0
Clinical Investigations: Miscellaneous |

Racial Differences in T-Lymphocyte Response to Glucocorticoids* FREE TO VIEW

Monica J. Federico, MD; Ronina A. Covar, MD; Eleanor E. Brown, BS; Donald Y. M. Leung, MD; Joseph D. Spahn, MD
Author and Funding Information

*From the Divisions of Pediatric Pulmonary Medicine and Pediatric Allergy & Immunology, National Jewish Medical & Research Center, and Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Ronina A. Covar, MD, National Jewish Medical & Research Center, 1400 Jackson St J316, Denver, CO 80206; e-mail covarr@njc.org



Chest. 2005;127(2):571-578. doi:10.1378/chest.127.2.571
Text Size: A A A
Published online

Background: Asthma morbidity and mortality is increased in blacks.

Objective: The primary objective of this cross-sectional study was to determine if blacks, asthmatic or nonasthmatic, displayed diminished T-lymphocyte response to glucocorticoids in vitro compared to their white counterparts. If differences were noted, this would suggest a racial predisposition to decreased glucocorticoid responsiveness among blacks.

Methods: Asthmatic (n = 395, 27% blacks) and control (n = 202, 52% blacks) subjects recruited from National Jewish Medical and Research Center and from the surrounding community participated in the study. In vitro glucocorticoid responsiveness was determined by assessing the log-transformed concentration of dexamethasone required to suppress phytohemagglutinin-induced T-lymphocyte proliferation by 50% (log10 IC50). Asthma medication history, atopic status, and spirometric lung function measures corrected for race were collected.

Results: Black and white asthmatic subjects had similar FEV1 percentage of predicted values and inhaled and oral glucocorticoid requirements. Black asthmatic subjects displayed significantly diminished glucocorticoid responsiveness compared to white asthmatic subjects, as follows: median (first, third quartile) log10 IC50 values of 1.00 nmol (0.48, 1.83) vs 0.78 nmol (0.29, 1.45) [p = 0.028]. Similar results were found between black and white control subjects, as follows: median, 1.26 nmol (0.70, 2.14) vs 0.95 nmol (0.55, 1.48) [p = 0.01]. Age, race, and basal T-lymphocyte activity were significantly positively correlated to the log10 IC50 values.

Conclusion: Our observation that black asthmatic subjects and non-asthmatic control subjects require greater concentrations of glucocorticoid in vitro to suppress T-lymphocyte activation suggests that blacks have a racial predisposition to diminished glucocorticoid responsiveness, which may contribute to their heightened asthma morbidity.

Figures in this Article

Although the prevalence of asthma appears to have stabilized in the past few years, morbidity and mortality continue to increase, especially among blacks. In the United States, asthma mortality and the rate of hospitalization for asthma are approximately four times greater for black children compared to white children.1The striking discrepancy in disease morbidity and mortality in blacks persists after controlling for known risk factors such as socioeconomic level, access to care, and urban living.23 Grant et al2showed race to be an independent factor in asthma mortality after controlling for socioeconomic status and educational level. Joseph et al3 minimized the impact of socioeconomic factors on disease severity by studying differences in middle-class children living in suburban Detroit. They found that black children had lower FEV1 values, elevated serum IgE levels, and increased airway reactivity compared to white children. The authors postulated that black children are predisposed to asthma and to heightened asthma severity.

Airway inflammation plays a critical role in the pathogenesis of asthma. Hence, glucocorticoids are considered to be the most effective asthma controller therapy to date. However, not all subjects will display a favorable response to glucocorticoid treatment. Szefler et al4reported that nearly 30% of adults with moderate persistent asthma failed to show an improvement in FEV1 despite increasing doses of inhaled glucocorticoids. Similar findings were reported by Chan et al,5 who found approximately 25% of children with difficult-to-control asthma referred to the National Jewish Medical and Research Center failed to display a favorable response to systemic glucocorticoid therapy and were termed glucocorticoid resistant (ie, failure to improve their baseline morning FEV1 values by > 15% of predicted after at least 1 week of prednisone therapy, 20 mg bid).

T lymphocytes play a pivotal role in both atopic and nonatopic asthma through the production of proinflammatory cytokines, exerting fundamental effects in the inflammatory process.67 Poor clinical response to glucocorticoids has been associated with underlying immune mechanisms involving T lymphocytes. For instance, several studies810 have found T lymphocytes from glucocorticoid-resistant patients to require higher concentrations of glucocorticoids to suppress in vitro proliferation compared to the lymphocytes of glucocorticoid-sensitive patients. Leung et al11 found glucocorticoid-resistant asthmatic subjects to have greater numbers of BAL cells expressing interleukin (IL)-2 and IL-4 messenger RNA compared with glucocorticoid-sensitive asthmatic patients. In addition, a 1-week course of prednisone failed to reduce IL-4 and IL-5 messenger RNA expression among the glucocorticoid-resistant asthmatic patients. In contrast, a significant reduction in cytokine expression was noted among the glucocorticoid-sensitive subjects. These studies suggest an inherent difference in the T-lymphocyte response between glucocorticoid-sensitive and glucocorticoid-resistant patients with asthma.

