Inhaled Corticosteroid Response Research Articles

Variation at GLCCI1 and FCER2 : One Step closer to Personalized Asthma Treatment

Asthma is a chronic lung disorder characterized by recurrent episodes of wheezing, shortness of breath and coughing [101]. It is a common dis­ ease in children and its prevalence in Europe is approximately 10% [102]. It is generally accepted that asthma is not simply caused by one under­ lying factor but that it can be caused by different disease mechanisms [1]. This heterogeneity can be determined by sputum ana lysis [1], disease control [103], and also sensitivity to treatment [104]. Until now, none of these domains have been able to fully explain the heterogeneity in phenotypes that lead to the same symptoms that are so characteristic for the disease. The treatment of asthma can be summarized into two categories: symptom­relieving therapy via broncho dilatation, mainly using inhaled b­agonists on an as­needed basis, and in chronic asthma, continuous anti­inflammatory therapy with inhaled corticosteroids (ICS). For the majority of children with asthma these therapeutic approaches enable them to lead a normal life. However, 10–15% of children have serious asthma symptoms despite optimal treatment with ICS and are often referred to as having “difficult­to­treat asthma” [2]. This means an important reduction in the quality of life in this group of children. When looking into this in more detail, there appears to be a significant interindividual variability in ICS responsiveness; however, the intraindividual response is highly consistent [3]. This strongly suggests the influence of a genetic component, which may be responsible for the heterogeneity of response. Several pharmacogenetic studies have been performed, and several candidate genes have been identif ied (e.g., CRHR1, TBX21 and NR3C1) [4]. However, by far the majority of these findings still need more replication and, until recently, none of these findings appear to have come close to clinical relevance. Recently

Symptoms, but Not a Biomarker Response to Inhaled Corticosteroids, Predict Asthma in Preschool Children with Recurrent Wheeze

Background. A reliable asthma diagnosis is challenging in preschool wheezing children. As inhaled corticosteroids (ICS) are more effective in asthmatics than in children with transient wheeze, an ICS response might be helpful in early asthma diagnosis. Methods. 175 children (aged two–four years) with recurrent wheeze received 200 μg Beclomethasone extra-fine daily for eight weeks. Changes in Exhaled Breath Condensate (EBC) biomarkers (pH, interleukin (IL)-1α, IL-2, IL-4, IL-5, IL-10, IFN-γ, sICAM, and CCL-11), Fractional exhaled Nitric Oxide (FeNO), airway resistance, and symptoms were assessed. At six years of age a child was diagnosed as transient wheezer or asthmatic. Adjusted logistic regression analysis was performed with multiple testing correction. Results. 106 transient wheezers and 64 asthmatics were analysed at six years of age. Neither changes in EBC biomarkers, nor FeNO, airway resistance, or symptoms during ICS trial at preschool age were related to asthma diagnosis at six years of age. However, asthmatics had more airway symptoms before the start of the ICS trial than transient wheezers (P < 0.01). Discussion. Although symptom score in preschool wheezing children at baseline was associated with asthma at six years of age, EBC biomarkers, airway resistance, or symptom response to ICS at preschool age could not predict asthma diagnosis at six years of age.

Can exhaled inflammatory markers predict a steroid response in wheezing preschool children?

The efficacy of inhaled corticosteroids (ICS) varies among wheezing preschool children. Currently, it is not possible to predict which fraction of wheezing children will benefit from an ICS treatment. We explored whether fractional exhaled nitric oxide (FeNO) and inflammatory markers in exhaled breath condensate (EBC) can predict an ICS response in preschool wheezers. An 8-week ICS study (registered at Clinicaltrial.gov: NCT 00422747; 200 μg; beclomethasone extra-fine daily) was performed in 93 wheezing children (age range 2.0-4.4 years). At baseline, FeNO was determined off-line. EBC was collected using a closed glass-condenser. The acidity of EBC was determined and other EBC markers [interleukin (IL)-1α, IL-2, IL-4, IL-5, IL-10, soluble intercellular adhesion molecule, interferon-γ, eotaxin] were measured using a multiplex immunoassay. The change in airway resistance (Rint) and symptom score following ICS treatment was related to atopy (positive Phadiatop Infant test), FeNO and EBC markers. Airway resistance and symptoms mildly improved after ICS treatment [median (IQR): 1.4 (1.2-1.7) to 1.3 (1.1-1.5) kPa s/L, symptom score: 26 (23-28) to 28 (24-29), P < 0.01, respectively]. Only IL-10 and atopy had limited predictive value regarding a change in symptoms [β (SE) =-0.13 (0.07), P = 0.08, β (SE) = 2.05 (1.17), P = 0.08, respectively]. We did not find convincing evidence that FeNO and EBC markers could predict an ICS response in preschool wheezers. Recommendations for future studies on this topic are given.

