Corticosteroid Response Research Articles

GLCCI1 Variation Is Associated with Asthma Susceptibility and Inhaled Corticosteroid Response in a Chinese Han Population

GLCCI1 variations are found to be associated with response to glucocorticoid therapy in non-Hispanic white subjects with asthma. However, there are also other relevant studies that were not consistent with this finding. In this study we aimed to evaluate the association of GLCCI1 variations with asthma susceptibility and inhaled corticosteroid (ICS) response in a Chinese adult Han population. We genotyped 24 single nucleotide polymorphisms of GLCCI1 in 182 asthmatic patients and 180 healthy controls. Furthermore, we analyzed the association of GLCCI1 variations with ICS response in 30 mild-to-moderate asthmatics. rs11976862 homozygote mutant genotype GG was nominally associated with increased asthma risk (OR=2.435, 95% CI: 1.221-4.854, p=0.01148, p(corr)=0.0127). Recessive model of rs37972, rs37973 and rs11976862 showed that the rare alleles were correlated with less improvement in FEV1 after fluticasone treatment for 12weeks (p=0.004, p=0.009 and p=0.039, respectively). The GLCCI1 mRNA expression level decreased obviously in asthmatics than in healthy controls (0.037663±0.0216833 vs. 0.046352±0.0235812, p=0.000). For asthmatics, GLCCI1 mRNA expression level significantly increased after fluticasone treatment for 12weeks (0.067641±0.031547 vs. 0.030048±0.014613, p=0.000). Moreover, changes of GLCCI1 mRNA expression were significantly related with rs37973 and rs11976862 in a recessive model (p=0.014 and p=0.033, respectively). GLCCI1 variations are associated with asthma susceptibility and ICS response in a Chinese Han adult population. GLCCI1 variations may affect ICS response by modulating GLCCI1 expression.

Multicentric Castleman Disease With Tubulointerstitial Nephritis Mimicking IgG4-related Disease

Multicentric Castleman disease is a benign lymphoproliferative disorder with heterogenous clinical symptoms and involves systemic organs in addition to lymph nodes. Elevated serum IgG4 levels and IgG4-positive plasma cell (IgG4+PC) infiltrates have been reported in lymph nodes, lung and skin in some multicentric Castleman disease cases, resembling IgG4-related disease (IgG4-RD) histologically. However, no report has been available regarding IgG4+PC infiltration in the kidneys of multicentric Castleman disease. Here, we report 2 cases of multicentric Castleman disease complicated by IgG4-related disease (IgG4-RD) histologically. However, there has been no report published on PC-rich tubulointerstitial nephritis, lymphadenopathy, with numerous IgG4+PC infiltration, and elevated serum IgG4 levels, mimicking IgG4-RD. The blood examinations revealed systemic inflammation and elevated C-reactive protein and interleukin-6 levels. Corticosteroid therapy was partially effective in both cases, and combination therapy of corticosteroid and tocilizumab was needed in both cases. Moreover, after triple therapy with corticosteroid, rituximab and cyclophosphamide were used in 1 case to tame the severe inflammation. The present cases suggest that if continuously elevated serum C-reactive protein levels and partial corticosteroid responsiveness are encountered, multicentric Castleman disease should be considered rather than IgG4-RD as a differential diagnosis even if serum IgG4 is elevated and IgG4+PCs infiltrate systemic organs.

Review article: the practical management of acute severe ulcerative colitis.

