ranged from 2 x 10(-10) mol/L for budesonide to 7 x 10(-8) mol/L for hydrocortisone, whereas the mean IC50s for the steroid-resistant group ranged from approximately 2 x 10(-8) mol/L for budesonide to greater than 10(-6) mol/L for hydrocortisone. In addition, a significant correlation was noted between the degree of inhibition of lymphocyte proliferation (IC50) and the binding affinity of dexamethasone to the GCR. Patients with steroid-resistant asthma have been shown to have a reduced GCR binding affinity. The GCR binding affinity for budesonide was significantly higher in both groups (i.e., lower dissociation constant) than that obtained for dexamethasone. CONCLUSION: These data suggest that glucocorticoids such as budesonide, by virtue of their high GCR binding affinities and greater ability to suppress lymphocyte proliferation, may therefore be beneficial in the management of difficult-to-control asthma.

The etiology and control of bronchial hyperresponsiveness in children.

Bronchial hyperresponsiveness (BHR) describes the exaggerated bronchoconstrictor response to a host of stimuli such as cold air or exercise that occurs in most patients with asthma. It is an important feature of asthma because BHR correlates with diurnal peak expiratory flow variation, bronchospasm following exercise, the need for asthma medications, and asthma severity. Many studies published in the past year have increased our understanding of BHR. First, epidemiologic studies have revealed BHR to be a risk factor for the subsequent development of asthma. BHR is also more common in children than adults, and the persistence of BHR is related to atopy. Second, genetic and pathophysiologic studies have improved our understanding of the etiology of BHR. The genetic basis for BHR, atopy, and asthma was further elucidated with the finding of a cluster of potential candidate genes for asthma susceptibility on chromosome 5. In addition, eosinophilic infiltration and basement membrane thickening of the airways, both characteristic findings noted in patients with asthma, were found to correlate with pulmonary function and degree of BHR. Lastly, studies on treatment of BHR confirmed the beneficial effects of inhaled glucocorticoid therapy and allergen avoidance on BHR in children with asthma. In addition, a new type of asthma medication, the leukotriene inhibitors, has been shown to decrease BHR in adults with asthma and may eventually prove to be an effective medication for children with chronic asthma.

Steroid-resistant asthma: evaluation and management.

LEARNING OBJECTIVES: Reading this article will reinforce the reader's knowledge of the definition, pathophysiology, differential diagnosis, and treatment of the steroid-resistant asthmatic patient. DATA SOURCES: Prospective and retrospective data from the authors' experience were evaluated. In addition, a Medline database was searched from 1981, using the key words "asthma," "glucocorticoids," and "glucocorticoid resistance" with the restrictions of English language and human subjects. Relevant articles referenced in retrieved sources and current texts on severe asthma were also utilized. STUDY SELECTION: Data source abstracts, pertinent articles, and book chapters meeting the objectives were critically reviewed. RESULTS: Although rare, individuals with steroid-resistant asthma are often the most difficult-to-manage asthmatic patients in that they have severe disease yet fail to respond to glucocorticoids. To make the diagnosis of steroid-resistant asthma, the patient must fail to respond to a 7 to 14-day course of daily prednisone as measured by less than a 15% improvement in morning prebronchodilator FEV1 following the glucocorticoid course. Ongoing inflammation is thought to play a major role in the pathogenesis of steroid-resistant asthma, and recent studies have demonstrated diminished glucocorticoid receptor to glucocorticoid, or diminished glucocorticoid receptor to DNA binding as possible mechanisms for diminished glucocorticoid responsiveness. Alternative asthma therapies such as methotrexate, cyclosporine, and intravenous gammaglobulin are often used in this group of asthmatic patients. CONCLUSIONS: The patient with steroid-resistant asthma presents several challenges. These individuals often display many of the sequelae of long-term systemic glucocorticoid use while achieving little therapeutic benefit. Prior to making the diagnosis of steroid-resistant asthma, diseases that can contribute to poor control of asthma must be ruled out, and noncompliance issues addressed. Alternative asthma therapies are often used; however, they also carry the potential for adverse effects, and have not been thoroughly studied in this population of asthmatic patients.

The role of glucocorticoids in the management of asthma.

Glucocorticoids (GCs) are a highly effective class of medication used in the treatment of airway inflammation associated with chronic asthma. Nevertheless, there remain concerns regarding potential adverse effects accompanying the use of systemic and high-dose inhaled GC therapy. Recent studies also suggest that there is high variability in airway response to GCs. Indeed, the immunopathogenesis of a subset of asthmatics poorly responsive to glucocorticoid therapy have been studied and may provide new insights into mechanisms by which glucocorticoids act in chronic asthma. The current review will examine a number of these issues, particularly mechanisms by which GCs act in asthma, the immunology of steroid resistance, and adverse effects associated with GC treatment.