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Validation of the DECA criteria for allergic conjunctivitis severity and control

Validation of the DECA criteria for allergic conjunctivitis severity and control Background: Allergic conjunctivitis (AC) is usually associated to allergic rhinitis (AR), but the severity and control of ocular symptoms should be assessed independently to improve diagnosis and treatment. The criteria from the Spanish consensus document on allergic conjunctivitis (DECA) aimed to be used as a patient‑reported instrument for AC management. Here we validate these criteria for classifying AC severity and defining its control following COSMIN guidelines recommendations. Methods: Patients with moderate or severe AR [reflective total nasal symptom score (rTNSS) score ≥ 8] and concomi‑ tant AC were recruited from hospitals in Spain. Patients were classified according to the severity of ocular symptoms as mild, moderate, or severe, and classified with respect to control as controlled and non‑ controlled, using the DECA criteria. To validate these criteria, comparisons with the validated modified allergic rhinitis and its impact on asthma (mARIA), reflective total ocular symptom score (rTOSS), rhinitis control assessment test (RCAT ), ESPRINT ‑15 question‑ naires, a conjunctival hyperemia scale and a visual analogue scale ( VAS) for ocular symptoms were performed. Results: A total of 128 patients participated in the validation. Mean age was 34.4 ± 12.1 years; 72.7% were women. The DECA criteria showed a good discriminant validity, reflecting a high capacity to differentiate between mild, mod‑ erate, and severe patients, and controlled from uncontrolled patients. A strong association between AC and AR was reflected in the comparison between the DECA and the mARIA criteria (p < 0.0001). The DECA criteria for severity and control presented satisfactory properties for longitudinal validity and responsiveness. Conclusions: Validation of the DECA criteria for severity and control of AC suggested that it can be useful in the evaluation of eye symptoms and follow‑up of therapies. Keywords: Allergic conjunctivitis, Allergic rhinoconjunctivitis, Conjunctivitis classification, Control, Ocular allergy Introduction allergic disorders in most patients, but the ocular symp- Allergic conjunctivitis (AC) is an immunological hyper- toms can be present without nasal involvement in 2–7% sensitivity disorder of the ocular conjunctiva, predomi- of AC patients [2, 3]. AC is a highly prevalent disease, nantly mediated by an IgE mechanism [1]. AC occurs affecting up to 40% of the adult population [1]. The most concomitantly with allergic rhinitis (AR) and other frequent symptoms are pruritus, tearing, and conjuncti- val hyperemia. These symptoms can cause a significant impact on quality of life (QoL), affecting sleep and result - *Correspondence: anam.navarro.sspa@juntadeandalucia.es ing in emotional problems and impairment of activities of M. Cesárea Sánchez‑Hernández and Ana M. Navarro contributed equally daily living or social functions, such as work productivity as first authors Joaquim Mullol and Antonio Valero contributed equally with senior or performance at school [4, 5]. AC is often underdiag- responsibilities nosed and undertreated, as only a small proportion of Department of Allergy, Hospital El Tomillar, Dos Hermanas, Seville, Spain patients (~ 10%) with AC symptoms seek medical advice Full list of author information is available at the end of the article © The Author(s) 2020. 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The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Sánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 2 of 9 [6]. Failure to recognize and treat ocular symptoms asso- classification, control and treatment of patients with AC ciated with AR can increase the burden of the disease [13]. This consensus (henceforth named DECA, for its substantially for allergy patients. acronym in Spanish) was based on the modified ARIA To better understand disease progression and to help (mARIA) classification of AR [14] adapted to AC (Fig.  1). assessing the effectiveness of treatment pathways, in The mARIA criteria classified patients as mild (when no the last two decades the concepts of ‘disease severity’ items are affected), moderate (involvement of 1, 2 or 3 and ‘disease control’ have been established for chronic items) and severe (involvement of the 4 items) in both allergic diseases [7]. Thus, several patient-reported out - untreated and treated patients [14, 15]. Accordingly, in come (PRO) instruments have been developed to meas- the DECA classification three levels of severity were pro - ure severity and control of AR [8, 9]. A successful and posed (mild, moderate, severe) and the criteria for fre- widely discussed initiative was the allergic rhinitis and quency were retained (intermittent/persistent). its impact on asthma (ARIA) approach, which classified The novel DECA criteria for control were based on the patients according to severity and, more recently, also to analysis of control criteria proposed for various allergic