Acute severe ulcerative colitis (ASUC) is a life-threatening condition for which optimal management strategies remain ill-defined. To review the evidence regarding the natural history, diagnosis, monitoring and treatment of ASUC to inform an evidence-based approach to management. Relevant articles addressing the management of ASUC were identified from a search of MEDLINE, the Cochrane Library and conference proceedings. Of ASUC, 31-35% is steroid-refractory. Infliximab and ciclosporin salvage therapies have improved patient outcomes in randomised controlled trials. Short-term response rates (within 3 months) have ranged from 40% - 54% for ciclosporin and 46-83% for infliximab. Long-term clinical response rates (≥1 year) have ranged from 42%-50% for ciclosporin and 50-65% for infliximab. Short-term and long-term colectomy rates have been respectively: 26-47% and 36-58% for ciclosporin, and 0-50% and 35-50% for infliximab. Mortality rates for ciclosporin and infliximab-treated patients have been: 0-5% and 0-2%, respectively. At present, management challenges include the selection, timing and assessment of response to salvage therapy, utilisation of therapeutic drug monitoring and long-term maintenance of remission. Optimal management of acute severe ulcerative colitis should be guided by risk stratification using predictive indices of corticosteroid response. Timely commencement and assessment of response to salvage therapy is critical to reducing morbidity and mortality. Emerging pharmacokinetic models and therapeutic drug monitoring may assist clinical decision-making and facilitate a shift towards individualised acute severe ulcerative colitis therapies.

Frequency of polymorphic variants in CRHR1, GLCCI1 and FCER2 genes in healthy and asthmatic Tamilian population

Background: Asthma is a chronic airway inflammatory disease characterized by increased hyper-responsiveness and recurrent episodes of reversible obstructions. Asthma pharmacogenomic studies report significant association of single nucleotide polymorphisms (SNPs) in genes corticotropin releasing hormone receptor 1 (CRHR1), Fc fragment of IgE receptor II (FCER2) and glucocorticoid induced 1 (GLCCI1) with inhaled corticosteroid (ICS) response. The present study was aimed to establish the allelic and genotypic frequencies of polymorphisms rs242941, rs28364072 & rs37972 in CRHR1, FCER2 and GLCCI1 genes, respectively in Tamilian healthy population and asthma patients and to compare with established frequencies of global populations. Methods: The study groups consisted of healthy volunteers and persistent asthma patients who were drug naive or without ICS treatment in the last ≥2 months, attending JIPMER hospital (n=111 and 78, respectively). SNP genotyping was done using PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) and real time-PCR methods. Results: Allelic and genotypic frequencies for all the studied variants found to be in hardy-weinberg equilibrium with minor allele frequencies (MAF) of rs 242941, rs 28364072 and rs 37972 at 0.51, 0.33 and 0.38, respectively, in healthy population. No significant difference in gene frequencies was obtained between healthy control and asthma patient groups. Significant difference in allele frequencies was observed between Tamilian healthy and specific global populations. West African frequency was found to be significantly different for all 3 SNPs (p<0.0001). Conclusions: MAF of rs 242941, rs 28364072 and rs 37972 were 0.51, 0.33 and 0.38, respectively in Tamilian population which were significantly different from various global populations. The frequency distribution found helps to further with ICS response association studies in larger cohorts of asthma patients.

Clinical Utility of Fractional exhaled Nitric Oxide (FeNO) as a Biomarker to Predict Severity of Disease and Response to Inhaled Corticosteroid (ICS) in Asthma Patients.

