RATIONALE Airway inflammation in asthma is heterogeneous with different phenotypes. The inflammatory cell phenotype is modified by corticosteroids and smoking. Steroid therapy is beneficial in ...eosinophilic asthma (EA), but evidence is conflicting regarding non-eosinophilic asthma (NEA). OBJECTIVES To assess the inflammatory cell phenotypes in asthma after eliminating potentially confounding effects; to compare steroid response in EA versus NEA; and to investigate changes in sputum cells with inhaled corticosteroid (ICS). METHODS Subjects undertook ICS withdrawal until loss of control or 28 days. Those with airway hyper-responsiveness (AHR) took inhaled fluticasone 1000 microg daily for 28+ days. Cut-off points were > or = or <2% for sputum eosinophils and > or = or <61% for neutrophils. RESULTS After steroid withdrawal (n=94), 67% of subjects were eosinophilic, 31% paucigranulocytic and 2% mixed; there were no neutrophilic subjects. With ICS (n=88), 39% were eosinophilic, 46% paucigranulocytic, 3% mixed and 5% neutrophilic. Sputum neutrophils increased from 19.3% to 27.7% (p=0.024). The treatment response was greater in EA for symptoms (p<0.001), quality of life (p=0.012), AHR (p=0.036) and exhaled nitric oxide (p=0.007). Lesser but significant changes occurred in NEA (ie, paucigranulocytic asthma). Exhaled nitric oxide was the best predictor of steroid response in NEA for AHR (area under the curve 0.810), with an optimum cut-off point of 33 ppb. CONCLUSIONS After eliminating the effects of ICS and smoking, a neutrophilic phenotype could be identified in patients with moderate stable asthma. ICS use led to phenotype misclassification. Steroid responsiveness was greater in EA, but the absence of eosinophilia did not indicate the absence of a steroid response. In NEA this was best predicted by baseline exhaled nitric oxide.
Background Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms. Objective This study aimed to identify and validate a sputum gene expression ...signature that discriminates asthma inflammatory phenotypes. Methods An asthma phenotype biomarker discovery study generated gene expression profiles from induced sputum of 47 asthmatic patients. A clinical validation study (n = 59 asthmatic patients) confirmed differential expression of key genes. A 6-gene signature was identified and evaluated for reproducibility (n = 30 asthmatic patients and n = 20 control subjects) and prediction of inhaled corticosteroid (ICS) response (n = 71 asthmatic patients). Receiver operating characteristic curves were calculated, and area under the curve (AUC) values were reported. Results From 277 differentially expressed genes between asthma inflammatory phenotypes, we identified 23 genes that showed highly significant differential expression in both the discovery and validation populations. A signature of 6 genes, including Charcot-Leydon crystal protein (CLC) ; carboxypeptidase A3 (CPA3) ; deoxyribonuclease I-like 3 (DNASE1L3) ; IL-1β (IL1B) ; alkaline phosphatase, tissue-nonspecific isozyme (ALPL) ; and chemokine (C-X-C motif) receptor 2 (CXCR2) , was reproducible and could significantly ( P < .0001) discriminate eosinophilic asthma from other phenotypes, including patients with noneosinophilic asthma (AUC, 89.6%), paucigranulocytic asthma (AUC, 92.6%), or neutrophilic asthma (AUC, 91.4%) and healthy control subjects (AUC, 97.6%), as well as discriminating patients with neutrophilic asthma from those with paucigranulocytic asthma (AUC, 85.7%) and healthy control subjects (AUC, 90.8). The 6-gene signature predicted ICS response (>12% change in FEV1 ; AUC, 91.5%). ICS treatment reduced the expression of CLC , CPA3 , and DNASE1L3 in patients with eosinophilic asthma. Conclusions A sputum gene expression signature of 6 biomarkers reproducibly and significantly discriminates inflammatory phenotypes of asthma and predicts ICS treatment response. This signature has the potential to become a useful diagnostic tool to assist in the clinical diagnosis and management of asthma.
