Kayoko Matsunaga

Kazunobu Kuwabara

Mamoru Shiga

Masahiro Hirose

Masashi Nakamura

Rieko Kondo

Takahiko Horiguchi

Takazumi Yoshida

Tatsuyoshi Yokoi

English

Kuwabara, Kazunobu

Yokoi, Tatsuyoshi

Yoshida, Takazumi

Shiga, Mamoru

Hirose, Masahiro

Kondo, Rieko

Matsunaga, Kayoko

Nakamura, Masashi

Horiguchi, Takahiko

Fujita Health University Academic Information Repository / 藤田保健衛生大学学術情報リポジトリ

Comparison between ImmunoCAP and multiple antigensimultaneous tests for measuring Aspergillus-specificImmunoglobulin E levels in Aspergillus-sensitized patientsKazunobu Kuwabara, MD, PhD1, Tatsuyoshi Yokoi, MD1, Takazumi Yoshida, MD1, Mamoru Shiga, MD, PhD1,Masahiro Hirose, MD, PhD1, Rieko Kondo, MD, PhD1, Kayoko Matsunaga, MD, PhD2,Masashi Nakamura, PhD2,3, Takahiko Horiguchi, MD, PhD11 Department of Internal Medicine Fujita Health University Banbuntane Houtokukai Hospital, Nagoya, Aichi, Japan, 2 Department of Integrative MedicalScience for Allergic Disease, Fujita Health University School of Medicine, Toyoake, Aichi, Japan, 3 General Research and Development Institute, HoyuCo., Ltd.AbstractObjectives: Aspergillus sensitization is important for patients with asthma. In Japan, the methods applied tomeasure allergen-specific immunoglobulin E (IgE) levels in blood are the single antigen test, ImmunoCAP (IC), andmultiple antigen simultaneous tests, View Allergy® (VA) or MAST IV® (MA). Here, we report the concordance rates(CR) for Aspergillus-specific IgE levels between IC and VA or MA.Methods: Aspergillus-specific IgE levels in serum samples from 34 male and 23 female patients with bronchialasthma were measured by ImmunoCAP, View Allergy® (both Thermo Fisher Scientific, Uppsala, Sweden) and MASTIV® (Hitachi Chemical Diagnostics, Inc. Mountain View, CA, USA). Results of Class 1 or greater were regarded aspositive, and the CRs between the methods were assessed.Results: Of the 57 patients, 24 were found to be positive for Aspergillus-specific IgE by IC, and 5 had allergicbronchopulmonary aspergillosis (ABPA). Significant intraclass correlations were observed between IC and VA(r=0.964, p<0.001) and between IC and MA (r=0.620, p<0.001). Between IC and VA, the CR, positive concordanceratio, and negative concordance ratio was 98.2%, 100%, and 96.9%, respectively; between IC and MA, these valueswere 77.2%, 45.8%, and 100%, respectively. All five patients with ABPA were found to be positive for Aspergillus-specific IgE by VA, whereas only three of these patients (60%) were found to be positive by MA.Conclusions: In patients with asthma, measurements obtained by IC were more concordant with those obtained byVA compared with those obtained by MA.Keywords: Asthma, ImmunoCAP, AspergillusIntroductionIn Japan, the mortality from bronchial asthma (BA) was 4.5%–5.0% per 100,000 individuals between 1975 and 1994. Mortalityfrom BA began to decrease in 1997 and reached 1.2 per 100,000population (1,510 deaths) in 2015.1 However, some patients stillsuffer from poorly controlled asthma. According to a report fromthe Netherlands, 3.6% of adult patients with asthma are classifiedas having severe refractory asthma despite adequate adherenceto treatment with inhaled corticosteroids and long-actingbronchodilators with correct inhalation technique.2 In thiscircumstance, the assessment and treatment of patients withrefractory asthma is an extremely important issue for thetherapeutic management of BA.In addition to well-known risk factors for refractory asthma,such as obesity and gastroesophageal reflux, fungal sensitizationcan also induce this condition, as was recently proposed in theconcept of severe asthma with fungal sensitization (SAFS).3Received 11 November, 2017, Accepted 13 February, 2018.Corresponding author: Kazunobu Kuwabara, MD, PhD, Department of Internal Medicine Fujita Health University BanbuntaneHoutokukai Hospital, 3-6-10 Otobashi, Nakagawa-ku, Nagoya, Aichi454-8509 Japan E-mail: kuwabara.1980@gmail.comSensitization to fungi is thought to lead to the development ofrefractory BA, and sensitization to Aspergillus is particularlycommon. Because several studies have demonstrated thatsensitization of immunoglobulin E (IgE) to Aspergillus fumigatusis a risk factor for reduction and acute deterioration of pulmonaryfunction,4,5 caution should be taken to detect the development ofallergic bronchopulmonary aspergillosis (ABPA) during treatmentof refractory asthma. In Japan, because several epidemiologicalstudies have shown that approximately 10% of patients withasthma are sensitized to A. fumigatus,6,7 early and correctrecognition of sensitization