SERPINE1 -675 4G/5G polymorphism is associated with asthma severity and inhaled corticosteroid response

Asthma is characterised by chronic airway inflammation and remodelling, which can be (partially) suppressed by inhaled corticosteroids (ICSs). Plasminogen activator inhibitor-1, encoded by the SERPINE1 gene, is the key inhibitor of the plasminogen activator system, which affects tissue repair and remodelling. We studied associations between a functional SERPINE1 -675 4G/5G promoter polymorphism and asthma development, severity and response to ICSs. Longitudinal cohorts of 281 asthmatics and their nonasthmatic spouses, and the general population (n=1,390) were studied. No significant associations were found with asthma development and immunoglobulin (Ig)E levels, or with forced expiratory volume in 1 s (FEV₁) in nonasthmatic controls. Asthmatic subjects carrying the SERPINE1 5G allele had higher IgE and lower lung function levels at follow-up, lower maximally attained lung function levels, and faster lung function decline compared with individuals with the 4G/4G genotype. ICS treatment showed an immediate improvement in FEV₁ in asthmatics carrying the 5G allele. However, these asthmatics still had the fastest rate of FEV₁ decline after initiating ICS treatment. Finally, the 5G allele was associated with a lower prevalence of complete asthma remission at follow-up. These findings suggest that SERPINE1 is not an asthma susceptibility gene, but rather affects the severity, progression and long-term ICS response in asthma.

Vitamin D and responses to inhaled fluticasone in severe chronic obstructive pulmonary disease

BackgroundPatients with chronic obstructive pulmonary disease (COPD) demonstrate variable responses to inhaled corticosteroids (ICS). The factors contributing to this variability are not well understood. Data from patients with asthma have suggested that low 25-hydroxyvitamin D [25(OH)D] levels contribute to a lack of ICS response in asthma. The objective of this study was to determine whether serum levels of 25(OH)D were related to ICS responses in patients with COPD.MethodsA total of 60 exsmokers with severe COPD (mean forced expiratory volume in one second [FEV1] 1.07 L, 36% of predicted) spent 4 weeks free of any ICS, followed by 4 weeks of ICS use (fluticasone propionate 500 μg twice daily). Spirometry was performed prior to and after 4 weeks of ICS use. Blood 25(OH)D levels were measured prior to ICS use and examined for relationships to changes in FEV1 following the 4 weeks of ICS use.ResultsThe mean 25(OH)D level was 23.3 ± 9.3 ng/mL. There was a high prevalence of vitamin D insufficiency (35%) and deficiency (40%). There was no relationship between baseline 25(OH)D and changes in FEV1 following 4 weeks of ICS.ConclusionBaseline 25(OH)D does not contribute to the variation in short-term FEV1 responses to ICS in patients with severe COPD.

Factors predicting inhaled corticosteroid responsiveness in African American patients with asthma

Factors predicting inhaled corticosteroid responsiveness in African American patients with asthma

Factors predicting inhaled corticosteroid responsiveness in African American patients with asthma

African American patients disproportionately experience uncontrolled asthma. Treatment with an inhaled corticosteroid (ICS) is considered first-line therapy for persistent asthma. We sought to determine the degree to which African American patients respond to ICS medication and whether the level of response is influenced by other factors, including genetic ancestry. Patients aged 12 to 56 years who received care from a large health system in southeast Michigan and who resided in Detroit were recruited to participate if they had a diagnosis of asthma. Patients were treated with 6 weeks of inhaled beclomethasone dipropionate, and pulmonary function was remeasured after treatment. Ancestry was determined by genotyping ancestry-informative markers. The main outcome measure was ICS responsiveness defined as the change in prebronchodilator FEV(1) over the 6-week course of treatment. Among 147 participating African American patients with asthma, average improvement in FEV(1) after 6 weeks of ICS treatment was 11.6%. The mean proportion of African ancestry in this group was 78.4%. The degree of baseline bronchodilator reversibility was the only factor consistently associated with ICS responsiveness, as measured by both an improvement in FEV(1) and patient-reported asthma control (P= .001 and P= .021, respectively). The proportion of African ancestry was not significantly associated with ICS responsiveness. Although baseline pulmonary function parameters appear to be associated with the likelihood to respond to ICS treatment, the proportion of genetic African ancestry does not. This study suggests that genetic ancestry might not contribute to differences in ICS controller response among African American patients with asthma.

