Inhaled Glucocorticoid Therapy Research Articles

Asthma in the elderly: underperceived, underdiagnosed and undertreated; a community survey

Bronchial asthma is now increasingly recognized in the elderly and is associated with significant morbidity and mortality. The aims of this study were two-fold: first, to assess the prevalence and, second, to evaluate diagnostic awareness, therapeutic management and patient perception of bronchial asthma among elderly patients in the community. From the age-sex register of an urban general practice in NE England, 2004 patients aged >65 years were eligible for inclusion. Response to an initial screening questionnaire on respiratory symptomatology was 68% ( n = 1362). Of these, 869 patients had respiratory symptoms: 390 voluntarily agreed to be evaluated further including assessment of airway physiology. In this group 369 390 had obstructive spirometry and, of these, 95 patients fulfilled clinical and physiological criteria of bronchial asthma. Prevalence of asthma within this age cohort was minimally and rather crudely assigned at 4.5% ( 95 2004 ). Among the 95 patients so-defined patients with asthma [age 70 ± 8 years (mean ± sd), FEV 1 = 0·96 ± 0.41, 33 male, 75 life-long non-smokers], subjective awareness, perception and attribution of pulmonary symptoms were poor. Further, despite tangible evidence of reversible and significant airflow limitation, only 21 were receiving inhaled glucocorticoid therapy (median daily dose 400 μg). Asthma in the elderly remains poorly perceived, poorly recognized and suboptimally treated. These findings are particularly apposite in the light of current epidemiological trends in asthma mortality and morbidity in elderly age cohorts.

Glucocorticoid receptor expression in human bronchial epithelial cells: effects of smoking and COPD.

Previously, we found that inflammatory mediators modulated the number and binding affinity of glucocorticoid receptors (GR) in human bronchial epithelial cell lines. In this study we investigated whether smoking and chronic obstructive pulmonary disease (COPD), both characterized by airway inflammation with increased levels of inflammatory mediators, affect GR characteristics in cultured human bronchial epithelial cells (HBEC). A statistically significant difference was found between the dissociation constant (Kd) values in HBEC from smoking (Kd = 0.98+/-0.08 nM; n = 6) and nonsmoking controls (Kd = 0.76+/-0.10 nM, P = 0.03; n = 5), but no significant difference was found between the mean number of binding sites. Our results are the first indication that cultured HBEC from smokers possess GR with a lower binding affinity. This may result from the inflammation found in the airways from smokers. Furthermore, these results provide further evidence that the bronchial epithelium may be an actual target for inhaled glucocorticoid therapy.

Inhaled glucocorticoid therapy of childhood asthma is associated with reduced peripheral blood T cell activation and 'Th2-type' cytokine mRNA expression.

To investigate the role of activated T cells and their cytokine products in the pathogenesis of childhood asthma. PBMC were obtained from 17 symptomatic asthmatic children (age 7 to 15 yr) and 7 nonasthmatic controls matched for age and atopic status. Asthmatics were placed in 2 groups with initial prebronchodilator FEV1 <75% (Group I, n = 9) or >/=75% (Group II, n = 8) predicted. Expression of activation markers on peripheral blood T cells (asthmatics), and expression of cytokine mRNA (asthmatics and controls) were measured using flow cytometry and in situ hybridization respectively. Measurements were repeated in the asthmatics 3 to 6 months later following initiation or escalation of inhaled GC therapy for control of symptoms. The more severe (Group I) as compared with the milder (Group II) asthmatics showed evidence of increased peripheral blood T cell activation, with elevated percentages of CD4 cells expressing the activation markers CD25 and HLA-DR, and CD8 cells expressing CD25. Elevated percentages of CD4 cells also expressed CD45RO, consistent with ongoing cellular activation. The asthmatics had higher percentages of PBMC expressing mRNA encoding IL-5, IL-4, GM-CSF and IL-2, but not IFN-gamma, as compared with controls. The percentages of PBMC expressing IL-5 mRNA correlated with disease severity (% predicted FEV1). During follow up, patients in both groups required increased mean daily dosages of inhaled GC. In Group I this was associated with improvements in PEFR, FEV1 and night time wheeze and reduced percentages of CD4/CD25 and CD4/HLA-DR peripheral blood T cells. Reductions in the percentages of CD4/CD25 T cells correlated with improvements in baseline FEV1. Group II patients showed improvement in FEV1 and day time cough and wheeze but no significant changes in PEFR, other symptoms or peripheral blood T cell marker expression. Increased GC therapy of both groups taken together was associated with significant reductions in the percentages of PBMC expressing mRNA encoding IL-5, IL-4 and IL-2 and an increase in those expressing IFN-gamma mRNA. Compared with controls, children with symptomatic asthma have higher percentages of activated peripheral blood T cells synthesising cytokines believed to regulate bronchial mucosal eosinophilic inflammation. Clinical improvement with increased inhaled GC therapy is associated with reduced T cell activation and cytokine mRNA expression.