to Aspergillus is also important formanagement of patients with asthma.Although sensitization to Aspergillus can be determined byblood or skin tests, the blood test is more frequently conductedto measure Aspergillus-specific IgE levels because of itssimplicity and minimal invasiveness. ImmunoCAP (IC) iscommonly performed to measure allergen-specific IgE levelsowing to the large quantity of accumulated data on this assay.8However, because the IC is a single-antigen test, a multipleantigen simultaneous test is often applied to measure allergen-specific IgE levels in daily clinical practice. At present, allergen-specific IgE multiple antigen simultaneous tests are performed inJapan using either MAST IV® (MA) or VIEW Allergy® (VA). Theinitial version of the MAST kit allowed the measurement of only16 allergen types, but the MAST IV®, which includes AspergillusOriginal Article Open Access66 as a test item, was recently released. Additionally, VA, a newmultiple allergen-specific IgE assay, was released in 2016. VA issold by the same manufacturer and includes the same antigen asIC.9MA and IC are different in terms of the applied measurementprinciple, so the results were assessed after class conversion.The measurement principles of these three test methods areshown in Table 1. In the present study, because previous studiesreported that measurements obtained by MA sometimes do notagree with those obtained by IC, we assessed the concordancerates of Aspergillus-specific IgE levels between the IC and thenewly available multiple antigen simultaneous test methods, i.e.,VA and MA.MethodsWe used serum samples obtained from 57 patients with BAwho visited Fujita Health University Second Teaching Hospitalbetween February and September 2017 and provided consent toparticipate in this study. The diagnosis of BA was made bypulmonologists according to the 2015 Japanese AsthmaPrevention and Management Guidelines,10 and the treatmentlevel required for each patient was classified according to the2017 Global Initiative for Asthma (GINA) guidelines.11 ABPA wasdefined as a condition that was diagnosed by pulmonologistsaccording to the Patterson criteria12 and that presented withchest imaging findings of central bronchodilatation andinfiltration. This study was conducted after review and approvalby the Medical Research Ethics Committee of Fujita HealthUniversity (Approval No. HM16-371).The Aspergillus-specific IgE levels in the serum samples weremeasured separately by IC, VA, and MA. Measurement ofAspergillus-specific IgE antibody levels by IC and VA wasoutsourced to Thermo Fisher Diagnostic K.K., and measurementby MA was outsourced to testing centers (BML, Inc. and SRL,Inc.). Results of Class 1 or greater, as determined by IC, MA, andVA, were regarded as positive, and concordance rates of IC withMA and VA were assessed. The class conversion table for eachtest method is shown in Table 2.The statistical analysis software used was StatMate version3.19 (ATMS, Co., Ltd., Tokyo, Japan). Two independent groupswere compared by the Mann‒Whitney U test. The degree ofassociation between two variables was determined usingSpearman’s rank correlation coefficients. Differences acrossthree or more independent groups were assessed by theKruskal‒Wallis test. Values of p<0.05 were considered toindicate a statistically significant difference.ResultsThis study included 34 men (mean±standard deviation for age:57.5±20.77 years) and 23 women (49.8±15.07 years). Of the 57patients, 8 (14.0%), 6 (10.5%), 24 (42.1%), 11 (19.2%), and 8(14.0%) were assessed as needing Step 1, 2, 3, 4, and 5 treatmentlevels, respectively, based on the guidelines set by GINA. Themedian disease duration was 12 years (Q1–Q3: 3–30 years). Themedian total IgE level was 520 IU/mL (Q1–Q3: 172–1538 IU/mL)(Table 3). Of the 57 patients, 24 (42.1%) were found to bepositive for Aspergillus-specific IgE by IC. This group included 5patients with ABPA. The measurements obtained by IC weresignificantly correlated with those obtained by both VA (r=0.976,p<0.001) and MA (r=0.635, p<0.001). All 5 patients with ABPA(n=5/5) were found to be positive for Aspergillus-specific IgE byVA, whereas 60% (n=3/5) were found to be positive by MA(Figure 1). Between IC and VA, the concordance rate was 98.2%,the positive concordance ratio was 100%, and the negativeconcordance ratio was 96.9%. Between IC and MA, theconcordance rate was 77.2%, the positive concordance ratio was45.8%, and the negative concordance ratio was 100% (Figure 2).DiscussionThe antibody class IgE was first reported by Ishizaka et al. in1967,13 and IC has been widely