This cross-sectional study sought to evaluate whether blacks have a racial predisposition to diminished glucocorticoid response. The second aim was to explore the relationship between glucocorticoid response and clinical features such as age, asthma duration, age at asthma diagnosis, lung function, and glucocorticoid requirement.

Self-identified black and non-Hispanic white asthmatic patients and nonasthmatic control subjects 5 to 65 years of age were recruited from the Denver metropolitan area and from the National Jewish Medical and Research Center over 5 years. Patients (local and out-of state) included those who had been referred to the Clinical Pharmacology Service, which performs the clinical glucocorticoid lymphocyte stimulation (GCLS) assay for evaluation of steroid response. Fifty-seven percent of asthmatic subjects (of whom 22% were black) came from this data set. The other patients were recruited from the outpatient clinics and metropolitan Denver using advertisements through fliers and posters. The race was obtained from the subject and/or parent’s response to questions asking in which racial group(s) he/she would be classified. A subject was classified as black if he/she has origins in any of the black racial groups in Africa and/or at least one parent was identified as black or African American. Terms such as Haitian or Negro can be used in addition to black or African American. White subjects are those having origins in any of the original peoples of Europe, the Middle East, or North Africa. Subjects themselves or those whose parents are either Hispanic (ie, a person of Mexican, Puerto Rican, Cuban, South or Central American, or other Spanish culture or origin), Asian (ie, a person having origins in the Far East, Southeast Asia, or the Indian subcontinent), or American Indian (ie, a person having origins in any of the original peoples of North, Central, or South America, who maintains tribal affiliation or community attachment) but not black were not enrolled in the study.

Asthmatic patients were included based on a history of physician-diagnosed asthma and a history of asthma medication use (β-agonist or inhaled glucocorticoids). The control group included patients with no established diagnosis of asthma by history or report. Exclusion criteria included other racial groups, a history of smoking within the last 5 years or > 5 pack-years, pregnancy, or a history of chronic lung disease. Patients and/or their guardians signed informed consents that were approved by the National Jewish Medical and Research Center Institutional Review Board. Asthma history (ie, asthma duration, age at asthma diagnosis, current inhaled and oral steroid, other asthma medications, and history of hospitalization and intubation) was obtained, and a physical examination was performed for these subjects.

Spirometry was performed (Jaeger Master Screen, MS Pneumo; Erich Jaeger GmbH; Hoechberg, Germany) with predicted values from the National Health and Examination Survey III study12 of > 7,000 children and adults. The predicted values were corrected for age, race, height, and gender. Skin-prick testing was performed using a standard panel of indoor and local outdoor allergens including cat, dog, dust mites, cockroach, Alternaria, Cladosporium, Bermuda grass, KY blue/June grass mix, tree mix, and weed mix, with histamine and saline solution controls (Bayer/Hollister; Spokane, WA; and Greer Laboratories; Lenoir, NC). Subjects were asked to withhold all antihistamines for 1 week prior to their scheduled visit. A positive skin-prick test result was read as any wheal > 3 mm larger than the negative control. Atopy was defined as positive skin test reactivity to at least one allergen.

The GCLS assay was performed after heparinized blood was obtained and before the patients’ morning dose of glucocorticoids. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation and suspended in RPMI/10% fetal calf serum at a density of 106/mL. The PBMCs were then incubated with phytohemagglutinin (PHA) [Sigma; St. Louis, MO] at a final concentration of 5 μg/mL and increasing concentrations of dexamethasone (10−10 to 10−6 mol/L) for 72 h at 37°C in 5% CO2. Six hours before harvesting, the PBMCs were transferred to 96-well plates and pulse labeled with [3H]-thymidine at a final concentration of 1 μCi per well. The cells were then harvested, counted in a β-scintillation counter, and the results expressed as counts per minute (cpm) [3H]-thymidine incorporation. To quantitate glucocorticoid responsiveness, the means of the triplicate counts were determined including positive (PHA alone) and negative (no PHA, no glucocorticoid) control wells. The higher the log10 nanomolar concentration of dexamethasone required to suppress PHA-induced lymphocyte proliferation by 50% (log10 IC50) value, the more insensitive the lymphocytes are to dexamethasone. In addition, the percentage of inhibition at the maximum concentration (10−6 mol/L) of dexamethasone (Imax) and serial determinations of the percentage inhibition of lymphocyte proliferation at each dexamethasone concentration were evaluated (ie, high Imax values suggest greater sensitivity). The intraassay and interassay variations of the log10 IC50 are low (coefficient of variation, 2.9% and 2.4%, mean [± SD], − 8.67 ± 0.26 mol/L and − 7.48 ± 0.18 mol/L, respectively). The intraassay and interassay variations of Imax were slightly higher (coefficient of variation, 3.9% and 3.6%, respectively; mean, 73.9 ± 2.9% and 94.4 ± 3.4%, respectively).13

Data Analysis

Comparisons between the racial groups and associations between variables were assessed using the χ2 test and Wilcoxon rank-sum test. Data are expressed as median (first, third quartiles), unless otherwise specified; p values are two sided and considered to be significant if < 0.05. The correlation of various continuous variables to the log10 IC50 values was determined using the Spearman rank correlation. The influence of several variables, namely age, presence of asthma, unstimulated and PHA-stimulated T-lymphocyte counts, race, gender, inhaled and oral glucocorticoid doses, and FEV1 percentage of predicted on the T-lymphocyte response to dexamethasone, was evaluated using stepwise backward regression (with a p value < 0.05 used to leave the model).