control [8, 10, 11]. The original ARIA document classi - diseases [13]. AC was classified as controlled or uncon - fied AR severity based on the impact of AR on 4 items: trolled based on 3 evaluation criteria: occurrence and sleep, activities/leisure/sports, work productivity/school frequency of ocular symptoms, a VAS score, and the performance and bothersome symptoms [8]. Based on degree of conjunctiva hyperemia as determined by the the original ARIA criteria, a severity classification for AC Efron scale [16]. patients based on ocular symptoms was also proposed The objective of this study was to validate the DECA [12]. criteria for classifying severity and control in AC patients, In 2015, experts from the Spanish Societies of Aller- following the recommendations from the Consensus- gology and Ophthalmology proposed a consensus of based Standards for the Selection of Health Measure- basic criteria that could be useful for both specialists ment Instruments (COSMIN) initiative [17], in a sample and primary care physicians to facilitate the diagnosis, Fig. 1 The criteria from the Spanish consensus document on allergic conjunctivitis (DECA). a Criteria for severity; b Criteria for control S ánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 3 of 9 of AC patients included in an observational study on the severity or control. These patients were defined as those control of allergic rhinitis in Spain (CORINA) study. who had < 1.2 changes in the VAS score or ≤ 1 point in ESPRINT-15 question 4. Methods 3. Responsiveness was assessed comparing the magni- This study was part of a larger observational, prospective, tude of the change in the different PROs (rTOSS, VAS, and multicenter real-life study to assess the epidemiol- the Efron scale, and ESPRINT-15 question 4 for severity ogy of patients with moderate and severe AR in Spain and rTOSS, ESPRINT-15 question 4, and RCAT question in terms of control (CORINA), carried out between 3 for control) for three options of change in severity and November 2015 and October 2016. Research was per- control: worse, equal and improved. formed by allergists and/or otorhinolaryngologists work- ing at reference hospitals and health centers throughout Patient‑reported outcomes and assessments Spain. To avoid a possible bias due to seasonality, each The values of all the study variables were extracted from researcher included no more than 4 consecutive patients the patients’ medical records and from the study ques- meeting the inclusion criteria each month until reach- tionnaires filled out during the visits. Data was collected ing the target figure of 15 patients per investigator. The on demography, concomitant diseases and medication study was non-interventional as the clinical decision use, etiology of allergic sensitization, and severity and to prescribe treatments for the management of AC was control of AC. made according to the usual clinical practice and was AC symptoms evaluated were pruritus, tearing and prior and independent of any consideration of the pos- redness. Each of the symptoms was evaluated on a scale sible participation of patients in this study. During the between 0 (no symptom) and 3 (severe symptom) and study, patients received standard medical care without on a VAS (0–10  cm; 0 = no symptoms, 10 = maximum analytical tests or other clinical procedures specific to the severity). Conjunctive hyperemia was measured with study. All included patients had to sign informed consent the grading scale by Efron (0–4; 0 = normal, 4 = severe) and be able to attend the follow-up visit. The study was [16]. The rTOSS was calculated as the sum to the indi - approved by the Ethics Committee for Clinical Research vidual score at 3 symptoms, with a maximum score of 9. of the Hospital Clínic de Barcelona. Question 3 of the Spanish-validated RCAT was used to evaluate control: “During the past week, how often did Patient population and study design you have watery eyes?” (5–1; 5 = never, 1 = extremely The inclusion criteria were age ≥ 18 years and a diagnosis often) [18, 19]. Question 4 of the Spanish version of the of AC according to the criteria in the DECA document ESPRINT-15 questionnaire was used to evaluate affec - [13] (Fig.  1). All patients had moderate or severe AR tation of quality of life: “In the past 2  weeks, how much according to mARIA criteria [14], with a reflective total have you been bothered by itchy eyes or having to rub nasal symptom score (rTNSS) of ≥ 8 (scale 0–12). your eyes?” (0–6; 0 = not at all; 6 = extremely) [20, 21]. The patients made a first visit (baseline visit) and a AC severity was classified according to the DECA cri - second visit 4–5  weeks later (follow-up visit). We fol- teria based on the impact on 4 items: bothersome symp- lowed COSMIN recommendations, as this international toms, affectation of vision, interference with academic consensus established how to measure and evaluate in a or work tasks, or interference with daily activities, read- uniform and consensual way the different health instru - ing and/or sport (Fig.  1a) [13]. Based on these criteria, ments [17]. According to COSMIN, the DECA