Biomarker Commons

Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study.

Am J Respir Crit Care Med. 2013 Apr 15;187(8):804-11

Authors: Hanania NA, Wenzel S, Rosén K, Hsieh HJ, Mosesova S, Choy DF, Lal P, Arron JR, Harris JM, Busse W

Abstract
RATIONALE: For many patients with asthma, allergic airway inflammation is primarily a Th2-weighted process; however, heterogeneity in patterns of inflammation suggests phenotypic distinctions exist that influence disease presentation and treatment effects.
OBJECTIVES: To assess the potential of fractional exhaled nitric oxide (FE(NO)), peripheral blood eosinophil count, and serum periostin as biomarkers of Th2 inflammation and predictors of treatment effects of omalizumab.
METHODS: The EXTRA omalizumab study enrolled patients (aged 12-75 yr) with uncontrolled severe persistent allergic asthma. Analyses were performed evaluating treatment effects in relation to FE(NO), blood eosinophils, and serum periostin at baseline. Patients were divided into low- and high-biomarker subgroups. Treatment effects were evaluated as number of protocol-defined asthma exacerbations during the 48-week treatment period (primary endpoint).
MEASUREMENTS AND MAIN RESULTS: A total of 850 patients were enrolled. Data were available from 394 (46.4%), 797 (93.8%), and 534 (62.8%) patients for FE(NO), blood eosinophils, and serum periostin, respectively. After 48 weeks of omalizumab, reductions in protocol-defined exacerbations were greater in high versus low subgroups for all three biomarkers: FE(NO), 53% (95% confidence interval [CI], 37-70; P = 0.001) versus 16% (95% CI, -32 to 46; P = 0.45); eosinophils, 32% (95% CI, 11-48; P = 0.005) versus 9% (95% CI, -24 to 34; P = 0.54); and periostin, 30% (95% CI, -2 to 51; P = 0.07) versus 3% (95% CI, -43 to 32; P = 0.94).
CONCLUSIONS: The difference in exacerbation frequency between omalizumab and placebo was greatest in the three high-biomarker subgroups, probably associated with the greater risk for exacerbations in high subgroups. Additional studies are required to explore the value of these biomarkers in clinical practice. Clinical trial registered with www.clinicaltrials.gov (NCT00314574).

PMID: 23471469 [PubMed - indexed for MEDLINE]

Cotinine versus questionnaire: early-life environmental tobacco smoke exposure and incident asthma.

BMC Pediatr. 2012;12:187

Authors: Carlsten C, Dimich-Ward H, DyBuncio A, Becker AB, Chan-Yeung M

Abstract
BACKGROUND: The use of biomarkers has expanded considerably, as an alternative to questionnaire-based metrics of environmental tobacco smoke (ETS); few studies have assessed the affect of such alternative metrics on diverse respiratory outcomes in children, and we aimed to do so.
METHODS: We evaluated various measures of birth-year ETS, in association with multiple respiratory endpoints early years of life, in the novel context of a birth cohort at high risk for asthma. We administered questionnaires to parents, both at the end of pregnancy and at one year of life, and measured cotinine in cord blood (CCot; in 275 children) and in urine (UCot; obtained at 12 months in 365 children), each by radioimmunoassay. Multiple logistic regression was used to assess the association of the various metrics with recurrent wheeze at age 2 and with bronchial hyperresponsiveness (BHR) and asthma at age 7.
RESULTS: Self-reported 3rd trimester maternal smoking was associated with significantly increased risk for recurrent wheeze at age 2 (odds ratio 3.5 [95% confidence interval = 1.2,10.7]); the risks associated with CCot and 3rd trimester smoking in any family member were similar (OR 2.9 [1.2,7.0] and 2.6 [1.0,6.5], respectively). No metric of maternal smoking at 12 months appeared to significantly influence the risk of recurrent wheeze at age 2, and no metric of ETS at any time appeared to significantly influence risk of asthma or BHR at age 7.
CONCLUSIONS: Biomarker- and questionnaire-based assessment of ETS in early life lead to similar estimates of ETS-associated risk of recurrent wheeze and asthma.