To confirm our results based on differences in age between black and white asthmatics, a match-paired t test analysis was performed. For each black asthmatic, a white asthmatic was matched for age within a year. In addition, to ensure match in asthma severity, the FEV1 percentage of predicted values had to fall within 5% of each other. Only black asthmatics with corresponding white asthmatics matched for age and FEV1 percentage of predicted were included in the analysis. Analyses were performed using statistical software (JMP version 5.0; SAS Institute; Cary, NC).

Patient Characteristics

A total of 597 subjects (395 asthmatic subjects) were enrolled in the study (Table 1 ). Blacks comprised 27% and 52%, respectively, of the asthmatic and nonasthmatic control subjects. The black and white control subjects were older, less atopic, and had higher FEV1 percentage of predicted values compared to their asthmatic counterparts (Table 1). Among blacks, a third of the control group and half of the asthmatic subjects were male (p = 0.03). There were no differences in gender distribution, age, atopic status, and FEV1 percentage of predicted between black and white control subjects.

Black asthmatic subjects were significantly younger than the white asthmatic subjects, as follows: median age, 14.0 years (first quartile, 10.0 years; third quartile, 22.5 years) vs 17.5 years (first quartile, 13.0 years; third quartile, 38.0 years; p < 0.0001. In addition, black asthmatic subjects were younger at the time of asthma diagnosis (Table 1). Both black and white asthmatic subjects had evidence for moderate airflow limitation based on their median FEV1 values (70% predicted [first quartile, 58.5% predicted; third quartile, 80.2% predicted] vs 80.2% predicted [first quartile, 62.0% predicted; third quartile, 95.0% predicted; p = 0.1], respectively), despite receiving treatment with moderate-to-high doses of inhaled glucocorticoids (median, 840.0 μg [first quartile, 0 μg; third quartile, 1,320.0 μg] vs 880 μg [first quartile, 88.0 μg; third quartile, 1,600.0 μg; p = 0.24], respectively. Nineteen percent of black asthmatic subjects and 35% of white asthmatic subjects required long-term oral glucocorticoid therapy (median dose, 30.0 mg/d [first quartile, 16.2 mg/d; third quartile, 40.0 mg/d] vs 40.0 mg/d [first quartile, 20.0 mg/d; third quartile, 50.0 mg/d; p = 0.36], respectively).

GCLS Assay

Asthmatic subjects had lower log10 IC50 values (median, 0.84 nmol; first quartile, 0.35 nmol; third quartile, 1.49 nmol) than control subjects (median, 1.09 nmol; first quartile, 0.65 nmol; third quartile, 1.69 nmol; p = 0.0001), and asthmatic subjects had higher Imax values (median, 89.2%; first quartile, 73.1%; third quartile, 96.0%) than control subjects (median, 76.2%; first quartile, 55.6%; third quartile, 91.5%; p < 0.0001). There were no racial differences in basal activity (asthmatic subjects: black, 756.0 cpm [first quartile, 404.5 cpm; third quartile, 1,060.5 cpm] vs white, 678.0 cpm [first quartile, 355.0 cpm; third quartile, 1,199.0 cpm; p = 0.5]; control subjects: black, 792.5 cpm [first quartile, 513.2 cpm; third quartile, 1,187.5 cpm] vs white, 1,072.0 cpm [first quartile, 606.0 cpm; third quartile, 1,622.0 cpm; p = 0.051]) and in magnitude of proliferative response to PHA (asthmatic subjects: black, 33,311.0 cpm [first quartile, 19,842.5 cpm; third quartile, 46,546.8 cpm] vs white, 35,085.0 cpm [first quartile, 20,878.0 cpm; third quartile, 52,669.5 cpm; p = 0.36]; control subjects: black, 35,070.5 cpm [first quartile, 24,830.0 cpm; third quartile, 57,533.2 cpm] vs white, 39,562.5 cpm [first quartile, 29,164.2 cpm; third quartile, 54,956.2 cpm; p = 0.7]). Significant differences in the response to glucocorticoids, as measured by dexamethasone log10 IC50 values (black asthmatic subjects: median, 1.10 nmol; first quartile, 0.60 nmol; third quartile, 1.96 nmol; vs white asthmatic subjects: median, 0.85 nmol; first quartile, 0.36 nmol; third quartile, 1.45 nmol; p < 0.0001) and Imax values (black asthmatic subjects: median, 78.8%; first quartile, 58.2%; third quartile, 92.1%; vs white asthmatic subjects, 90.2%; first quartile, 73.5%; third quartile, 96.1%; p < 0.0001) were seen, regardless of disease state. Specifically, black asthmatic subjects had significantly higher log10 IC50 values (black asthmatic subjects: median, 1.00 nmol; first quartile, 0.48 nmol; third quartile, 1.83 nmol; vs white asthmatic subjects: median, 0.78 nmol; first quartile, 0.29 nmol; third quartile, 1.45 nmol; p = 0.028) and lower Imax values (black asthmatic subjects: median, 85.9%; first quartile, 69.7%; third quartile, 94.3%; vs white asthmatic subjects: median, 91.5%; first quartile, 75.8%; third quartile, 96.6%; p = 0.0047) compared to white asthmatic subjects (Fig 1 ). In addition, black control subjects also had higher log10 IC50 values (black control subjects: median, 1.26 nmol; first quartile, 0.70 nmol; third quartile, 2.14 nmol; vs white control subjects: median, 0.95 nmol; first quartile, 0.55 nmol; third quartile, 1.48 nmol; p = 0.01) and lower Imax values (black control subjects: median, 71.3%; first quartile, 51.0%; third quartile, 89.2%; vs white control subjects: median, 82.7%; first quartile, 60.8%; third quartile, 92.9%; p = 0.008) compared to white control subjects (Fig 1). In other words, black subjects (asthmatic or nonasthmatic) required greater concentrations of dexamethasone to suppress lymphocyte activation by 50%.