Bronchial asthma is a common chronic inflammatory airway disease diagnosed and is based on symptomatic history and Pulmonary Function Tests (PFT). Fractional exhaled Nitric Oxide (FeNO) is exclusively a non-invasive biomarker of on-going eosinophilic airway inflammation which remains unpredictable only with PFTs. FeNO measurement is recommended in predicting asthma severity and Inhaled Corticosteroid (ICS) response but further research is required to understand its clinical utility and agreement with current recommendations in a specific population. To estimate FeNO levels in Tamilian patients with mild-to-moderate persistent asthma and to correlate with disease severity and ICS response. The study was a prospective cohort with a single group of 102 persistent asthma patients under standard ICS regimen for 8 weeks (follow-up period). PFT and FeNO were measured using portable spirometry and chemiluminescence based exhaled breath analyser, at baseline and during follow-up visits. Based on PFT and FeNO parameters, the study population was sub-grouped with respect to asthma severity (as mild, moderate and moderately severe), FeNO cut-off (> or < 50ppb) and ICS response classification (good vs poor ICS responders). Significant decrease in mean FeNO levels were found in mild, moderate and moderately severe asthmatic groups following ICS treatment (90.15±27.36, 75.74±31.98 and 77.18±32.79 ppb) compared to similar baseline FeNO levels (103.03±34.08, 91.38±37.60 and 97.90±43.84 ppb) in all the above groups. Similarly, significant decrease in mean FeNO levels was found - FeNO>50ppb, good and poor ICS responders groups, in post- ICS treatment (89.63±24.04, 77.90±31.12 and 86.49±32.57 ppb) compared to baseline levels (110.183±1.23, 97.12±42.04 and 99.68±34.71 ppb). The observed baseline FeNO values in all groups as stated above did not show significant difference to differentiate asthma severity or ICS responders groups. The present study results do not support the predictive association of baseline FeNO levels with asthma severity and future ICS response, but the decrements in FeNO levels on ICS treatment, supports its clinical utility in monitoring of ongoing airway inflammation and understanding treatment response rate.

Sputum mast cell subtypes relate to eosinophilia and corticosteroid response in asthma

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.

Blood profiles in unanesthetized and anesthetized guinea pigs (Cavia porcellus).

The guinea pig is a common animal model that is used in biomedical research to study a variety of systems, including hormonal and immunological responses, pulmonary physiology, corticosteroid response and others. However, because guinea pigs are evolutionarily a prey species, they do not readily show behavioral signs of disease, which can make it difficult to detect illness in a laboratory setting. Minimally invasive blood tests, such as complete blood counts and plasma biochemistry assays, are useful in both human and veterinary medicine as an initial diagnostic technique to rule in or rule out systemic illness. In guinea pigs, phlebotomy for such tests often requires that the animals be anesthetized first. The authors evaluated hematological and plasma biochemical effects of two anesthetic agents that are commonly used with guinea pigs in a research setting: isoflurane and a combination of ketamine and xylazine. Hematological and plasma biochemical parameters were significantly different when guinea pigs were under either anesthetic, compared to when they were unanesthetized. Plasma proteins, liver enzymes, white blood cells and red blood cells appeared to be significantly altered by both anesthetics, and hematological and plasma biochemical differences were greater when guinea pigs were anesthetized with the combination of ketamine and xylazine than when they were anesthetized with isoflurane. Overall these results indicate that both anesthetics can significantly influence hematological and plasma biochemical parameters in guinea pigs.

Rare idiopathic interstitial pneumonias: LIP and PPFE and rare histologic patterns of interstitial pneumonias: AFOP and BPIP.

In the 2013 reclassification of the idiopathic interstitial pneumonias (IIPs), two rare IIPs (idiopathic lymphoid interstitial pneumonia (LIP), idiopathic pleuroparenchymal fibroelastosis (IPPFE)) and two rare histologic patterns (acute fibrinous and organizing pneumonia (AFOP), bronchiolocentric pattern of interstitial pneumonia (BPIP)) are described. All these entities are rare with small series published to date, mostly containing primary and secondary forms of disease. LIP is histologically characterized by diffuse polyclonal lymphoid cell infiltrate surrounding the airways and expanding the interstitium. Thin-walled cysts and diffuse ground glass are considered the typical radiologic features. The clinical course is highly variable with corticosteroid responsiveness evident in approximately half of cases. IPPFE is defined histologically by coexisting upper lobe pleural and intra-alveolar fibrosis with elastosis. Dense subpleural irregular fibrosis and consolidation are the cardinal radiologic features. A history of recurrent lower respiratory tract infection is frequent. Responses to immunomodulation have not been reported and the rate of progression appears to be highly variable. AFOP is a rare histologic pattern lying within the spectrum of acute/subacute lung injury, characterized by organizing pneumonia and intra-alveolar fibrin deposition without hyaline membranes. BPIP is characterized histologically by fibrosis and/or inflammation confined to the alveolar interstitium around bronchovascular bundles, overlapping with peribronchial metaplasia and fibrosis in some series. Currently, AFOP and BPIP are both best viewed as histological entities rather than true clinical disorders, in the absence of characteristic associated imaging patterns and clinical features.