used for measuring allergen-specific IgE levels for more than 40 years. IC is regarded as thegold standard for the in vitro measurement of allergen-specificIgE levels.8 Thus, IC results are used as the benchmark againstwhich the results of screening for allergen-specific IgE arecompared.This study found that, in patients with BA, Aspergillus-specificIgE levels measured by IC were more concordant with thoseTable 2 Patient backgroundAsthma PatientAge (years), mean±SD 54.5±19.0Gender (male:female), n (%) 34 (60%):23 (40%)GINA treatment step, n (1:2:3:4:5) 8:6:24:11:8Duration of asthma (years), median (IQR) 12 (3–30)Total IgE (IU/mL), median (IQR)* 520 (172–1538)BA: bronchial asthma, IQR: interquartile range, SD: standard deviation* The same serum as used in this study.Table 3 Class conversion table for ImmunoCAP, View Allergy®, andMAST IV®Class ImmunoCAP(UA/mL)View allergy®(Index)MAST IV®(LC)6 ≧100.0 ≧29.31 160–2005 50.00–99.99 17.35–29.30 120–1594 17.5–49.99 7.05–17.34 58.1–1193 3.50–17.49 1.80–7.04 13.5–58.02 0.70–3.49 0.50–1.79 2.78–13.41 0.35–0.69 0.27–0.49 1.40–2.770 0–0.34 0–0.26 0–1.39LC: lumicountTable 1 Comparison of inspection methodsImmunoCAP View Allergy® MAST IV®Manufacturer Thermo Fisher Diagnostics, Ltd. Thermo Fisher Diagnostics, Ltd. Hitachi Chemical Co., Ltd.Measurement principle FEIA FEIA CLEIAResults UA/mL Class (0–6) Class (0–6)FEIA: Fluorescence Enzyme ImmunoassayCLEIA: Chemiluminescent Enzyme ImmunoassayFujita Medical Journal 2018 Volume 4 Issue 367measured by VA than with those measured by MA. The higherconcordance rate between IC and VA is presumably attributableto the fact that both test methods were developed by the samemanufacturer and use the same antigen.9 Unfortunately, we couldnot obtain information on the Aspergillus strain used for MA.Because it has been reported that fungal antigen components arelikely to differ among culture methods, deviations in the testresults were assumed to be attributable to differences in theantigen components of the test kits and the inactivation ofantigens during test kit production.14Of the five patients with ABPA, 60% (3/5) were identified aspositive for Aspergillus-specific IgE by MA, whereas VA identifiedall ABPA patients (5/5) as positive. A recent report indicated thatmany patients with ABPA are sensitized to Asp f 1 and Asp f 2,based on component analysis.15 The differing sensitivity of theMA and VA tests for patients with ABPA may be attributable toFigure 1 The degree of association between two variables was determined using Spearman’s rank correlation coefficients. Association of Aspergillus-specific immunoglobulin E classes determined by ImmunoCAP with those determined by VIEW Allergy and MAST IV. The numerical values in cells arethe number of patients. ImmunoCAP showed significant correlations with both test methods. Of the 5 patients with allergic bronchopulmonaryaspergillosis included in this study, 5 were found to be positive by VIEW Allergy, and 3 were found to be positive by MAST IV.*; Including 1 ABPA patient, **; Including 2 ABPA patientsFigure 2 Concordance rates, positive concordance ratios, and negative concordance ratios of Aspergillus-specific immunoglobulin E levels betweenImmunoCAP and VIEW Allergy and between ImmunoCAP and MAST IV. The numerical values in cells are the number of patients.CR; concordance rate, PCR; positive concordance ratio, NCR; negative concordance ratioSignificance of multiple antigen simultaneous test for Aspergillus-specific IgE68differences in the content of these components.For optimal management of patients with asthma, it isimportant to determine whether they are sensitized to inhalantantigens, such as fungi, mites, and pollen. The allergen-specificIgE multiple antigen simultaneous test is widely applied inclinical practice because it allows the examination ofsensitizations to a wide range of antigens, including not onlyinhalant antigens but also food antigens and latex. Recently, it hasbecome increasingly important to clarify Aspergillus sensitizationin asthma patients, and the screening method used in the initialphase of asthma treatment requires a high level of sensitivity.Based on reports demonstrating an increase in Aspergillus-specific IgE during medical treatment and occasional ABPAdevelopment during asthma treatment,16,17 Aspergillus-specificIgE should be monitored over time in the treatment of asthma,and it is therefore important to confirm Aspergillus sensitizationin ABPA diagnosis.When a simultaneous multi-parameter screening of allergen-specific IgE is used to determine the sensitization status of a