Combining both asthmatic and control subjects, using the Spearman rank correlation, age (ρ = 0.28, p < 0.0001) and basal T-lymphocyte activity (ρ = 0.24, p < 0.0001) were significantly positively correlated to log10 IC50 values, while no significant correlations to log10 IC50 values were seen with the following: inhaled glucocorticoids (ρ = − 0.04, p = 0.3), oral glucocorticoids (ρ = − 0.07, p = 0.09), FEV1 percentage of predicted (ρ = − 0.02, p = 0.64), and number of PHA-stimulated T-lymphocyte counts expressed as cpm [3H]-thymidine incorporation (ρ = 0.009, p = 0.83). The relationships remained using a stepwise backward regression analysis with the following as covariates: age, race, gender, FEV1 percentage of predicted, presence of asthma, inhaled and oral glucocorticoid dose, and number of unstimulated and PHA-stimulated T-lymphocyte counts expressed as cpm [3H]-thymidine incorporation. Using this test, age (p < 0.0001), basal T-lymphocyte activity (cpm) (p = 0.012), and race (ie, black, p = 0.00026) positively correlated to the log10 IC50 values.

Among the asthmatic subjects, the effects of age, asthma duration, age at asthma diagnosis, FEV1 percentage of predicted, inhaled and oral glucocorticoid doses, and number of unstimulated and PHA-stimulated T-lymphocyte counts expressed as cpm [3H]-thymidine incorporation on log10 IC50 were examined. When all these covariates were entered in a stepwise backward regression analysis, age (p = <0.0001), race (p = 0.047), inhaled glucocorticoid dose (p = 0.028), and basal T-lymphocyte activity (cpm) [p = 0.03] were found to correlate to the log10 IC50 values. Among the control subjects, when age, race, presence of atopy, FEV1 percentage of predicted, and number of unstimulated and PHA-stimulated T-lymphocyte counts expressed as cpm [3H]-thymidine incorporation were evaluated using the backward stepwise procedure, age was the only variable that remained significant (p = 0.0003).

Due to the significant effect of age on measures of T-lymphocyte steroid response and the differences in age between the asthmatic subjects, a post hoc, match-paired, t test analysis was done. Seventy-eight pairs were matched for age and FEV1 percentage of predicted (Table 2 ). The mean paired difference in log10 IC50 values between black and white asthmatic subjects was − 0.39 (95% confidence interval, − 0.72 to − 0.06; p = 0.02).

Our study is the first report of racial differences in in vitro T-lymphocyte glucocorticoid responsiveness between blacks and whites. In this study, both black and white asthmatic subjects had evidence for moderate airflow limitation and comparable controller medication requirement. Despite this finding of relatively similar asthma severity, we found that blacks required approximately 50% more dexamethasone to suppress PHA-stimulated lymphocytes compared to whites. In addition, this difference was seen in subjects without asthma.

Although speculative, diminished glucocorticoid responsiveness may be a contributor to the disproportionate morbidity and mortality among black asthmatic subjects. In a previous report5 from our group, black children with poorly controlled asthma referred to our institution were more likely to inadequately respond to a course of prednisone as measured by a failure to improve baseline lung function by 15%. In that study,5 black asthmatic patients comprised only 17% of the cohort but accounted for nearly 40% of poor responders. The finding of a diminished response to glucocorticoids in blacks has been noted in other conditions that require immunomodulation. Among patients who have undergone renal transplantation, blacks have been shown to require larger concentrations of immunosuppressive agents compared to whites.1417

The racial difference in the response of T lymphocytes to glucocorticoids can be due to either one or a combination of the following: (1) differences in the immune response associated with the disease itself, leading to an exuberant production of proinflammatory cytokines and subsequent reduction in glucocorticoid responsiveness; and (2) genetic mechanisms that directly influence response to glucocorticoids. It is possible that environmental factors such as allergens could enhance the production of proinflammatory cytokines, which in turn could account for the decreased in vitro response to glucocorticoids found in black asthmatics. Previous studies have demonstrated that allergen exposure in atopic asthmatics could alter glucocorticoid responsiveness, associated with diminished glucocorticoid receptor binding affinity in vitro. Nimmagadda et al18found that incubation of lymphocytes with ragweed allergen in ragweed allergic subjects led to increased IL-2 and IL-4 production, decreased sensitivity of stimulated lymphocytes to dexamethasone, and decreased glucocorticoid receptor binding affinity. Antibodies to IL-4 and IL-2 reversed the effect, suggesting a direct relationship between increased IL-2 and IL-4 levels and decreased glucocorticoid receptor binding. However, atopy alone does not explain the differences noted in glucocorticoid responsiveness between black and white asthmatics, as similar proportions of patients were atopic in each group. This observation may not be at all surprising given that elevated messenger RNA and protein IL-4 and IL-5 levels were found in bronchial biopsy samples from both atopic and nonatopic asthmatic patients.1920 The exact mechanisms by which these proinflammatory cytokines induce glucocorticoid resistance are still unclear. One potential mechanism is by activation of transcription factors such as activator protein-1, which interfere with glucocorticoid-receptor binding to glucocorticoid-response elements.21Alternatively, induction of the glucocorticoid receptor β may cause inhibition of the glucocorticoid response.22