Exhaled nitric oxide in relation to asthma control: A real-life survey

BackgroundAsthma is characterised by chronic airway inflammation, a complex cascade of events, mostly sustained by eosinophil recruitment and activation. Fractional exhaled nitric oxide (FeNO) is a surrogate marker of airway inflammation closely associated with bronchial eosinophilia. FeNO is used to define asthma phenotype, to assess eosinophilic inflammatory severity and to predict corticosteroid responsiveness. ObjectiveThe aim of this study was to investigate whether FeNO may be associated with some clinical and functional factors in asthmatics evaluated in a real life setting. MethodsGlobally 363 patients (150 males, mean age 46.3 years) with asthma were consecutively evaluated. The following parameters were assessed: history, including comorbidities, physical examination, body mass index (BMI), lung function, asthma control grade, asthma control test (ACT), and FeNO. ResultsFeNO values were significantly higher in patients with poorly controlled asthma (p<0.01), asthma symptoms (p=0.015), wheezing (p<0.001), rhinitis diagnosis, (p=0.049) and rhinitis symptoms (p=0.019), but lower in patients with GERD (p=0.024) and pneumonia history (p=0.048). FeNO values increased in patients with the lowest corticosteroid dose (p=0.031). FeNO values>25ppb were associated with poorly controlled asthma (OR 3.71), asthma signs (OR 3.5) and symptoms (OR 1.79). A FeNO value cut-off of 29.9ppb was fairly predictive of (AUC 0.7) poorly controlled asthma. ConclusionsFeNO assessment in clinical practice may be a useful tool for monitoring asthmatics as it is associated with several clinical factors, including asthma control.

Long-term variability of exhaled nitric oxide measurements

Measurement of fractional exhaled nitric oxide (FENO) is recommended as an adjunct in the diagnosis of eosinophilic airway inflammation, to determine the likelihood of corticosteroid responsiveness, to monitor therapy, and to assess adherence to inhaled corticosteroid therapy. The American Thoracic Society Guidelines for the interpretation of FENO concentrations identify cut points in children of greater than 35 parts per billion (ppb) for eosinophilic airway inflammation and less than 20 ppb for no inflammation. For adults, the guidelines recommend greater than 50 ppb and less than 25 ppb, respectively. The NIOX MINO (Aerocrine AB, Solna, Sweden) is a commonly used portable method of analyzing FENO that does not require calibration. The accuracy and precision of this device were largely determined by extensive in vitro testing for US Food and Drug Administration clearance. The same is true for its successor, the NIOX VERO. The clinical study in the MINO FDA submission was a single measurement before and after beginning inhaled corticosteroids, which demonstrated a decrease in FENO. Other published clinical studies are single visit comparisons with other methods or multiple technicians. Only one study compared 2 measurements on different days. Because there are no published reports on the long-term reproducibility of devices used to measure FENO, we undertook the following study. We analyzed 451 quality control measurements obtained over a 2-year period from 5 devices. There were 5 nonasthmatic technicians (quality control subjects) who performed these measurements on each day that the device was used for a clinical study or patient care (see Table E1 in this article’s Online Repository at www.jaci-inpractice.org for more details). All control subjects met the manufacturer’s criteria, which included >18 years old, no ongoing cold or known airway disorder, nonsmoker, expected stable exhaled nitric oxide values between 5 and 40 ppb during the qualification period, and preferably no allergies (except seasonal) or asthma. To obtain a control FENO measurement, each technician was required to empty his or her lungs by slowly exhaling and then forming a tight seal around the mouthpiece, making sure not to let the air leak out. Then, they inhaled to total lung capacity and exhaled forcefully for approximately 10 seconds through the mouthpiece while responding to sound and light cues on the LCD to guide the rate of exhalation. The general linear model procedure was used to determine whether there was a device*subject interaction. Because the interaction was significant (P .05). Measurements for subjects 3-5 who used device 5 were 31.79 (7.2), 11.51 (4.2), and 15.0 (4.1) ppb, respectively (Figure 2). Measurements for subject 3 were significantly higher than those for subjects 4 and 5 (P < .0001). Eighty-two percent of her values were above 25 ppb. The NIOX MINO portable device employing an electrochemical methodology was cleared by FDA as “substantially equivalent” to the chemiluminescence stationary method (NIOX), largely based on extensive in vitro testing using certified nitric oxide in nitrogen calibration gas. Similarly, the new NIOX VERO was cleared in the same way as “substantially