The proper management of asthma with the use of inhaled corticosteroids requires the adjustment of doses in proportion to the patient's need for treatment. In this study, the investigators compared ...groups treated according to two regimens, one based on conventional guidelines for the treatment of asthma and one based on measurements of the fraction of nitric oxide in the exhaled air. In the latter group, equivalent control of asthma was maintained with lower doses of inhaled corticosteroids.
The investigators compared groups treated according to two regimens, one based on conventional guidelines for the treatment of asthma and one based on measurements of the fraction of nitric oxide in the exhaled air.
Inhaled corticosteroids are the mainstay of treatment for chronic asthma, the doses of which should be adequate to control asthma symptoms but also as low as possible in order to prevent adverse effects. Since the dose required is highly variable, both among patients and within individual patients, physicians need an easy, effective, and safe method to guide dose titration. Current treatment guidelines recommend that adjustments in doses should be based on asthma symptoms and the results of basic pulmonary-function tests. Two proof-of-concept studies have demonstrated that the use of alternative criteria — namely, airway hyperresponsiveness
1
or eosinophilia in induced sputum . . .
Biomarker-based asthma phenotypes of corticosteroid response Cowan, Douglas C., BMedSci, MBChB, MRCP, PhD; Taylor, D. Robin, MD, DSc, FRCP (Ed); Peterson, Laura E., BA ...
Journal of allergy and clinical immunology,
04/2015, Letnik:
135, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Background Asthma is a heterogeneous disease with different phenotypes. Inhaled corticosteroid (ICS) therapy is a mainstay of treatment for asthma, but the clinical response to ICSs is variable. ...Objective We hypothesized that a panel of inflammatory biomarkers (ie, fraction of exhaled nitric oxide F eno , sputum eosinophil count, and urinary bromotyrosine BrTyr level) might predict steroid responsiveness. Methods The original study from which this analysis originates comprised 2 phases: a steroid-naive phase 1 and a 28-day trial of ICSs (phase 2) during which F eno values, sputum eosinophil counts, and urinary BrTyr levels were measured. The response to ICSs was based on clinical improvements, including a 12% or greater increase in FEV1 , a 0.5-point or greater decrease in Asthma Control Questionnaire score, and 2 doubling dose or greater increase in provocative concentration of adenosine 5′-monophosphate causing a 20% decrease in FEV1 (PC20 AMP). Healthy control subjects were also evaluated in this study for comparison of biomarkers with those seen in asthmatic patients. Results Asthmatic patients had higher than normal F eno values, sputum eosinophil counts, and urinary BrTyr levels during the steroid-naive phase and after ICS therapy. After 28-day trial of ICSs, F eno values decreased in 82% of asthmatic patients, sputum eosinophil counts decreased in 60%, and urinary BrTyr levels decreased in 58%. Each of the biomarkers at the steroid-naive phase had utility for predicting steroid responsiveness, but the combination of high F eno values and high urinary BrTyr levels had the best power (13.3-fold, P < .01) to predict a favorable response to ICS therapy. However, the magnitude of the decrease in biomarker levels was unrelated to the magnitude of clinical response to ICS therapy. Conclusion A noninvasive panel of biomarkers in steroid-naive asthmatic patients predicts clinical responsiveness to ICS therapy.