The genetic basis for our observation of a disparate response to glucocorticoid in vitro based on race is at present unknown. Cox et al23 found that black patients with end-stage renal disease were significantly more likely to have a polymorphism in the IL-6 gene that is associated with an increase in the production of IL-6. The investigators found unique polymorphisms in the IL-2 gene in black subjects that were not found in whites, with unclear clinical significance.,23

Studies suggest black asthmatic subjects have an inherent predisposition to overproduce proinflammatory cytokines such as IL-4 compared to whites. One of the first studies demonstrating an association between IL-4 promoter region polymorphisms and asthma severity came from Burchard et al,24who found an association between IL-4 C-589T sequence and enhanced IL-4 gene transcription. Although an association was found between the homozygous presence of the C-589T polymorphism in the IL-4 gene promoter region and lower FEV1 only in white asthmatic subjects, the frequency of the polymorphism in the IL-4 gene promoter region (C-589T) was greater among black compared to white asthmatic subjects (0.544 vs 0.183, p = 1 × 10−23). In a more recent study, the association of C-589T sequence variant in the IL-4 promoter region and glucocorticoid-resistant asthma was examined. Compared to glucocorticoid-sensitive patients, there was an overexpression of the C-589T allele found in glucocorticoid-resistant patients with asthma.25

The fact that nonasthmatic blacks required greater concentrations of glucocorticoids to inhibit lymphocyte activation argues against the possible role the disease itself may have on glucocorticoid response, and suggests an inherent genetic predisposition toward diminished response. In order to determine the relative contributions that genetics and the disease itself play on glucocorticoid responsiveness, further studies will need to be performed.

There is indeed significant variability in the log10 IC50 values, such that an overlap is noted between black and white subjects (Fig 1). This suggests that although there is a statistically significant difference between the groups, racial classification alone cannot completely account for the difference in T-lymphocyte sensitivity to glucocorticoids, and other factors such as those related to disease activity and severity may play a role. In addition, while the current racial grouping may not be mutually exclusive given the heterogeneity of the race in the United States, it may provide an initial basis to evaluate for the epidemiologic differences in some disease states that have already been well described.

Among asthmatic subjects, when the effects of age, asthma duration, age at asthma diagnosis, FEV1 percentage of predicted, inhaled and oral glucocorticoid doses, and number of unstimulated and PHA-stimulated T-lymphocyte counts on log10 IC50 were appraised in a regression analysis, race, age, inhaled glucocorticoid dose, and basal T-lymphocyte activity (cpm) were found to independently correlate to the log10 IC50 values. The association between the inhaled glucocorticoid dose and basal T-lymphocyte activity on the in vitro T-lymphocyte response to glucocorticoid could be reflective of the underlying disease activity and severity. In other words, patients with more severe asthma requiring higher doses of inhaled glucocorticoid as recommended in the clinical practice guidelines, or manifesting with increased basal T-lymphocyte activity may actually be relatively insensitive to glucocorticoid due to heightened airway inflammation. These findings suggest that both nonmodifiable factors (eg, age and race) and dynamic features related to disease severity may affect the in vitro response of T lymphocytes.

Among the control subjects, when multiple variables were evaluated in the regression analysis, only age remained significant. The association between increasing age and diminishing glucocorticoid responsiveness demonstrated in either asthmatic or control subjects has not, to our knowledge, been described before. The etiology of this finding and its clinical relevance are unknown at present. This finding is of interest in the context of this study because the black asthmatic subjects were significantly younger than their white peers. This association between age and log10 IC50 may also explain why, in this study, the asthmatic subjects who were younger than the nonasthmatic control subjects had lower log10 IC50 values.

Of note, lower log10 IC50 and higher Imax values were found among asthmatic subjects compared to the control subjects. Although speculative, we believe that this finding is a result of an ex vivo effect of topical and/or systemic glucocorticoids on lymphocyte inhibition. The vast majority of the asthmatics in this study were receiving inhaled glucocorticoids and many were receiving oral glucocorticoids, while none of the control subjects were. In order to determine whether oral or inhaled glucocorticoids display an ex vivo effect on lymphocyte proliferation and responsiveness to glucocorticoids, a GCLS assay on nonasthmatic controls will need to be performed before and after a course of glucocorticoids.