A retrospective analysis of computed tomography findings in patients with pulmonary complications after allogeneic hematopoietic stem cell transplantation

ObjectiveThe purpose of this study was to review the high-resolution computed tomography (CT) findings in patients with pulmonary complications after allogeneic hematopoietic stem cell transplantation (HSCT), and to evaluate the relationship between CT findings and clinical outcomes. Patients and methodsWe collected the clinical data in 96 consecutive patients who underwent CT scan for pulmonary complications after allogeneic HSCT and analyzed the relationships among these clinical characteristics, CT findings and clinical responses. Radiologists who were blinded to clinical information evaluated the CT findings. ResultsIn multivariate analyses, the presence of chronic graft-versus-host disease (GVHD) and non-segmental multiple consolidations were significantly associated with a poor response to antimicrobial therapies, and the disease risk was significantly associated with a poor corticosteroid response. In addition, the existence of cavity formation and pleural effusion were significantly associated with a fatal prognosis. Twenty-five patients underwent bronchoscopic examination and 4 of them also underwent transbronchial lung biopsy (TBLB), but diagnostic information was not obtained in 15 patients. There was no significant association between specific CT findings and the diagnosis based on bronchoscopic examination. ConclusionsNo specific CT finding was identified as a predictor for either an antimicrobial response or for a corticosteroid response in this study. The presence of cavity formation and pleural effusion may predict a poor prognosis.

Blood eosinophils as a marker of likely corticosteroid response in children with preschool wheeze: time for an eosinophil guided clinical trial?

Childhood wheezing is common particularly in children under the age of 6 years and in this age group is generally referred to as preschool wheezing. Particular diagnostic and treatment uncertainties exist in these young children due to the difficulty in obtaining objective evidence of reversible airways narrowing and inflammation. A diagnosis of asthma depends on the presence of relevant clinical signs and symptoms and the demonstration of reversible airways narrowing on lung function testing, which is difficult to perform in young children. Few treatments are available and inhaled corticosteroids are the recommended preventer treatment in most international asthma guidelines. There is, however, considerable controversy about its effectiveness in children with preschool wheeze and a corticosteroid responder phenotype has not been established. These diagnostic and treatment uncertainties in conjunction with the knowledge of corticosteroid side effects, in particular the reduction of growth velocity, have resulted in a variable approach to inhaled corticosteroid prescribing by medical practitioners and a reluctance in carers to regularly administer the treatment. Identifying children who are likely responders to corticosteroid therapy would be a major benefit in the management of this condition. Eosinophils have emerged as a promising biomarker of corticosteroid responsive airways disease, and evaluation of this biomarker in sputum has successfully been employed to direct management in adults with asthma. Obtaining sputum from young children is time consuming and difficult, and it is hard to justify more invasive procedures such as a bronchoscopy in young children routinely. Recently, in children, interest has shifted to assessing the value of less invasive biomarkers of likely corticosteroid response and the biomarker 'blood eosinophils' has emerged as an attractive candidate. The aim of this review was to summarize the evidence for blood eosinophils as a predictive biomarker for corticosteroid responsive disease with a particular focus on the difficult area of preschool wheeze.