PMID: 23216797 [PubMed - indexed for MEDLINE]

Association of airway pentosidine levels with bronchodilator response mediated by salbutamol administration in asthmatic patients.

Pulm Pharmacol Ther. 2012 Dec;25(6):478-82

Authors: Tamagaki G, Kanazawa H, Hirata K

Abstract
BACKGROUND: Recently, increased levels of pentosidine, an intermolecular cross-linking type of advanced glycation end products, are observed in the airways of asthmatic patients. This study was designed to determine whether differences in bronchodilator response among individuals with asthma are attributable to pentosidine levels in their airways.
METHODS: Fifty-six asthmatic patients (21 with airway obstruction, 35 without airway obstruction) and 10 normal controls were included in this study. For asthmatic patients, we evaluated the spontaneous reversibility of airway obstruction or the reversibility that can be obtained after methacholine provocation. And we also measured pentosidine levels and percentage of sputum eosinophils in induced sputum, and exhaled nitric oxide (NO) levels.
RESULTS: The pentosidine levels did not significantly differ between the two asthmatic subgroups with and without airway obstruction. In asthmatic patients without airway obstruction, airway hyperresponsiveness to methacholine (PC20 methacholine) was significantly correlated with sputum eosinophils and exhaled NO levels. In contrast, PC20 methacholine was not significantly correlated with pentosidine levels. In asthmatic patients with or without airway obstruction, bronchodilator response was not significantly correlated with sputum eosinophils and exhaled NO levels. However, bronchodilator response was closely correlated with pentosidine levels (asthmatics without airway obstruction: r = -0.54, p = 0.002; asthmatics with airway obstruction: r = -0.48, p = 0.03).
CONCLUSIONS: Our results showed that pentosidine might be a potential biomarker reflecting the reduced bronchodilator response in asthma. This study will provide new insights into the mechanisms underlying persistent airway obstruction.

PMID: 22982562 [PubMed - indexed for MEDLINE]

IL-22 mRNA expression in blood samples as a useful biomarker for assessing the adverse health effects of PCBs on allergic children.

Int J Environ Res Public Health. 2012 Dec;9(12):4321-32

Authors: Tsuji M, Kawamoto T, Koriyama C, Matsumura F

Abstract
To facilitate the assessment of adverse effects of very low concentrations of air pollutants on general populations, we planned to establish a reliable biomarker that is also useful in identifying vulnerable populations. For this purpose we monitored several inflammation markers in blood samples from 2 year old Japanese children (N = 30), and found that those children living close to major highways (<50 m) show higher levels of mRNA expression IL-22 in their blood samples than those living further away (+50 m). This tendency was more pronounced among subjects showing positive IgE against egg and milk. We further examined association between IL-22 mRNA expression and PCB residues and found a number of significant positive correlations between each individual PCB congener and IL-22 expression. To identify the most vulnerable population among those children we selected asthma as a typical allergy-related disease, and could show that there are significant differences in the levels of IL-22 mRNA expression between IgE negative non-asthmatic subject and asthmatic children showing positive IgE reaction toward egg or milk, again. These observations support our main conclusion that IL-22 expression is a sensitive biomarker which is useful in identifying sub-populations of children who are especially vulnerable to air pollution.

PMID: 23330224 [PubMed - indexed for MEDLINE]

Therapeutic potential of ASP3258, a selective phosphodiesterase 4 inhibitor, on chronic eosinophilic airway inflammation.