This present cross-sectional study has its limitations. Most of the asthmatic subjects were referred to a tertiary referral center; thus, the findings might not reflect the phenomenon that occurs in the general population. The control group were nonasthmatic control subjects who included patients without an established diagnosis of asthma by history or report; hence, it is possible that some of them have undiagnosed asthma. Nevertheless, similar recruitment process applied regardless of race. Given these limitations, the results suggest that diminished glucocorticoid responsiveness may be a contributing factor in patients inadequately controlled on usual doses of inhaled glucocorticoids, especially among blacks. In this situation, the patient would likely require a higher dose. Alternatively, use of other controller medications in addition to, or instead of, glucocorticoids may be required to optimize control of the inflammatory response in blacks with severe asthma.

Abbreviations: cpm = counts per minute; IL = interleukin; Imax = percentage inhibition at the maximum concentration (10−6 mol/L) of dexamethasone; GCLS = glucocorticoid lymphocyte stimulation; log10 IC50 = log-transformed concentration of dexamethasone required to suppress phytohemagglutinin-induced T-lymphocyte proliferation by 50%; PBMC = peripheral blood mononuclear cell; PHA = phytohemagglutinin

Supported in part by contracts from the General Clinical Research Center grant from the National Center for Research Resources M01 RR00051.

Table Graphic Jump Location
Table 1. Characteristic Features of Black and White Asthmatic and Nonasthmatic Control Subjects*
* 

Data are expressed as median (first, third quartile) unless otherwise specified. BC = black control subjects; BA = black asthmatic subjects; WC = white control subjects; WA = white asthmatic subjects.

 

p Values considered significant at < 0.05, using Wilcoxon rank-sum test and Fisher exact test for test of proportions.

Figure Jump LinkFigure 1. Blacks (asthmatic or nonasthmatic) required greater log10 IC50 (top left, A, and top right, B) and less Imax (bottom left, A, and bottom right, B) compared to whites. Dex = dexamethasone; AA = African American.Grahic Jump Location
Table Graphic Jump Location
Table 2. Comparison of Black and White Asthmatic Subjects Included in the Match-Paired Analysis*
* 

Data are expressed as median (first, third quartiles) unless otherwise specified.

 

p Values considered significant at < 0.05, using Wilcoxon rank-sum test and Fisher exact test for test of proportions.

The authors thank Trudi Morgan, Deborah Corliss, and Janice Herrell for their help with data collection.

Akinbami, LJ, Schoendorf, KC (2002) Trends in childhood asthma: prevalence, health care utilization, and mortality.Pediatrics110,315-322. [CrossRef] [PubMed]
 
Grant, EN, Lyttle, CS, Weiss, KB The relation of socioeconomic factors and racial/ethnic differences in US asthma mortality.Am J Public Health2000;90,1923-1925. [CrossRef] [PubMed]
 
Joseph, CLM, Ownby, DR, Peterson, EL, et al Racial differences in physiologic parameters related to asthma among middle class children.Chest2000;117,1336-1344. [CrossRef] [PubMed]
 
Szefler, SJ, Martin, RJ, King, TS, et al Asthma Clinical Research Network of the National Heart Lung, and Blood Institute: significant variability in response to inhaled corticosteroids for persistent asthma.J Allergy Clin Immunol2002;109,410-418. [CrossRef] [PubMed]
 
Chan, MTS, Leung, DYM, Szefler, SJ, et al Difficult to control asthma: clinical characteristics of steroid-insensitive asthma.J Allergy Clin Immunol1998;101,594-601. [CrossRef] [PubMed]
 
Walker, C, Bode, E, Boer, L, et al Allergic and nonallergic asthmatics have distinct patterns of T cell activation and cytokine production in peripheral blood and bronchoalveolar lavage.Am Rev Respir Dis1992;146,109-115. [PubMed]
 
Larché, M, Robinson, DS, Kay, AB The role of T lymphocytes in the pathogenesis of asthma.J Allergy Clin Immunol2003;111,450-463. [CrossRef] [PubMed]
 
Corrigan, CJ, Bungre, JK, Assoufi, AE, et al Glucocorticoid-resistant asthma: T-lymphocyte steroid metabolism and sensitivity to glucocorticoids and immunosuppressive agents.Eur Respir J1996;9,2077-2086. [CrossRef] [PubMed]
 
Corrigan, CJ, Brown, PH, Barnes, NC, et al Glucocorticoid resistance in chronic asthma: glucocorticoid pharmakokinetics, glucocorticoid receptor characteristics, and inhibition or peripheral blood T cell proliferation by glucocorticoidsin vitro.Am Rev Respir Dis1991;144,1016-1025. [CrossRef] [PubMed]
 
Spahn, JD, Landwehr, LP, Nimmagadda, S, et al Effects of glucocorticoids on lymphocyte activation in steroid-sensitive and steroid-resistant asthmatics.J Allergy Clin Immunol1996;98,1073-1079. [CrossRef] [PubMed]
 
Leung, DYM, Martin, RJ, Szefler, SJ, et al Dysregulation of interleukin-4, interleukin 5, and interferon γ gene expression in steroid resistant asthma.J Exp Med1995;181,33-40. [CrossRef] [PubMed]
 
Hankinson, JL, Odencrantz, JR, Fedan, KB Spirometric reference values from a sample of the general population.Am J Respir Crit Care Med1999;159,179-187. [PubMed]
 
