Joseph D. Spahn

Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy

Methylprednisolone elimination is reduced in the presence of treatment with troleandomycin (TAO), a macrolide antibiotic. To assess whether a similar interaction occurs with a more commonly used and less hepatotoxic macrolide antibiotic, erythromycin, we evaluated methylprednisolone pharmacokinetics before and after a 1 wk course of erythromycin base in nine adolescent patients with chronic asthma. These data were compared to results of studies of the troleandomycin methylprednisolone interaction evaluated in 10 adolescent asthmatic patients. Methylprednisolone clearance and apparent volume of distribution were significantly decreased and mean residence time and half-life significantly increased in the presence of both erythromycin and troleandomycin. The latter caused greater inhibition of methylprednisolone elimination. A nonlinear pattern of methylprednisolone disposition was observed in the presence of concomitant macrolide antibiotic administration. Addition of erythromycin base to methylprednisolone therapy results in inhibition of methylprednisolone elimination and may potentially increase the beneficial and adverse effects of this corticosteroid.

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.

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.

Predictors of remitting, periodic, and persistent childhood asthma

BACKGROUND The course of mild to moderate persistent asthma in children is not clearly established. OBJECTIVE To determine the rate and predictors for remitting, periodic, and persistent asthma in adolescence. METHODS The Childhood Asthma Management Program (CAMP) was a 4.3-year randomized, double-masked, multicenter trial in children with mild to moderate persistent asthma that compared continuous therapy with either budesonide or nedocromil, each to placebo, followed by a 4-year observational follow-up period. Asthma activity during the observation period included remitting (no asthma activity in the last year), persistent (asthma activity in every quarter), and periodic asthma (neither remitting nor persistent). RESULTS Asthma was identified as remitting in 6%, periodic in 39%, and persistent in 55% of the 909 participants, with no effect noted from earlier anti-inflammatory treatment during the CAMP trial. Within all 3 asthma activity categories, improvements in airway hyperresponsiveness, eosinophilia, and asthma morbidity were observed over time. Features at entry into CAMP associated with remitting versus persistent asthma were lack of allergen sensitization and exposure to indoor allergens (odds ratio [OR], 3.23; P < .001), milder asthma (OR, 2.01; P = .03), older age (OR, 1.23; P = .01), less airway hyperresponsiveness (higher log methacholine FEV(1) PC(20) (OR, 1.39; P = .03), higher prebronchodilator FEV(1) percent predicted (OR, 1.05; P = .02), and lower forced vital capacity percent predicted (OR, 0.96; P = .04). CONCLUSION Remission of asthma in adolescence is infrequent and not affected by 4 years of anti-inflammatory controller therapy. Factors such as sensitization and exposure, low lung function, and airway greater hyperresponsiveness decrease the likelihood of remitting asthma.

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.

The Influence of Variation in Type and Pattern of Symptoms on Assessment in Pediatric Asthma

OBJECTIVE. We conducted a national, population-based survey to examine the asthma-related health burden of US children. METHODS. A telephone-based survey was conducted in 2004 of children 4 to 18 years of age with current asthma in the United States. In 41433 households screened, 1089 children reported current asthma; 801 interviews were completed by parents of children aged 4 to 15 years and by children themselves aged 16 to 18 years. The survey included questions about symptoms, perceived level of control, activity limitations, health care use, medicines, disease management, and knowledge. Global asthma symptom burden, derived from the National Asthma Education and Prevention Program guidelines, was composed of 3 components: short-term symptom burden (4-week recall), long-term symptom burden (past year), and functional impact (activity limitation). RESULTS. The majority of children were classified with mild intermittent disease on the basis of recent daytime symptoms alone (80%); yet, when report of nighttime symptoms was included, the proportion of children classified as having mild intermittent symptoms decreased (74%). When asthma burden was assessed on the basis of the global symptom burden construct, only a minority (13%) of individuals was classified as having an asthma symptom burden consistent with mild intermittent disease; the majority (62%) was classified as having moderate/severe disease. In addition, the impact of asthma on the daily activities is substantial; avoiding exertion (47%) and staying inside (34%) are common approaches to improve control of asthma symptoms. CONCLUSIONS. The goals of therapy for asthma, based on the National Asthma Education and Prevention Program guidelines, have not been achieved for the majority of children. In addition, parents and children overestimate the childs asthma control and commonly restrict activities to control asthma symptoms. Deficiencies in the control of asthma may be related to the underestimation of the burden of disease.