Pharmacology. 2012;90(3-4):223-32

Authors: Kobayashi M, Kubo S, Shiraki K, Iwata M, Hirano Y, Ohtsu Y, Takahashi K, Shimizu Y

Abstract
We investigated and compared the pharmacological effects of a PDE4 inhibitor ASP3258 (3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] propanoic acid), with those of roflumilast, the most clinically advanced PDE4 inhibitor known. ASP3258 inhibited human PDE4A, 4B, 4C, and 4D with respective IC(50) values of 0.036, 0.050, 0.45, and 0.035 nmol/l, all approximately 3-6 times more potent than roflumilast. ASP3258 inhibited LPS-induced TNF-α production and PHA-induced IL-5 production in human whole blood cells with respective IC(50) values of 110 and 100 nmol/l, both approximately 10 times less potent than roflumilast. Repeatedly administered ASP3258 and roflumilast both suppressed chronic airway eosinophilia induced by repeated exposure to ovalbumin in Brown Norway rats with respective ED(50) values of 0.092 and 0.17 mg/kg. We also evaluated the toxicological profiles of ASP3258. Although PDE4 inhibitors induce emesis by mimicking the pharmacological action of an α(2)-adrenoceptor antagonist, repeated administration of ASP3258 (3 mg/kg) had no such inhibitory effect on rats anesthetized with α(2) - adrenoceptor agonist. PDE4 inhibitors are also known to induce vascular injury in rats. Although repeatedly administered ASP3258 (3 and 10 mg/kg) significantly increased plasma fibrinogen, a biomarker for toxicity, 1 mg/kg of ASP3258 did not. These results suggest that ASP3258 is an attractive PDE4 inhibitor for treating chronic eosinophilic airway inflammation due to asthma.

PMID: 23038661 [PubMed - indexed for MEDLINE]

An environmental epigenetic study of ADRB2 5'-UTR methylation and childhood asthma severity.

Clin Exp Allergy. 2012 Nov;42(11):1575-81

Authors: Fu A, Leaderer BP, Gent JF, Leaderer D, Zhu Y

Abstract
BACKGROUND: Beta-2 adrenergic receptor (ADRB2) is the primary target of both short- and long-acting beta-agonist asthma medications. ADRB2 5'-UTR methylation changes in blood have the potential to act as a surrogate biomarker of responsiveness to beta-agonist treatment and childhood asthma severity.
OBJECTIVE: To study the association between ADRB2 5'-UTR methylation, NO (2) exposure and childhood asthma severity.
METHODS: We compared ADRB2 5'-UTR methylation levels in blood between 60 children with mild asthma and 122 children with severe asthma using methylation-specific PCR. We also investigated potential joint effects between NO (2) exposure and ADRB2 5'-UTR methylation.
RESULTS: We found a significant association between intermediate (OR: 4.11, 95% CI: 1.58-10.73) and high levels (OR: 7.63, 95% CI: 3.02-19.26) of ADRB2 methylation and severe childhood asthma. In addition, we found a significant association between indoor exposure to NO (2) , an air pollutant and known asthmogen, and severe asthma among children exhibiting high ADRB2 methylation (OR: 4.59, 95% CI: 1.03-20.55) but no association among children exhibiting low levels of ADRB2 methylation (OR: 0.35, 95% CI: 0.01-14.13).
CONCLUSIONS AND CLINICAL RELEVANCE: These findings support the potential use of ADRB2 5'-UTR methylation as a biomarker of both asthma severity and risk for NO (2) -associated asthma exacerbations in children, and present the first evidence of an epigenetic link between an important environmental exposure and childhood asthma severity.

PMID: 22862293 [PubMed - indexed for MEDLINE]

Allostatic load biomarkers and asthma in adolescents.

Am J Respir Crit Care Med. 2013 Jan 15;187(2):144-52

Authors: Bahreinian S, Ball GD, Vander Leek TK, Colman I, McNeil BJ, Becker AB, Kozyrskyj AL