The effects of corticosteroids on COPD lung macrophages: a pooled analysis.

BackgroundThere is large variation in the therapeutic response to inhaled corticosteroids (ICS) in COPD patients. We present a pooled analysis of our previous studies investigating the effects of corticosteroids on lung macrophages, in order to robustly determine whether corticosteroid sensitivity in COPD cells is reduced compared to controls, and also to evaluate the degree of between individual variation in drug response.MethodsData from 20 never smokers (NS), 27 smokers (S) and 45 COPD patients was used. Lung macropahges had been stimulated with lipopolysaccharide (LPS), with or without the corticosteroid dexamethasone, and tumour necrosis factor (TNF)-α, interleukin (IL)-6 and chemokine C-X-C motif ligand (CXCL) 8 production was measured.ResultsThere was no difference in the anti-inflammatory effects of corticosteroids when comparing group mean data of COPD patients versus controls. The inhibition of TNF-α and IL-6 was greater than CXCL8. The effects of corticosteroids varied considerably between subjects, particularly at lower corticosteroid concentrations.ConclusionsWe confirm that overall corticosteroid sensitivity in COPD lung macrophages is not reduced compared to controls. The varied effect of corticosteroids between subjects suggests that some individuals have an inherently poor corticosteroid response. The limited suppression of lung macrophage derived CXCL8 may promote neutrophilic inflammation in COPD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0260-0) contains supplementary material, which is available to authorized users.

Hypothalamic-Pituitary--Adrenal Axis-Feedback Control.

The hypothalamo-pituitary-adrenal axis (HPA) is responsible for stimulation of adrenal corticosteroids in response to stress. Negative feedback control by corticosteroids limits pituitary secretion of corticotropin, ACTH, and hypothalamic secretion of corticotropin-releasing hormone, CRH, and vasopressin, AVP, resulting in regulation of both basal and stress-induced ACTH secretion. The negative feedback effect of corticosteroids occurs by action of corticosteroids at mineralocorticoid receptors (MR) and/or glucocorticoid receptors (GRs) located in multiple sites in the brain and in the pituitary. The mechanisms of negative feedback vary according to the receptor type and location within the brain-hypothalmo-pituitary axis. A very rapid nongenomic action has been demonstrated for GR action on CRH neurons in the hypothalamus, and somewhat slower nongenomic effects are observed in the pituitary or other brain sites mediated by GR and/or MR. Corticosteroids also have genomic actions, including repression of the pro-opiomelanocortin (POMC) gene in the pituitary and CRH and AVP genes in the hypothalamus. The rapid effect inhibits stimulated secretion, but requires a rapidly rising corticosteroid concentration. The more delayed inhibitory effect on stimulated secretion is dependent on the intensity of the stimulus and the magnitude of the corticosteroid feedback signal, but also the neuroanatomical pathways responsible for activating the HPA. The pathways for activation of some stressors may partially bypass hypothalamic feedback sites at the CRH neuron, whereas others may not involve forebrain sites; therefore, some physiological stressors may override or bypass negative feedback, and other psychological stressors may facilitate responses to subsequent stress.

