Received: 24 September 2020 | Revised: 22 April 2021 | Accepted: 23 April 2021 DOI: 10.1111/cea.13888 RESEARCH LETTER Aeroallergen sensitization for detecting asthma in primary care: A diagnostic test accuracy study To the Editor, medical history, Asthma Control Questionnaire (ACQ), Clinical Physicians still have great difficulty in diagnosing asthma. COPD Questionnaire (CCQ) and spirometry. Overdiagnosis and under diagnosis both occur for this lung disease Measurement of specific sIgE is not part of the standard assess- from which around 300 million people suffer world-­wide.1 For diag- ment within the asthma/COPD-­service. However, in a subset of nosing asthma, after careful history taking, lung function testing is patients sIgE test results were available by combining coded sIgE considered the most relevant investigation. However, other parame- data with the coded asthma/COPD data. The Phadiatop test was ters could also assist in completing the asthma jigsaw. Since atopy is performed for sIgE measurements, which includes common aeroal- one of the predisposing factors for asthma, measurement of specific lergens (grass pollen, tree pollen, house dust mite, cat dander, dog IgE (sIgE) could be of assistance. This statement only applies to sIgE dander, moulds and weed pollen).5 The test was considered positive and not to total IgE measurement, which cannot be used as crucial when a sIgE level of ≥0.35 kU/L was obtained (i.e. sensitization). The 2 evidence for allergy diagnosis. average time between sIgE screening and asthma diagnosis by the Currently, there is a lack of diagnostic accuracy data for sIgE asthma/COPD-­service was 1.84 years (median 0.90 years, maximum to aeroallergens in relation to the diagnosis of asthma. In the 9.5 years). Netherlands, measurement of sIgE to aeroallergens in relation to The data were analysed using IBM SPSS Statistics for Mac, ver- diagnosis of asthma is recommended by the national primary care sion 26.0 (IBM Corp., Armonk, NY). Sensitivity, specificity, PPV and asthma guideline.3 Therefore, the aim of this study was to investi- NPV of sIgE test result in relation to the diagnosis of asthma were gate the sensitivity, specificity, positive predicted value (PPV) and calculated using crosstabs. A sensitivity analysis was performed in a negative predicted value (NPV) of sIgE to aeroallergens in primary subsample of patients who had not been prescribed inhaled cortico- care patients who were diagnosed with asthma confirmed by remote steroids (ICS) at the moment they visited the asthma/COPD-­service assessment of a pulmonologist in the asthma/COPD-­service and for the first time (ICS naïve). The Standards for Reporting Diagnostic showing clear bronchodilator reversibility. Accuracy (STARD) checklist was used for reporting. The study population of this retrospective cross-­sectional data- A total of 258 patients who were examined for the diagnosis base study consists of primary care patients, who visited the asthma/ of asthma were included (Figure 1). Of the included patients, 186 COPD-­service for the first time between 2007 and 2016. According (72%) patients were diagnosed with asthma (mean age 30.2 years to Dutch regulations, ethical approval was not required because the (SD 8.2 years) and 68% female). In this group of asthma patients, data were used anonymously. Patients (aged 18–­45 years and sIgE 136 (73%) patients were sensitized. The sensitivity of being sen- data available) who were examined for the diagnosis of asthma were sitized in relation to the diagnosis of asthma was 0.73. Of all included and divided into two groups. One group included asthma sensitized patients (n = 169), 136 (80%) had asthma. The PPV patients with a confirmed pulmonologist diagnosis of asthma and of a positive sIgE test in this group of asthma patients was 0.80 bronchodilator reversibility >12%. The other group included “con- (Table 1). trol” patients where the pulmonologist indicated no obstructive lung Of the included patients, 72 (27%) patients were classified as disease