Abstract
RATIONALE: Allostatic load (AL), a novel measure of the physiologically dysregulated response of the body to stress, represents a biomarker of chronic stress exposure.
OBJECTIVES: To determine whether preadolescent children with high AL are more susceptible to asthma as adolescents.
METHODS: This was a prospective evaluation of children recruited at 7 to 10 years of age in the nested case-control arm of the Study of Asthma, Genes and Environment and followed until 11 to 14 years of age. AL was measured using eight biomarkers: fasting glucose, total cholesterol, high-density lipoprotein cholesterol, dehydroepiandrosterone sulfate, cortisol, systolic and diastolic blood pressure, and waist-to-hip ratio. AL, created from the sum of biomarkers in a high-risk quartile, was related to prevalence and incidence of asthma using logistic regression.
MEASUREMENTS AND MAIN RESULTS: Among 352 participants followed until 11 to 14 years of age, prevalent asthma was four times more likely in boys with high (>3) versus low (≤2) AL after adjusting for current asthma/atopy, age, ethnicity, parental history of asthma, and overweight status. Similar results were observed in the analysis of new-onset asthma in boys (adjusted odds ratio, 4.35; 95% confidence interval, 1.19-15.9). In girls, there were no associations between AL and asthma. In the analysis of a subset of biomarkers, combinations of total cholesterol, glucose, and cortisol were associated with similar or greater risk of asthma prevalence or onset in boys.
CONCLUSIONS: AL and its biomarkers are associated with an increased likelihood of asthma in adolescent boys. The observed association between AL and asthma may be attributable to a combined subset of AL biomarkers.

PMID: 22955315 [PubMed - indexed for MEDLINE]

Genetics of asthma susceptibility and severity.

Clin Chest Med. 2012 Sep;33(3):431-43

Authors: Slager RE, Hawkins GA, Li X, Postma DS, Meyers DA, Bleecker ER

Abstract
This article summarizes major findings in genome-wide studies of asthma susceptibility and severity. Two large meta-analyses identified four chromosomal regions which were consistently associated with development of asthma. Genes that are associated with asthma subphenotypes such as lung function, biomarker levels, and asthma therapeutic responses can provide insight into mechanisms of asthma severity and disease progression. Future genetic studies will incorporate sequencing in comprehensively phenotyped asthmatics to lead to the development of personalized therapy.

PMID: 22929093 [PubMed - indexed for MEDLINE]

Sputum hydrogen sulfide as a novel biomarker of obstructive neutrophilic asthma.

J Allergy Clin Immunol. 2013 Jan;131(1):232-4.e1-3

Authors: Saito J, Zhang Q, Hui C, Macedo P, Gibeon D, Menzies-Gow A, Bhavsar PK, Chung KF

PMID: 23146380 [PubMed - indexed for MEDLINE]

Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma.

J Allergy Clin Immunol. 2013 Jan;131(1):110-6.e1

Authors: Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W, Hellings P, Brusselle G, De Bacquer D, van Cauwenberge P, Bachert C

Abstract
BACKGROUND: Adult patients with nasal polyps often have comorbid asthma, adding to the serious effect on the quality of life of these patients. Nasal polyps and asthma might represent a therapeutic challenge; inflammation in both diseases shares many features, such as airway eosinophilia, local IgE formation, and a T(H)2 cytokine profile. Omalizumab is a human anti-IgE mAb with proved efficacy in patients with severe allergic asthma. Omalizumab could be a treatment option for patients with nasal polyps and asthma.
OBJECTIVE: The goal of this study was to investigate the clinical efficacy of omalizumab in patients with nasal polyps and comorbid asthma.
METHODS: A randomized, double-blind, placebo-controlled study of allergic and nonallergic patients with nasal polyps and comorbid asthma (n = 24) was conducted. Subjects received 4 to 8 (subcutaneous) doses of omalizumab (n = 16) or placebo (n = 8). The primary end point was reduction in total nasal endoscopic polyp scores after 16 weeks. Secondary end points included a change in sinus computed tomographic scans, nasal and asthma symptoms, results of validated questionnaires (Short-Form Health Questionnaire, 31-item Rhinosinusitis Outcome Measuring Instrument, and Asthma Quality of Life Questionnaire), and serum/nasal secretion biomarker levels.
RESULTS: There was a significant decrease in total nasal endoscopic polyp scores after 16 weeks in the omalizumab-treated group (-2.67, P = .001), which was confirmed by means of computed tomographic scanning (Lund-Mackay score). Omalizumab had a beneficial effect on airway symptoms (nasal congestion, anterior rhinorrhea, loss of sense of smell, wheezing, and dyspnea) and on quality-of-life scores, irrespective of the presence of allergy.
CONCLUSION: Omalizumab demonstrated clinical efficacy in the treatment of nasal polyps with comorbid asthma, supporting the importance and functionality of local IgE formation in the airways.