25: Determinants of Oral Corticosteroid Responsiveness in Wheezing Asthmatic Youth (Doorway)

25: Determinants of Oral Corticosteroid Responsiveness in Wheezing Asthmatic Youth (Doorway)

Measuring the corticosteroid responsiveness endophenotype in asthmatic patients

Inhaled corticosteroids are the most commonly used controller therapies for asthma, producing treatment responses in 6 clinical phenotypes: lung function, bronchodilator response, airway responsiveness, symptoms, need for oral steroids and frequency of emergency department visits and hospitalizations. We hypothesize that treatment response in all of these phenotypes is modulated by a single quantitative corticosteroid responsiveness endophenotype. We sought to develop a composite phenotype that combines multiple clinical phenotypes to measure corticosteroid responsiveness with high accuracy, stability across populations, and robustness to missing data. We used principal component analysis to determine a composite corticosteroid responsiveness phenotype that we tested in 4 replication populations. We evaluated the relative accuracy with which the composite and clinical phenotypes measure the endophenotype using treatment effect area under the receiver operating characteristic curve (AUC). In the study population the composite phenotype measured the endophenotype with an AUC of 0.74, significantly exceeding the AUCs of the 6 individual clinical phenotypes, which ranged from 0.56 (P < .001) to 0.67 (P = .015). In 4 replication populations with a total of 22 clinical phenotypes available, the composite phenotype AUC ranged from 0.69 to 0.73, significantly exceeded the AUCs of 14 phenotypes, and was not significantly exceeded by any single phenotype. The composite phenotype measured the endophenotype with higher accuracy, higher stability across populations, and higher robustness to missing data than any clinical phenotype. This should provide the capability to model corticosteroid pharmacologic response and resistance with increased accuracy and reproducibility.

Corticosteroid responses following hypoxic preconditioning provide neuroprotection against subsequent hypoxic-ischemic brain injury in the newborn rats

Limited research has evaluated the corticosteroids (CS) response in hypoxic preconditioning (PC) induced neuroprotection against subsequent hypoxic-ischemic (HI) brain injury in newborns. To measure, CS response to hypoxic PC, at postnatal day 6 (P6), rat pups were randomly divided into sham, NoPC (exposure to 21% O2) and PC (exposure to 8% O2 for 3h) groups. In a separate experiment, at P6, rat pups were randomly divided into three groups (sham, NoPC+HI, PC+HI). Rat pups in NoPC+HI and PC+HI groups, respectively had normoxic or hypoxic exposure for 3h at P6 and then had the right carotid artery permanently ligated followed by 140min of hypoxia at P7 (HI). Plasma CS levels were measured at 0.5, 1, 3, 6 and 12h after hypoxic PC and hypoxic PC followed by HI. To investigate whether CS response to hypoxic PC provides neuroprotection against HI, at P6, rat pups were randomly divided into five groups. Fifteen minutes prior to PC or normoxic exposure, rat pups in DMSO+PC+HI and DMSO+NoPC+HI groups received DMSO while in RU486+PC+HI and RU486+NoPC+HI groups received RU486 (glucocorticoid receptor blocker, 60mg/kg) s.c., respectively. Afterwards, rat pups were exposed to normoxia (DMSO+NoPC+HI, RU486+NoPC+HI) or hypoxia (DMSO+PC+HI, RU486+PC+HI) for 3h and then HI 24h later (P7). Rat pups at the corresponding age without any exposure to PC or HI or RU486/DMSO were used as sham. We found that hypoxic PC caused CS surge as well as augmented CS surge and preserved the glucocorticoid feedback regulation after HI. Hypoxic PC reduced HI induced early and delayed brain damage. RU486 partially but significantly inhibited hypoxic PC induced neuroprotection.

Vanin-1 expression and methylation discriminate pediatric asthma corticosteroid treatment response