and no asthma or COPD and no bronchodilator reversibility “control” patients (no asthma or COPD and no bronchodilator re- (Figure 1). versibility) (mean age 33.3 years (SD 8.5 years) and 67% female). In The asthma/COPD-­service is an electronic service to support this group of “control” patients, 39 (54%) patients were not sensi- general practitioners (GPs) in the diagnosis and treatment of pa- tized. The specificity of being not sensitized in relation to not having tients with suspicion of obstructive lung disease. Since 2007, over asthma was 0.54. Of all patients with a negative sIgE test (n = 89), 39 19 000 patients have been assessed by this service.4 Variables ob- (44%) had no asthma. The NPV of a negative sIgE test in this group tained during the assessment of the asthma/COPD-­service include of “control” patients was 0.44 (Table 1). This is an open access article under the terms of the Creative Commons Attribution-­NonCommercial-­NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-­commercial and no modifications or adaptations are made. © 2021 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd. 1080 |  wileyonlinelibrary.com/journal/cea Clin Exp Allergy. 2021;51:1080–1084. | 13652222, 2021, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cea.13888 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [29/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License KOCKS et al. 1081 Additionally, 86 out of 258 (33%) patients were ICS naïve. This subgroup of ICS naïve patients revealed a sensitivity of 0.73 in rela- Key messages tion to the asthma diagnosis and a specificity of 0.46 in relation to -­ Measurement of sIgE might have additional utility in the not having asthma. PPV was 0.88 and NPV was 0.23 (Table 1). diagnosis of asthma in adults. This study found reasonable to high sensitivity and PPV for sIgE -­ Sensitized patients who are examined for asthma may to aeroallergens in relation to the diagnosis of asthma and low speci- be more likely to have asthma. ficity and NPV. Additional analysis showed comparable results in ICS Potentially eligible participants in astma/COPD-service database (n=19,077) Excluded: <18 or >45 years (n=13,853) Eligible participants aged 18-45 years (N=5224) No index test: No sIgE data(n=3652) Index test: sIgE data (n=1572) sIgE test negative sIgE test positive (n=738) (n=834) Excluded: Excluded: Other* (n=275) Other* (n=208) Reference standard: Reference standard: Patients examined for the diagnosis asthma (n=463) Patients examined for the diagnosis asthma (n=626) Asthma No asthma# Asthma No asthma# (n=424) (n=39) (n=592) (n=34) Excluded: Excluded: Excluded: Excluded: No BdR>12% BdR>12% No BdR>12% BdR>12% (n=374) (n=0) (n=456) (n=1) Asthma and BdR>12% No asthma and Asthma and BdR>12% No asthma and (n=50) no BdR>12% (n=39) (n=136) no BdR>12% (n=33) Excluded: Excluded: Excluded: Excluded: ICS use ICS use ICS use ICS use (n=30) (n=33) (n=83) (n=26) Asthma and BdR>12% No asthma andno Asthma and BdR>12% No asthma and no and no ICS (n=20) BdR>12%and no ICS (n=6) and no ICS (n=53) BdR>12%and no ICS (n=7) F I G U R E 1 Flow chart patient inclusion. sIgE, Specific immunoglobulin E; BdR ≥ 12%, Increase in FEV1 of ≥12% and ≥200 mL compared to the FEV1 prior to bronchodilatation; ICS, inhaled corticosteroids; *Patients examined for diagnoses other than asthma; #“Control” patients where the pulmonologist indicated no obstructive lung disease and no asthma or COPD | 13652222, 2021, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cea.13888 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [29/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1082 KOCKS et al. TA B L E 1 Crosstabs showing number of patients with positive or negative sIgE test results and asthma or no asthma diagnosis for all included patients (A) and ICS naïve patients (B) Patients examined for the diagnosis asthma A Asthma and BdR≥12% No asthma and no BdR≥12% Total, n sIgE, n Positive 136 (TP) 33 (FP) 169 PPV = 0.80 (95% CI = 0.74–­0.86) Negative 50 (FN) 39 (TN) 89 NPV = 