BApatient, it is important to consider that the results may not beconsistent among tests. This difference is clinically relevantbecause the gold standard Immuno CAP, rather than the initialscreening method, is often used for IgE measurement duringasthma management. Our results indicate that VA, whichachieved consistent results in comparison with historical data andexhibited a high sensitivity even in ABPA patients, is superior asa screening method for assessing Aspergillus sensitization inasthma patients.Conflict of InterestNo potentioal COI to disclose.AcknowledgementsWe would like to express our sincere appreciation to ThermoFisher Diagnostics in this study.References 1. Ichinose M, Sugiura H, Nagase H, Yamaguchi M, Inoue H, Sagara H,Tamaoki J, Tohda Y, Munakata M, Yamauchi K, Ohta K. Japaneseguidelines for adult asthma 2017. Allergol Int 2017; 66: 163–89. 2. Hekking P, Wener R, Amelink M, Zwinderman AH, Bouvy ML, BelEH. The prevalence of severe refractory asthma. J Allergy ClinImmunol 2015; 135: 896–902. 3. Denning DW, O’Driscoll BR, Hogaboam CM, Bowyer P, Niven RM.The link between fungi and severe asthma: a summary of theevidence. Eur Respir J 2006; 27: 615–26. 4. Fairs A, Agbetile J, Hargadon B, Bourne M, Monteiro WR, BrightlingCE, Bradding P, Green RH, Mutalithas K, Desai D, Pavord ID,Wardlaw AJ, Pashley CH. IgE sensitization to Aspergillus fumigatus isassociated with reduced lung function in asthma. Am J Respir CritCare Med 2010; 182: 1362–8. 5. Goh K, Yii ACA, Lapperre TS, Chan AK, Chew FT, Chotirmall SH,Koh MS. Sensitization to Aspergillus species is associated withfrequent exacerbations in severe asthma. J Asthma Allergy 2017; 10:131–40. 6. Adachi M, Inoue H, Tamura G, Sano Y, Ohta K, Nakagawa T, Ito K,Baba K, Hirata K, Tohda Y, Nakajima S, Takahashi K, Asai S,Miyamoto T. Sensitizing allergens of patients with bronchial asthmain Japan. Allergology & Immunology 2006; 13: 548–54 (in Japanese). 7. Ohira D, Shiga M, Kuwabara K, Ban N, Hata H, Nasu T, Hirose M,Kondo R, Horiguchi T. Importance of insect inhalant allergens(including cockroach allergen) in adult bronchial asthma.Occupational and Environmental Allergy 2013; 20: 59–68 (inJapanese). 8. Akdis C, Agache I. Global atlas of allergy. European Academy ofAllergy and Clinical Immunology 2014: 166. 9. Harita M. Fundamental study on multiple allergen specific IgE assay:“View allergy 39”. Japanese Journal of Medicine and PharmaceuticalScience 2016; 73: 721–6 (in Japanese).10. Japanese Society of Allergology. Asthma Prevention and ManagementGuidelines (JGL). Tokyo: Kyowa Kikaku; 2015 (in Japanese).11. Global Initiative for Asthma. GINA Report. Global Strategy forAsthma Management and Prevention 2017; 2017: 43. <http://ginasthma.org/gina-reports>. (Accessed November 2, 2017).12. Greenberger PA, Patterson R. Allergic bronchopulmonaryaspergillosis and the evaluation of the patient with asthma. J AllergyClin Immunol 1988; 81: 646–50.13. Ishizaka K, Ishizaka T, Hornbrook MM. Physico-chemical propertiesof human reaginic antibody: IV. Presence of a unique immunoglobulinas a carrier of reaginic activity. J Immunol 1966; 97: 75–85.14. Esch RE. Manufacturing and standardizing fungal allergen products. JAllergy Clin Immunol 2004; 113: 210–5.15. Tanimoto H, Fukutomi Y, Yasueda H, Takeuchi Y, Saito A, Watai K,Sekiya K, Tsuburai T, Asano K, Taniguchi M, Akiyama K. Molecular-based allergy diagnosis of allergic bronchopulmonary aspergillosis inAspergillus fumigatus-sensitized Japanese patients. Clin Exp Allergy2015; 45: 1790–800.16. Agarwal R. Role of inhaled corticosteroids in the management ofserological allergic bronchopulmonary aspergillosis (ABPA). InternMed 2011; 50: 855–60.17. Greenberger PA, Miller TP, Roberts M, Smith LL. Allergicbronchopulmonary aspergillosis in patients with and withoutbronchiectasis. Ann Allergy 1993; 70: 333–8.Copyright©2018 Kazunobu Kuwabara, MD, PhD et al. This is an Open access article distributed under the Terms of CreativeCommons Attribution License, which permits unrestricted use,distribution, and reproduction in any medium, provided the originalauthor and source are credited.Fujita Medical Journal 2018 Volume 4 Issue 369

Comparison between ImmunoCAP and multiple antigen simultaneous tests for measuring Aspergillus-specific Immunoglobulin E levels in Aspergillus-sensitized patients

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Comparison between ImmunoCAP and multiple antigen simultaneous tests for measuring Aspergillus-specific Immunoglobulin E levels in Aspergillus-sensitized patients

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