Hearing, SD, Norman, M, Smyth, C, et al Wide variation in lymphocyte steroid sensitivity among healthy human volunteers.J Clin Endocrinol Metab1999;84,4149-4154. [CrossRef] [PubMed]
 
Kerman, RH, Kimball, PM, Van Buren, CT, et al Possible contribution of pretransplant immune responder status to renal allograft survival differences of black vs. white recipients.Transplantation1991;51,338-342. [CrossRef] [PubMed]
 
Nagashima, N, Watanabe, T, Nakamura, M, et al Decreased effect of immunosuppression on immunocompetence in African Americans after kidney and liver transplantation.Clin Transplant2001;15,111-115. [CrossRef] [PubMed]
 
Isaacs, RB, Nock, SL, Spencer, CE, et al Racial disparities in renal transplant outcomes.Am J Kidney Dis1999;34,706-712. [CrossRef] [PubMed]
 
Hricik, DE, Anton, HA, Knauss, TC, et al Outcomes of African American kidney transplant recipients treated with sirolimus, tacrolimus, and corticosteroids.Transplantation2002;74,189-193. [CrossRef] [PubMed]
 
Nimmagadda, SR, Szefler, SJ, Spahn, JD, et al Allergen exposure decreases glucocorticoid receptor binding affinity and steroid responsiveness in atopic asthmatics.Am J Respir Crit Care Med1997;155,87-93. [PubMed]
 
Humbert, M, Durham, SR, Ying, S, et al IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against “intrinsic” asthma being a distinct immunopathologic entity.Am J Respir Crit Care Med1996;154,1497-1504. [PubMed]
 
Ying, S, Humbert, M, Barkans, J, et al Expression of IL-4 and IL-5 mRNA and protein product by CD4+ and CD8+ T cells, eosinophils, and mast cells in bronchial biopsies obtained from atopic and nonatopic (intrinsic) asthmatics.J Immunol1997;158,3539-3544. [PubMed]
 
Adcock, IM, Lane, SJ, Brown, CR, et al Abnormal glucocorticoid receptor-activation protein interaction in steroid-resistant asthma.J Exp Med1995;182,1951-1958. [CrossRef] [PubMed]
 
Leung, DY, Bloom, JW Update on glucocorticoid action and resistance.J Allergy Clin Immunol2003;111,3-22. [CrossRef] [PubMed]
 
Cox, ED, Hoffman, SC, DiMercurio, BS, et al Cytokine polymorphic analyses indicate ethnic differences in the allelic distribution of interleukin-2 and interleukin-6.Transplantation2001;72,720-726. [CrossRef] [PubMed]
 
Burchard, EG, Silverman, EK, Rosenwasser, LJ, et al Association between a sequence variant in the IL-4 gene promoter and FEV1in asthma.Am J Respir Crit Care Med1999;160,919-922. [PubMed]
 
Rossenwasser, L, Klemm, JD, Klemm, DJ, et al Association of asthmatic steroid insensitivity with an IL-4 gene promoter polymorphism [abstract]. J Allergy Clin Immunol. 2001;;107 ,.:S235. [CrossRef]
 

Figures

Figure Jump LinkFigure 1. Blacks (asthmatic or nonasthmatic) required greater log10 IC50 (top left, A, and top right, B) and less Imax (bottom left, A, and bottom right, B) compared to whites. Dex = dexamethasone; AA = African American.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Characteristic Features of Black and White Asthmatic and Nonasthmatic Control Subjects*
* 

Data are expressed as median (first, third quartile) unless otherwise specified. BC = black control subjects; BA = black asthmatic subjects; WC = white control subjects; WA = white asthmatic subjects.

 

p Values considered significant at < 0.05, using Wilcoxon rank-sum test and Fisher exact test for test of proportions.

Table Graphic Jump Location
Table 2. Comparison of Black and White Asthmatic Subjects Included in the Match-Paired Analysis*
* 

Data are expressed as median (first, third quartiles) unless otherwise specified.

 

p Values considered significant at < 0.05, using Wilcoxon rank-sum test and Fisher exact test for test of proportions.

References

Akinbami, LJ, Schoendorf, KC (2002) Trends in childhood asthma: prevalence, health care utilization, and mortality.Pediatrics110,315-322. [CrossRef] [PubMed]
 
Grant, EN, Lyttle, CS, Weiss, KB The relation of socioeconomic factors and racial/ethnic differences in US asthma mortality.Am J Public Health2000;90,1923-1925. [CrossRef] [PubMed]
 
Joseph, CLM, Ownby, DR, Peterson, EL, et al Racial differences in physiologic parameters related to asthma among middle class children.Chest2000;117,1336-1344. [CrossRef] [PubMed]
 
Szefler, SJ, Martin, RJ, King, TS, et al Asthma Clinical Research Network of the National Heart Lung, and Blood Institute: significant variability in response to inhaled corticosteroids for persistent asthma.J Allergy Clin Immunol2002;109,410-418. [CrossRef] [PubMed]
 
Chan, MTS, Leung, DYM, Szefler, SJ, et al Difficult to control asthma: clinical characteristics of steroid-insensitive asthma.J Allergy Clin Immunol1998;101,594-601. [CrossRef] [PubMed]
 