Mast cells are a resident inflammatory cell of the airways, involved in both the innate and adaptive immune response. The relationship between mast cells and inflammatory phenotypes and treatment ...response of asthma is not clear.Clinical characteristics of subjects with stable asthma (n=55), inflammatory cell counts and gene expression microarrays in induced sputum were analysed. Sputum mast cell subtypes were determined by molecular phenotyping based on expression of mast cell biomarkers (tryptase (TPSAB1), chymase (CMA1) and carboxypeptidase A3 (CPA3)). Effects of mast cell subtypes on steroid response were observed in a prospective cohort study (n=50).MCT(n=18) and MCT/CPA3(mRNA expression of TPSAB1 and CPA3; n=29) subtypes were identified, as well as a group without mast cell gene expression (n=8). The MCT/CPA3 subtype had elevated exhaled nitric oxide fraction, sputum eosinophils, bronchial sensitivity and reactivity, and poorer asthma control. This was accompanied by upregulation of 13 genes. Multivariable logistic regression identified CPA3(OR 1.21, p=0.004) rather than TPSAB1(OR 0.92, p=0.502) as a determinant of eosinophilic asthma. The MCT/CPA3 subtype had a better clinical response and reduced signature gene expression with corticosteroid treatment.Sputum mast cell subtypes of asthma can be defined by a molecular phenotyping approach. The MCT/CPA3 subtype demonstrated increased bronchial sensitivity and reactivity, and signature gene expression, which was associated with airway eosinophilia and greater corticosteroid responsiveness.
Statins have anti-inflammatory actions which in theory are potentially beneficial in asthma. Small trials have failed to show a significant benefit, but a systematic study to evaluate the ...steroid-sparing effect of statin treatment has not been carried out.
A randomised, placebo-controlled, crossover trial was conducted of simvastatin 40 mg at night with simultaneous stepwise reduction of fluticasone propionate dose until loss of control occurred, followed by an increase until regain of control ('minimum' dose required) in 51 patients with asthma and sputum eosinophils (steroid-free) ≥ 2%.
43 patients completed the study. There was no significant difference in 'minimum' inhaled corticosteroid (ICS) dose requirement between simvastatin and placebo: (median (IQR) 50 μg daily (0-250) vs 100 μg daily (0-250), p=0.931). 'Minimum' dose distribution was similar (p=0.269). The fluticasone dose at which loss of control occurred did not differ significantly between simvastatin and placebo (p=0.404). In patients with loss of control in both treatment arms, fluticasone dose at loss of control was similar with simvastatin and placebo (median (IQR) 50 μg daily (0-100) for both, p=0.620). In those patients who reached 0 μg/day (n=18), Astma Control Questionnaire (ACQ) was lower (p=0.037), forced expiratory volume in 1 s (FEV(1)) higher (p<0.01) and sputum eosinophils lower with simvastatin compared with placebo (9.5% compared with 25.4%, p=0.033).
Simvastatin does not have clinically important steroid-sparing effects in patients with eosinophilic asthma. In the absence of steroid, simvastatin is associated with minor improvements in symptoms and lung function, and a reduction in sputum eosinophils. Clinical trial number ACTRN12606000531516.
Exhaled nitric oxide (eNO) levels are increased in untreated or unstable asthma and measurements can be made easily. Our aim was to assess the usefulness of eNO for diagnosing and predicting loss of ...control (LOC) in asthma following steroid withdrawal. Comparisons were made against sputum eosinophils and airway hyperresponsiveness (AHR) to hypertonic saline (4.5%). Seventy-eight patients with mild/moderate asthma had their inhaled steroid therapy withdrawn until LOC occurred or for a maximum of 6 wk. Sixty (77.9%) developed LOC. There were highly significant correlations between the changes in eNO and symptoms (p < 0.0001), FEV(1) (p < 0.002), sputum eosinophils (p < 0.0002), and saline PD(15) (p < 0.0002), and there were significant differences between LOC and no LOC groups. Both single measurements and changes of eNO (10 ppb, 15 ppb, or an increase of > 60% over baseline) had positive predictive values that ranged from 80 to 90% for predicting and diagnosing LOC. These values were similar to those obtained using sputum eosinophils and saline PD(15) measurements. We conclude that eNO measurements are as useful as induced sputum analysis and AHR in assessing airway inflammation, with the advantage that they are easy to perform.
These investigators followed a large birth cohort with the use of questionnaires, lung-function tests, and allergy skin tests from the age of 3 to 26 years. Almost three quarters of the study ...participants had wheezing at one point in the follow-up, and 15 percent had wheezing at all points in the follow-up.