0.44 (95% CI = 0.34–­0.54) Total, n 186 72 258 Sensitivity = 0.73 (95% Specificity = 0.54 (95% CI = 0.66–­0.79) CI = 0.43–­0.65) ICS naïve patients examined for the diagnosis asthma No asthma and no B Asthma and BdR ≥ 12% BdR ≥ 12% Total, n sIgE, n Positive 53 (TP) 7 (FP) 60 PPV = 0.88 (95% CI = 0.78–­0.94) Negative 20 (FN) 6 (TN) 26 NPV = 0.23 (95% CI = 0.11–­0.42) Total, n 73 13 86 Sensitivity = 0.73 (95% Specificity = 0.46 (95% CI = 0.61–­0.82) CI = 0.23–­0.71) Sensitivity = TP/(TP + FN); Specificity = TN/(FP + TN); Positive predicted value (PPV) = TP/(TP + FP); Negative predicted value (NPV) = TN/(TN + FN); sIgE, Specific immunoglobulin E; BdR ≥ 12%, Increase in FEV1 of ≥12% and ≥200 mL compared to the FEV1 prior to bronchodilatation; ICS, inhaled corticosteroids; 95% CI, 95% confidence interval. naïve patients. These findings support the hypothesis that sensitized in relation to food allergy. However, the diagnostic test accuracy of patients may be more likely to have asthma. sIgE to aeroallergens in relation to allergy seems to be higher than in Although use of spirometry is recommended in most asthma relation to asthma as found in our study. guidelines, it has been reported that the sensitivity of spirometry The strengths of this study are the use of a very well-­structured for detecting asthma was 36% and the specificity was 75%.6 Given dataset which includes high-­quality spirometry and the diagnosis of these results, spirometry seems to have a higher specificity whereas asthma was remotely conformed by a pulmonologist. Based on the sIgE seems to have a higher sensitivity. Therefore, the combination Quality Assessment of Diagnostic Accuracy Studies (QUADAS-­2) of spirometry and measurement of sIgE to aeroallergens could assist tool, the overall risk of bias of the study is judged as low. Limitations in diagnosing asthma. of this study are that sIgE measurement is no part of the standard It has been reported that the greater the number of sensitiza- assessment of the asthma/COPD-­service and that sIgE levels were tions in childhood, the greater the risk of developing asthma later on measured in the past. However, it could be assumed that levels of in life.7 This risk is assumed to be similar for adults up to the age of sIgE are relatively stable over time when people are above 18 years. 40.8 Furthermore, there is a clear association between asthma and In addition, the population studied had a high prevalence of asthma allergy for grass pollen, birch pollen and house dust mite and food diagnosis, which may limit the applicability of the NPV and PPV esti- allergy and asthma often coexist.9 mates to other populations. It has been reported that sensitivity of sIgE in relation to the di- In conclusion, this study showed that measurement of sIgE agnosis of an allergy for grass pollen, birch pollen and house dust might have additional utility in the diagnosis of asthma in adults, mite ranged from 70% to 100% and specificity ranged from 80% to as sensitized patients are more likely to have asthma. These data 100%.5 This reported specificity range is higher than the specific- support the guidelines advising measurement of sIgE in panel of ity found in our study. Given the EAACI guidelines, the sensitivity common aeroallergens for assisting in making the asthma jigsaw of sIgE in relation to the diagnosis of a food allergy, including egg, more complete towards the diagnosis of asthma, recognizing wheat, soy and peanut, ranged from 70% to 100% and specificity that such a panel of aeroallergens would be subject to regional ranged from 40% to 70%.10 These reported ranges of sensitivity variation. and specificity are comparable with the results found in our study. Together these findings suggest that the diagnostic test accuracy of C O N FL I C T O F I N T E R E S T sIgE to aeroallergens in relation to asthma as found in our study is HJHA, EvH, RAR and BMJFdB declare that they have no compet- comparable to the diagnostic test accuracy of sIgE to food allergens ing interests. JWHK reports