There is considerable heterogeneity in asthma treatment response. We sought to identify biomarkers of corticosteroid treatment response in children with asthma and evaluate the utility and mechanistic basis of these biomarkers. Children (5-18 years) presenting to the emergency department with an acute asthma exacerbation were recruited and followed during hospitalization. Nasal epithelial cells were collected on presentation to the emergency department (T0) and 18 to 24 hours later (T1), and T1/T0 gene expression ratios were analyzed to identify genes associated with good and poor corticosteroid treatment response phenotypes. The utility of these genes in discriminating between systemic corticosteroid treatment response groups was then tested prospectively in a new cohort of patients. A gene candidate (vanin-1 [VNN1]) that consistently distinguished good versus poor response phenotypes was further studied in an experimental asthma model, and VNN1 promoter methylation was measured by means of bisulfite pyrosequencing in patients. VNN1 mRNA expression changes were associated with systemic corticosteroid treatment response in children with acute asthma, and VNN1 was required for optimal response to corticosteroid treatment in an experimental asthma model. A CpG site within the VNN1 promoter was differentially methylated between good versus poor treatment response groups, and methylation at this site correlated with VNN1 mRNA expression. We have identified a biological basis for poor corticosteroid treatment response that can be used to distinguish a subgroup of asthmatic children who respond poorly to systemic corticosteroid treatment. VNN1 contributes to corticosteroid responsiveness, and changes in VNN1 nasal epithelial mRNA expression and VNN1 promoter methylation might be clinically useful biomarkers of treatment response in asthmatic children.

Pharmacogenomic test that predicts response to inhaled corticosteroids in adults with asthma likely to be cost-saving.

To identify the clinical and economic circumstances under which a pharmacogenomic test that predicts response to inhaled corticosteroids might be a cost-effective option for individuals with asthma. We synthesized published data on clinical and economic outcomes to project 10-year costs, quality-adjusted life-years and cost-effectiveness of pharmacogenomic testing for inhaled corticosteroid response. We assumed the pharmacogenomic test cost was $500 with a sensitivity and specificity of 84 and 98%, respectively. These were varied in sensitivity analyses. Both strategies, pharmacogenomic testing for inhaled corticosteroid response and no testing conferred 7.1 quality-adjusted life-years. Compared with no testing, pharmacogenomic testing costs less. Pharmacogenomic testing for asthma is cost-saving and noninferior in improving health. Original submitted 19 November 2014; Revision submitted 23 February 2015.

Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis

Eosinophilic airway inflammation is associated with increased corticosteroid responsiveness in asthma, but direct airway sampling methods are invasive or laborious. Minimally invasive markers for airway eosinophilia could present an alternative method, but estimates of their accuracy vary. We did a systematic review and searched Medline, Embase, and PubMed for studies assessing the diagnostic accuracy of markers against a reference standard of induced sputum, bronchoalveolar lavage, or endobronchial biopsy in patients with asthma or suspected asthma (for inception to Aug 1, 2014). Unpublished results were obtained by contacting authors of studies that did not report on diagnostic accuracy, but had data from which estimates could be calculated. We assessed risk of bias with QUADAS-2. We used meta-analysis to produce summary estimates of accuracy. We included 32 studies: 24 in adults and eight in children. Of these, 26 (81%) showed risk of bias in at least one domain. In adults, three markers had extensively been investigated: fraction of exhaled nitric oxide (FeNO) (17 studies; 3216 patients; summary area under the receiver operator curve [AUC] 0·75 [95% CI 0·72-0·78]); blood eosinophils (14 studies; 2405 patients; 0·78 [0·74-0·82]); total IgE (seven studies; 942 patients; 0·65 [0·61-0·69]). In children, only FeNO (six studies; 349 patients; summary AUC 0·81 [0·72-0·89]) and blood eosinophils (three studies; 192 patients; 0·78 [0·71-0·85]) had been investigated in more than one study. Induced sputum was most frequently used as the reference standard. Summary estimates of sensitivity and specificity in detecting sputum eosinophils of 3% or more in adults were: 0·66 (0·57-0·75) and 0·76 (0·65-0·85) for FeNO; 0·71 (0·65-0·76) and 0·77 (0·70-0·83) for blood eosinophils; and 0·64 (0·42-0·81) and 0·71 (0·42-0·89) for IgE. FeNO, blood eosinophils, and IgE have moderate diagnostic accuracy. Their use as a single surrogate marker for airway eosinophilia in patients with asthma will lead to a substantial number of false positives or false negatives. None.