Walker, C, Bode, E, Boer, L, et al Allergic and nonallergic asthmatics have distinct patterns of T cell activation and cytokine production in peripheral blood and bronchoalveolar lavage.Am Rev Respir Dis1992;146,109-115. [PubMed]
 
Larché, M, Robinson, DS, Kay, AB The role of T lymphocytes in the pathogenesis of asthma.J Allergy Clin Immunol2003;111,450-463. [CrossRef] [PubMed]
 
Corrigan, CJ, Bungre, JK, Assoufi, AE, et al Glucocorticoid-resistant asthma: T-lymphocyte steroid metabolism and sensitivity to glucocorticoids and immunosuppressive agents.Eur Respir J1996;9,2077-2086. [CrossRef] [PubMed]
 
Corrigan, CJ, Brown, PH, Barnes, NC, et al Glucocorticoid resistance in chronic asthma: glucocorticoid pharmakokinetics, glucocorticoid receptor characteristics, and inhibition or peripheral blood T cell proliferation by glucocorticoidsin vitro.Am Rev Respir Dis1991;144,1016-1025. [CrossRef] [PubMed]
 
Spahn, JD, Landwehr, LP, Nimmagadda, S, et al Effects of glucocorticoids on lymphocyte activation in steroid-sensitive and steroid-resistant asthmatics.J Allergy Clin Immunol1996;98,1073-1079. [CrossRef] [PubMed]
 
Leung, DYM, Martin, RJ, Szefler, SJ, et al Dysregulation of interleukin-4, interleukin 5, and interferon γ gene expression in steroid resistant asthma.J Exp Med1995;181,33-40. [CrossRef] [PubMed]
 
Hankinson, JL, Odencrantz, JR, Fedan, KB Spirometric reference values from a sample of the general population.Am J Respir Crit Care Med1999;159,179-187. [PubMed]
 
Hearing, SD, Norman, M, Smyth, C, et al Wide variation in lymphocyte steroid sensitivity among healthy human volunteers.J Clin Endocrinol Metab1999;84,4149-4154. [CrossRef] [PubMed]
 
Kerman, RH, Kimball, PM, Van Buren, CT, et al Possible contribution of pretransplant immune responder status to renal allograft survival differences of black vs. white recipients.Transplantation1991;51,338-342. [CrossRef] [PubMed]
 
Nagashima, N, Watanabe, T, Nakamura, M, et al Decreased effect of immunosuppression on immunocompetence in African Americans after kidney and liver transplantation.Clin Transplant2001;15,111-115. [CrossRef] [PubMed]
 
Isaacs, RB, Nock, SL, Spencer, CE, et al Racial disparities in renal transplant outcomes.Am J Kidney Dis1999;34,706-712. [CrossRef] [PubMed]
 
Hricik, DE, Anton, HA, Knauss, TC, et al Outcomes of African American kidney transplant recipients treated with sirolimus, tacrolimus, and corticosteroids.Transplantation2002;74,189-193. [CrossRef] [PubMed]
 
Nimmagadda, SR, Szefler, SJ, Spahn, JD, et al Allergen exposure decreases glucocorticoid receptor binding affinity and steroid responsiveness in atopic asthmatics.Am J Respir Crit Care Med1997;155,87-93. [PubMed]
 
Humbert, M, Durham, SR, Ying, S, et al IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against “intrinsic” asthma being a distinct immunopathologic entity.Am J Respir Crit Care Med1996;154,1497-1504. [PubMed]
 
Ying, S, Humbert, M, Barkans, J, et al Expression of IL-4 and IL-5 mRNA and protein product by CD4+ and CD8+ T cells, eosinophils, and mast cells in bronchial biopsies obtained from atopic and nonatopic (intrinsic) asthmatics.J Immunol1997;158,3539-3544. [PubMed]
 
Adcock, IM, Lane, SJ, Brown, CR, et al Abnormal glucocorticoid receptor-activation protein interaction in steroid-resistant asthma.J Exp Med1995;182,1951-1958. [CrossRef] [PubMed]
 
Leung, DY, Bloom, JW Update on glucocorticoid action and resistance.J Allergy Clin Immunol2003;111,3-22. [CrossRef] [PubMed]
 
Cox, ED, Hoffman, SC, DiMercurio, BS, et al Cytokine polymorphic analyses indicate ethnic differences in the allelic distribution of interleukin-2 and interleukin-6.Transplantation2001;72,720-726. [CrossRef] [PubMed]
 
Burchard, EG, Silverman, EK, Rosenwasser, LJ, et al Association between a sequence variant in the IL-4 gene promoter and FEV1in asthma.Am J Respir Crit Care Med1999;160,919-922. [PubMed]
 
Rossenwasser, L, Klemm, JD, Klemm, DJ, et al Association of asthmatic steroid insensitivity with an IL-4 gene promoter polymorphism [abstract]. J Allergy Clin Immunol. 2001;;107 ,.:S235. [CrossRef]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

CHEST Journal Articles
CHEST Collections
PubMed Articles
Guidelines
Management of asthma.
Singapore Ministry of Health | 7/18/2008
Adapting your practice: treatment and recommendations for homeless patients with asthma.
National Health Care for the Homeless Council, Inc. | 6/13/2008
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543