grants, personal fees and non-­financial | 13652222, 2021, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cea.13888 by Spanish Cochrane National Provision (Ministerio de Sanidad), Wiley Online Library on [29/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License KOCKS et al. 1083 support from AstraZeneca, grants, personal fees and non-­financial Inigo Ojanguren Arranz6,7,8 support from Boehringer Ingelheim, grants and personal fees from Roland A. Riemersma1 Chiesi Pharmaceuticals, grants, personal fees and non-­financial Dermot Ryan9 support from GSK, grants and personal fees from Novartis, grants Omar S. Usmani10 from MundiPharma, grants from TEVA, outside the submitted work, Bertine M. J. Flokstra-­de Blok1,2,11 all paid to his institution; and JWHK holds 72.5% of shares in the 1 General Practitioners Research Institute. RL reports grants and per- General Practitioners Research Institute, Groningen, the sonal fees from GSK, grants and personal fees from AZ, grants and Netherlands 2 personal fees from Novartis, grants from Chiesi, outside the sub- GRIAC Research Institute, University of Groningen, University mitted work. IOA reports personal fees from Astrazeneca, grants Medical Center Groningen, Groningen, The Netherlands 3 and personal fees from Boehringuer Inguelheim, personal fees from Observational and Pragmatic Research Institute, Singapore, GlaxoSmithKlein, personal fees from Novartis, personal fees from Singapore 4 MSD, grants and personal fees from Chiesi, personal fees from Astma/COPD dienst, CERTE Laboratories, Groningen, the Menarini, personal fees from TEVA, personal fees from BIAL, grants Netherlands 5 and personal fees from Mundipharma, outside the submitted work. Department of Pneumology, CHU Liege, GIGA I3 Liege DR reports grants from EAACI, grants from AUKCAR, personal fees University, Liege, Belgium 6 from Regeneron, personal fees from MEDA, personal fees from Servei de Pneumología, Hospital Universitari Vall d'Hebron, AZ, personal fees from Chiesi, personal fees from BI, personal fees Departament de Medicina, Universitat Autònoma de Barcelona from Novartis, outside the submitted work. OSU reports grants (UAB, Barcelona, Spain 7 and personal fees from astra zeneca, grants and personal fees from Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain 8 boehringer ingelheim, grants and personal fees from chiesi, grants CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, and personal fees from glaxosmithkline, personal fees from napp, Spain 9 personal fees from mundipharma, personal fees from sandoz, per- Usher Institute, University of Edinburgh, Edinburgh, UK 10 sonal fees from takeda, grants from edmond pharma, personal fees Imperial College London, London, UK 11 from cipla, personal fees from covis, personal fees from novartis, Beatrix Children's Hospital, Department of Pediatric personal fees from mereobiopharma, personal fees from orion, per- Pulmonology and Pediatric Allergology, University of Groningen, sonal fees from menarini, outside the submitted work. The authors University Medical Center Groningen, Groningen, the report no other conflicts of interest in this work. The abstract of this Netherlands letter was presented at the ERS Virtual Congress 2020 as E-­poster. Correspondence AU T H O R C O N T R I B U T I O N Bertine Flokstra –­de Blok, General Practitioners Research All authors made substantial contributions to conception and design Institute, Professor Enno Dirk Wiersmastraat 5, 9713 GH (JWHK, RL, OSU and BFdB), acquisition of data (EvH, RAR), or analysis Groningen, the Netherlands. and interpretation of data (JWHK, HJHA, RL, IOA, DR, OSU and BFdB); Email: bertine@gpri.nl took part in drafting the article (JWHK, HJHA and BFdB) or revising it critically for important intellectual content (EvH, RL, IOA, RAR, DR and ORCID OSU); all authors gave final approval of the version to be published. Dermot Ryan https://orcid.org/0000-0002-4115-7376 Bertine M. J. Flokstra-­de Blok https://orcid. 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