Effect of montelukast on peripheral airflow obstruction in children with asthma

BACKGROUND Montelukast is a widely used controller agent in childhood asthma. It is modestly effective in reducing symptoms, decreasing the need for rescue albuterol, and improving forced expiratory volume in 1 second (FEV1). OBJECTIVE To determine whether montelukast therapy improves peripheral airway obstruction as measured by lung volumes, air trapping, airway resistance (Raw), and specific conductance (Sgaw). METHODS Twenty-one children aged 9 to 18 years with mild-to-moderate asthma were randomized into a double-blind, placebo-controlled study to receive montelukast (5 or 10 mg) or matching placebo daily for 8 weeks. Symptoms and albuterol use were recorded twice daily, and exhaled nitric oxide measurement, forced oscillometry, spirometry, and body box plethysmography (before and after beta-agonist use) were performed at randomization and at 2, 4, 6, and 8 weeks. Circulating eosinophil counts and serum eosinophil cationic protein (ECP) levels were obtained at randomization and at 8 weeks. RESULTS Montelukast-treated patients had lower residual volume (P = .05), residual volume-total lung capacity ratio (P = .04), Raw (P = .02), Sgaw (P = .03), and serum ECP levels (P = .02) at 8 weeks compared with those treated with placebo. There was a trend toward reduced daytime and nighttime albuterol use, although the difference did not reach statistical significance. There were no significant differences in FEV1, FEV1-forced vital capacity ratio, exhaled nitric oxide levels, or daytime and nighttime symptom scores between the 2 groups. CONCLUSIONS Montelukast therapy was associated with less air trapping, hyperinflation, and Raw and better Sgaw compared with placebo. Lower serum ECP levels, a surrogate measure of airway inflammation, were associated with improvements in lung function.

Clinical assessment of asthma progression in children and adults

Asthma is a heterogeneous disorder with a variable course, characterized by episodes of cough, wheezing and shortness of breath, reversible airflow limitation, and bronchial hyperresponsiveness. It begins early in life in many subjects with intermittent symptoms occurring with viral respiratory tract infections. Over time, and in genetically susceptible children (those with an atopic predisposition), the disease becomes more persistent with symptoms occurring in the absence of respiratory tract infections. Children with persistent wheezing are eventually diagnosed with asthma, with those at greatest risk having developed allergic sensitization early in life. Among children with asthma, some will have lifelong asthma with active symptoms and progressive loss of lung function over time, whereas other children will undergo asthma remission in adolescence. Once in remission, the disease may remain quiescent, or it may relapse in midadult life. This review focuses on studies that have enhanced our understanding of the progression of asthma from infancy to adulthood. Studies evaluating progressive loss of lung function, the best-studied measure of asthma progression, are also reviewed, followed by a brief discussion of whether asthma progression can be modified by inhaled glucocorticoid therapy.

Identifying the components of asthma health status in children with mild to moderate asthma.

BACKGROUND Weak and inconsistent correlations between measurements of asthma health status suggest that the disease is composed of nonoverlapping components. OBJECTIVE Factor analysis was used to explore the relationships between measures of asthma morbidity and to identify heterogeneous components of asthma health status in children 5 to 12 years old. Results were compared across time (baseline and 48-month visit) and treatment arms. METHODS Analyses were conducted in 7 different study windows in a database from a large clinical trial of children with mild to moderate asthma (n = 1041). Measurements of lung function, symptoms, and health care utilization from daily diary cards, serum IgE levels, total eosinophil count, skin test positivity, and airway hyperresponsiveness were included. Data on fractional exhaled nitric oxide and sputum eosinophil cationic protein were included in a subgroup of patients. RESULTS In each of the study windows, factor analysis identified 5 factors that explained between 50% and 60% of the common variance. Factors identified included (1) inflammatory markers, (2) symptoms/medication use, (3) asthma exacerbations, and measures of lung function, which subdivided into (4) FEV(1) and forced vital capacity, and (5) bronchodilator response and the FEV(1)/forced vital capacity ratio. Exploratory analyses suggest that fractional exhaled nitric oxide account for the atopy/inflammatory marker factor, and sputum measurements account for a sixth, separate factor. CONCLUSION The consistent identification of a 5-factor structure across time and treatment arms suggests that each of these factors provides independent information in the assessment of asthma.

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.