Patient characteristics associated with improved outcomes with use of an inhaled corticosteroid in preschool children at risk for asthma

Maintenance inhaled corticosteroid (ICS) therapy in preschool children with recurrent wheezing at high-risk for development of asthma produces multiple clinical benefits. However, determination of baseline features associated with ICS responsiveness may identify children most likely to benefit from ICS treatment. To determine if demographic and atopic features predict response to ICS in preschool children at high risk for asthma. Two years of treatment with an ICS, fluticasone propionate (88 microg twice daily), was compared with matching placebo in a double-masked, randomized, multicenter study of 285 children 2 and 3 years old at high risk for asthma development. Baseline demographic and atopic features were related to clinical outcomes in a post hoc subgroup analysis. Multivariate analysis demonstrated significantly greater improvement with fluticasone than placebo in terms of episode-free days among boys, white subjects, participants with an emergency department (ED) visit or hospitalization within the past year, and those who experienced more symptomatic days at baseline. Children with aeroallergen sensitization experienced greater benefits in terms of oral corticosteroid use, urgent care and ED visits, and use of supplemental controller medications. More favorable responses to ICS than placebo in high-risk preschool children over a 2-year period were more likely in those with a ED visit or hospitalization for asthma within the past year, children with aeroallergen sensitization, boys, and white subjects.

Commentary: Maziak's essay, seen from another angle

endotoxin exposure reverse atopy and atopic disease? J Allergy Clinic Immunol 2004;114:1051–54. 53 WHO MONICA Project Principal Investigators. The World Health Organization MONICA project (monitoring trends and determinants in cardiovascular disease): a major international collaboration. J Clinic Epidemiol 1988;41: 105–14. 54 Wenzel S, Holgate ST. The mouse trap: It still yields few answers in asthma. Am J Respir Crit Care Med 2006;174:1173–76; discussion 1176–78. 55 Berry M, Morgan A, Shaw DE et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax 2007;62:1043–49. 56 Enarson D. Fostering a spirit of critical thinking: the ISAAC story. Int J Tuberculosis Lung Disease 2005;9:1.

Chromosome 17: association of a large inversion polymorphism with corticosteroid response in asthma.

A 900-kb inversion exists within a large region of conserved linkage disequilibrium (LD) on chromosome 17. CRHR1 is located within the inversion region and associated with inhaled corticosteroid response in asthma. We hypothesized that CRHR1 variants are in LD with the inversion, supporting a potential role for natural selection in the genetic response to corticosteroids. We genotyped six single nucleotide polymorphisms (SNPs) spanning chromosome 17: 40,410,565-42,372,240, including four SNPs defining inversion status. Similar allele frequencies and strong LD were noted between the inversion and a CRHR1 SNP previously associated with lung function response to inhaled corticosteroids. Each inversion-defining SNP was strongly associated with inhaled corticosteroid response in adult asthma (P values 0.002-0.005). The CRHR1 response to inhaled corticosteroids may thus be explained by natural selection resulting from inversion status or by long-range LD with another gene. Additional pharmacogenetic investigations into regions of chromosomal diversity, including copy number variation and inversions, are warranted.

FCER2: A pharmacogenetic basis for severe exacerbations in children with asthma

Although inhaled corticosteroids (ICSs) generally protect against severe exacerbations in asthma, they may result in elevated IgE levels, which are associated with exacerbations. To determine whether variation in the low-affinity IgE receptor gene, FCER2, is associated with severe exacerbations defined as emergency department visits and/or hospitalizations in patients with asthma on ICSs. We resequenced, then genotyped 10 FCER2 single nucleotide polymorphisms (SNPs) in 311 children randomized to inhaled budesonide as part of the Childhood Asthma Management Program. We evaluated the association of FCER2 variants with IgE levels and presence or absence of severe exacerbations over the 4-year clinical trial. We also evaluated differences in cellular expression of the novel FCER2 SNP, T2206C. In white subjects, 3 FCER2 SNPs were significantly associated (P < .05) with elevated 4-year IgE level; each was also associated with increased severe exacerbations. Final multivariable models demonstrated associations between T2206C and severe exacerbations in both white and African American children (hazard ratio, 3.95; 95% CI, 1.64-9.51; and hazard ratio, 3.08; 95% CI, 1.00-9.47), despite ICS use. Interaction models supported a true gene-environment effect in white subjects (interaction P = .004). T2206C was also associated with decreased FCER2 expression (P = .02). FCER2 predicts the likelihood of treatment protocol success in asthma. The associations of T2206C with IgE level, severe exacerbations, and FCER2 expression may provide a mechanistic basis for the observed findings. Genetic variation in FCER2 may help form a prognostic model for ICS response in asthma.

Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma

Background:Non-eosinophilic asthma is a potentially important clinicopathological phenotype since there is evidence that it responds poorly to inhaled corticosteroid therapy. However, little is known about the underlying airway immunopathology and...

The Predicting Response to Inhaled Corticosteroid Efficacy (PRICE) trial

Although guidelines recommend anti-inflammatory therapy for persistent asthma, recent studies suggest that 25% to 35% of patients with asthma may not improve lung function with inhaled corticosteroids. To evaluate potential biomarkers of predicting short-term (6-week) response to inhaled corticosteroid with subsequent evaluation of responders and nonresponders to asthma control over a longer interval (16 additional weeks). Eighty-three subjects with asthma off steroid were enrolled in this multicenter study. Biomarkers and asthma characteristics were evaluated as predictors of inhaled corticosteroid response over a 6-week trial for changes in FEV(1) and methacholine PC(20). After this, an additional 4-month trial evaluated asthma control. Although multiple baseline predictors had significant correlations with improvements for short-term inhaled steroid success, the only strong correlations (r >or= +/- 0.6) were albuterol reversibility (r = 0.83; P < .001), FEV(1)/forced vital capacity (r = -0.75; P < .001), and FEV(1) % predicted (r = -0.71; P < .001). Dividing the subjects in the short-term inhaled steroid trial into responders (>5% FEV(1) improvement) and nonresponders (<or=5%) determined the longer-term need for steroids. For the nonresponders, asthma control remained unchanged whether inhaled corticosteroids were continued or were substituted with a placebo (P = .99). The good short-term responders maintained asthma control longer-term only if maintained on inhaled steroids (P = .007). The short-term response to inhaled corticosteroids with regard to FEV(1) improvement predicts long-term asthma control. The decision to use long-term inhaled steroids could be based on a short-term trial. Different therapeutic strategies would need to be established for nonresponders.

A meta-analysis of the dose-response relationship of inhaled corticosteroids in adolescents and adults with mild to moderate persistent asthma

Background: Although inhaled corticosteroids (ICS) are commonly used in the treatment of persistent asthma, the relationship between dose and clinical response remains unclear. Objective: This study investigated whether ICS exhibit a dose-response relationship in the treatment of mild to moderate persistent asthma. Methods: This was a meta-analysis of published randomized clinical trials concerning the relationship between ICS dose and response in asthma. Relevant studies were identified through a search of PubMed and MEDLINE for articles on asthma and ICS published between January 1996 and January 2001. The search was limited to publications classified as clinical trials that included the text words asthma and corticosteroids, glucocorticoids, beclomethasone, budesonide, fluticasone, flunisolide, mometasone, or triamcinolone acetonide. Five clinical measures were considered: morning peak expiratory flow rate ( am PEFR), evening PEFR ( pm PEFR), forced expiratory volume in 1 second (FEV 1), beta-agonist use, and asthma symptom score (severity of symptoms on a given day, as evaluated by patients). Results: Forty-three studies were identified, of which 16 met the criteria for inclusion in the meta-analysis. These studies involved 4 agents: fluticasone propionate, triamcinolone acetonide, budesonide, and mometasone furoate. A statistically significant dose response in am PEFR was observed with fluticasone propionate, triamcinolone acetonide, and budesonide (respective 95% CIs, 4.9 to 11.5, 4.7 to 18.0, and 5.8 to 24.9). A statistically significant dose response to fluticasone propionate and triamcinolone acetonide was also observed in pm PEFR (95% CIs, 2.0 to 8.7 and 2.4 to 13.7) and asthma symptom score (95% CI, −0.069 to −0.002 and −0.60 to −0.10). In terms of FEV 1, the dose response was statistically significant only with budesonide (95% CI, 0.025 to 0.17). Dose-response relationships were not disproportionately driven by the highest doses, and the greatest effects on response were seen at doses below or at the low end of the recommended range, suggesting that use of high doses of ICS may contribute only marginally to efficacy. Conclusions: Dose-response relationships were not uniformly observed with all drugs or for all measures of response. Use of higher doses of ICS in patients with mild to moderate persistent asthma does not appear to increase the efficacy of these drugs.