Attained adult height after childhood asthma: Effect of glucocorticoid therapy

Background: Although oral and inhaled glucocorticoid therapy may impair growth in children with asthma, the effect of glucocorticoid therapy and asthma on attained adult height has not been extensively studied in representative children in the community. Objectives: The study was designed to compare the attained adult height of children with asthma with the attained adult height of nonasthmatic children and to compare the attained adult height of asthmatic children treated with glucocorticoids with the attained adult height of asthmatic children who did not receive glucocorticoids. Methods: Residents of Rochester, Minnesota, with onset of asthma from 1964 to 1987 and age- and sex-matched nonasthmatic residents of Rochester were studied. Glucocorticoid exposure was assessed from medical records. The mean of 5 stadiometer measurements of adult height, adjusted for sex and parental height, was analyzed. Results: One hundred fifty-three patients with asthma (mean age at onset, 6.1 ± 4.8 years) and 153 age- and sex-matched nonasthmatic subjects were studied. Adult height of patients with asthma (mean age at measurement, 25.7 ± 5.2 years) was not significantly different from the adult height of nonasthmatic subjects; the overall difference, adjusted for mid-parental height, was –0.20 cm (95% confidence interval from –0.27 to 1.64). The adult height of asthmatic children treated with glucocorticoids was not significantly different from the adult height of patients with asthma not treated with glucocorticoids; the difference after adjusting for mid-parental height was –0.2 cm (95% confidence interval from –0.1 to 0.6). Conclusions: We conclude that the attained adult height of patients with asthma is not different from the adult height of age- and sex-matched nonasthmatic subjects and that the attained adult height of asthmatic children treated with glucocorticoids is not significantly different from the adult height of children not treated with glucocorticoids. (J Allergy Clin Immunol 1997;99:466-74.)

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.

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.

Measuring the systemic effects of inhaled beclomethasone: timed morning urine collections compared with 24 hour specimens.

Inhaled glucocorticoid therapy has systemic effects including hypothalamic-pituitary-adrenal (HPA) suppression. The optimal test for detecting these effects has not been defined. Timed urine collections and 09.00 hour plasma cortisol levels were obtained from 12 normal volunteers receiving inhaled placebo, beclomethasone (BDP) 800 or 2000 micrograms/day. The 24 hour urine samples were collected as follows: first hour after waking (hour 1), the next two hours after waking (hours 2 and 3), remainder of day, and overnight, with results expressed as urine cortisol/creatinine (UCC) ratios and as hourly cortisol output in the timed collections. Twenty four hour urinary cortisol excretion was also calculated. Medication was blinded and given in random order with a washout period of at least 11 days between each treatment arm. None of the UCC ratios changed with BDP 800 micrograms/day. UCC ratios at hour 1, hour 2 and 3, and overnight, and 24 hour urinary free cortisol excretion were reduced after BDP 2000 micrograms/day, whilst remainder of day UCC ratio and the plasma cortisol level did not change significantly. Cortisol output showed similar changes. In a follow up study BDP 1400 micrograms/day also reduced UCC ratios for the first two hours after waking. UCC ratios are as sensitive as the more cumbersome 24 hour urinary free cortisol excretion, and more sensitive than single morning plasma cortisol measurements, in detecting the effects of inhaled beclomethasone on the HPA axis.

Glucocorticoids and growth in asthmatic children.

The effects of asthma and oral and inhaled glucocorticoid therapy on growth in children are reviewed. Previous reports have shown that asthma itself may delay the onset of puberty, an effect which may masquerade as growth suppression. Oral glucocorticoids appear to impair growth; however, lower doses and alternate-day therapy may have less risk of this effect. While a controversial topic, inhaled glucocorticoids in lower doses appear to be associated with a small risk of adverse effects on growth. Minimal data are available for higher doses. Knemometry, a relatively new technique used for measuring small changes in growth, has detected short-term effects with both oral and inhaled glucocorticoids therapy. However, a number of limitations are associated with short-term growth studies. Clinicians should be aware of the potential for growth impairment with glucocorticoid therapy so adequate monitoring can be undertaken and appropriate intervention introduced when deemed necessary.