Clinical data on a large birth cohort.
The increase in the prevalence of wheezing disorders, whether or not they are labeled as asthma, could be related to an increased incidence or an increased persistence of asthma.
1
,
2
Studies of the natural history of asthma have often focused on selected populations. However, the outcomes in children referred to university clinics
3
,
4
or selected in high-risk cohorts
5
may not reflect the outcomes in the general population, since the initial selection criteria may predetermine the risk factors for persistence or relapse.
6
Most children attending asthma specialty clinics who have been followed have had atopy, with frequent symptoms and airway hyperresponsiveness, . . .
Breastfeeding is widely advocated to reduce risk of atopy and asthma, but the evidence for such an effect is conflicting. We aimed to assess long-term outcomes of asthma and atopy related to ...breastfeeding in a New Zealand birth cohort.
Our cohort consisted of 1037 of 1139 children born in Dunedin, New Zealand, between April, 1972, and March, 1973, and residing in Otago province at age 3 years. Children were assessed every 2–5 years from ages 9 to 26 years with respiratory questionnaires, pulmonary function, bronchial challenge, and allergy skin tests. History of breastfeeding had been independently recorded in early childhood.
504 (49%) of 1037 eligible children were breastfed (4 weeks or longer) and 533 (51%) were not. More children who were breastfed were atopic at all ages from 13 to 21 years to cats (p=0·0001), house dust mites (p=0·0010), and grass pollen (p<0·0001) than those who were not. More children who were breastfed reported current asthma at each assessment between age 9 (p=0·0008) and 26 years (p=0·0008) than those who were not. Breastfeeding effects were not affected by parental history of hayfever or asthma. Multifactor analysis controlling for socioeconomic status, parental smoking, birth order, and use of sheepskin bedding in infancy, showed odds ratios of 1·94 (95% CI 1·42–2·65, p<0·0001) for any allergen positive at age 13 years, 2·40 (1·36–4·26, p=0·0003) for current asthma at 9 years, and 1·83 (1·35–2·47, p<0·0001) for current asthma at 9–26 years by repeated-measures analysis.
Breastfeeding does not protect children against atopy and asthma and may even increase the risk.
Exhaled Nitric Oxide: A Predictor of Steroid Response Smith, Andrew D; Cowan, Jan O; Brassett, Karen P ...
American journal of respiratory and critical care medicine,
08/2005, Letnik:
172, Številka:
4
Journal Article
Recenzirano
The initial management of patients who present with persistent respiratory symptoms includes recognizing those with the potential to benefit from inhaled steroid therapy. To date, this has required ...undertaking a "trial of steroid" to identify responders. There is increasing evidence that steroid response is more likely in patients with eosinophilic airway inflammation, and this can be assessed indirectly using exhaled nitric oxide (FENO) measurements.
We aimed to assess the predictive accuracy of FENO to identify steroid response in 52 patients presenting with undiagnosed respiratory symptoms in a single-blind, fixed-sequence, placebo-controlled trial of inhaled fluticasone for 4 weeks.
Comparisons of predictive accuracy were made between FENO and other conventional predictors: peak flows, spirometry, bronchodilator response, and airway hyperresponsiveness measured at baseline. "Steroid response" was defined as change in symptoms, peak flows, spirometry, or airway hyperresponsiveness to adenosine based on established guidelines and recommendations.
Steroid response was significantly greater in the highest FENO tertile (> 47 ppb) for each endpoint. This outcome was independent of the diagnostic label. The predictive values for FENO were significantly greater than for almost all other baseline predictors, with an optimum cut point of 47 ppb.
FENO measurements greater than 47 ppb provide a means of predicting steroid response in patients with undiagnosed respiratory symptoms. Assessing airway inflammation is of more practical value than diagnostic labeling when considering the potential usefulness of inhaled antiinflammatory therapy.
PDF