PMID: 23021878 [PubMed - indexed for MEDLINE]

The impact of total antioxidant capacity on pulmonary function in asthma patients.

Int J Tuberc Lung Dis. 2012 Nov;16(11):1544-50

Authors: Yoon SY, Kim TB, Baek S, Kim S, Kwon HS, Lee YS, Lee T, Jang AS, Chang YS, Cho SH, Choi BW, Park JW, Nham DH, Yoon HJ, Cho YJ, Park CS, Moon HB, Cho YS, COREA Study Group

Abstract
BACKGROUND: Oxidative stress, mediated by an imbalance between oxidants and antioxidants, contributes significantly to the pathogenesis of asthma.
OBJECTIVE: To evaluate the impact of serum total antioxidant capacity (TAC) on the pulmonary function of Korean asthma patients.
METHOD: A total of 104 adult asthma patients enrolled from the COREA (Cohort for Reality and Evolution of Adult Asthma in Korea) programme participated in the study. Baseline clinical parameters at enrolment, and the results of pulmonary function tests at baseline and 1 and 2 years after enrolment were collected. TAC at baseline was measured using a Trolox-equivalent antioxidant capacity assay. Patients were divided into two groups based on TAC levels, and various clinical parameters were compared.
RESULT: Serum TAC levels correlated with forced expiratory volume in 1 second (FEV(1)) at baseline (r = 0.22, P = 0.03). The group with higher baseline TAC levels maintained greater mean FEV(1) both 1 and 2 years after enrolment, even after adjusting for sex, age, height, weight, body mass index and smoking status.
CONCLUSION: These results suggest an important link between serum TAC levels and pulmonary function, indicating that higher TAC levels may be a biomarker for favourable prognosis in asthma patients.

PMID: 23044449 [PubMed - indexed for MEDLINE]

Restoration of corticosteroid sensitivity by p38 mitogen activated protein kinase inhibition in peripheral blood mononuclear cells from severe asthma.

PLoS One. 2012;7(7):e41582

Authors: Mercado N, Hakim A, Kobayashi Y, Meah S, Usmani OS, Chung KF, Barnes PJ, Ito K

Abstract
BACKGROUND: Severe asthma accounts for a small number of asthmatics but represents a disproportionate cost to health care systems. The underlying mechanism in severe asthma remains unknown but several mechanisms are likely to be involved because of a very heterogeneous profile. We investigated the effects of a p38MAPK inhibitor in corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from severe asthmatics and the profile of its responders.
METHODOLOGY/PRINCIPAL FINDINGS: Corticosteroid sensitivity was determined by measuring dexamethasone inhibition of CD3/28 and TNF-α induced IL-8 production in PBMCs by using ELISA. PBMCs from severe asthmatics were relatively less sensitive to dexamethasone (Dex) as compared to those of non-severe asthmatics and healthy volunteers. The IC(50) values of Dex negatively correlated with decreased glucocorticoid receptor (GR) nuclear translocation assessed using immunocytochemistry (r = -0.65; p<0.0005) and with decreased FEV(1) (% predicted) (r = 0.6; p<0.0005). A p38α/β inhibitor (SB203580) restored Dex-sensitivity in a subpopulation of severe asthma that was characterized by a defective GR nuclear translocation, clinically by lower FEV(1) and higher use of oral prednisolone. We also found that SB203580 partially inhibited GR phosphorylation at serine 226, resulting in increased GR nuclear translocation in IL-2/IL-4 treated corticosteroid insensitive U937s.
CONCLUSIONS/SIGNIFICANCE: p38MAPKα/β is involved in defective GR nuclear translocation due to phosphorylation at Ser226 and this will be a useful biomarker to identify responders to p38MAPKα/β inhibitor in the future.

PMID: 22911818 [PubMed - indexed for MEDLINE]