severity patients were classified as mild (no items affected), mod - and control criteria were validated for: erate (involvement of 1, 2 or 3 items) and severe (involve- 1. Discriminant validity was evaluated by comparing ment of the 4 items). AC was also classified according to differences in the reflective total ocular symptom score its duration in intermittent (up to 4 days/week or up to 4 (rTOSS), the rTNSS, question 3 of the rhinitis control consecutive weeks) or persistent (more than 4 days/week assessment test (RCAT), a visual analogue scale (VAS), and more than 4 consecutive weeks). hyperemia scale and question 4 from the ESPRINT-15 The degree of AC control was assessed, according to the questionnaire between patients classified in the differ - DECA criteria, by symptoms, VAS and the Efron scale for ent categories of severity or control using DECA criteria. conjunctival hyperemia (Fig.  1b) [13]. AC was consid- Also, the percentage of patients classified in each cat - ered controlled if there were no symptoms or they were egory of severity using mARIA criteria was assessed for not bothersome 2 or more days per week, VAS < 5  cm each category of AC severity by the DECA criteria. and hyperemia scale was 0–1. It was considered uncon- 2. Test–retest reliability was evaluated by analyzing trolled if at least one of the following items was observed: the score agreement (kappa coefficient) in the basal and symptoms with any intensity 2 or more days per week, follow-up visits in those patients reporting equal AC VAS ≥ 5 cm and/or hyperemia scale was 2–4. Sánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 4 of 9 Statistical methods Table 1 Baseline characteristics of  the  patients included For the statistical analysis, the package SAS version in  the  DECA criteria for  AC severity and  control validation study (N = 128) 9.2 for Windows was used. The mean, median, stand - ard deviation, minimum and maximum, 25th and 75th Age, years, mean (SD) 34.4 (12.1) percentiles, and the number of valid cases were used Gender, female, N (%) 93 (72.7) for the description of continuous variables. The num - Allergic comorbidities, N (%) ber and percentage of patients per response category AR 128 (100.0) was used for categorical variables. Prior to performing Asthma 53 (41.4) parametric tests, we applied statistical techniques to Atopic dermatitis 14 (10.9) ensure compliance with the assumptions. In case the Urticaria 11 (8.6) established assumptions were not met, non-parametric Contact dermatitis 4 (3.1) tests were employed. A level of statistical significance Food allergy 4 (3.1) (p-value) of < 0.05 was used for all statistical tests. Other 14 (10.9) Type of AC sensitization, N (%) Perennial 40 (32.5) Results Seasonal 31 (25.2) The CORINA study recruited 252 patients [18]. Of Both 52 (42.3) these, 198 (78.6%) presented with AC symptoms in rTOSS score, mean (SD) 5.4 (2.3) the basal visit, and 128 patients (50.8%) in the follow- Hyperemia (Efron scale), N (%) Normal 26 (20.3) up visit. The validation of the DECA criteria for sever - Trace 62 (48.4) ity and control was performed on this sample of 128 Mild 29 (22.7) patients with AC symptoms and who attended both Moderate 11 (8.6) the baseline and the follow-up visits. Table  1 shows AC duration, N (%) the baseline characteristics of the patients included Intermittent 44 (34.4) in this study. The mean age of the AC patients was Persistent 84 (65.6) 34.4 ± 12.1  years and 72.7% were women. The mean Items reported (DECA), N (%) time elapsed between the date of diagnosis and the Bothersome symptoms 116 (90.6) study was 6.3 ± 9.7  years. At the basal visit, 94.5% of Aec ff ting vision 39 (30.5) patients presented pruritus, 85.9% tearing, and 85.9% Interference with academic or work tasks 54 (42.2) redness. All patients presented moderate or severe Interference with daily activity, reading, sport 66 (51.6) AR (100%) and 41.4% had concomitant asthma, 10.9% Severity (DECA criteria), N (%) atopic dermatitis, and 3.1% food allergy. The most fre - Mild (no items affected) 10 (7.8) quent allergen sensitizations were to dust mites (57.7%) Moderate (1–3 items affected) 93 (72.7) and grass pollens (45.5%), while 63% of the patients Severe (4 items affected) 25 (19.5) presented polysensitization. Regarding type of AC sen- Control (DECA criteria), N (%) sitization, for 25.2% of the patients it was seasonal, for Controlled 27 (21.1) 32.5% perennial, and for 42.3% both. Table 1 shows the Not controlled 101 (78.9) treatment followed by the patients at baseline, which Ophthalmic treatments at baseline, N (%) the specialist adjusted according to current guidelines Azelastine 34 (26.6) at baseline, modifying it in 63.3% of cases and initiating Ketotifen 11 (8.6) it in 20.3%. Olopatadine 3 (2.3) Levocabastine 1 (0.8) Others 1 (0.8) Validation of the DECA criteria for AC severity Nasal treatments at baseline, N (%) Discriminant validity Budesonide 2 (1.6) Table  2 shows the scores of the different validated PROs Fluticasone 12 (9.4) when assessed according to the severity categories Mometasone 22 (17.2) defined by using the DECA criteria. A highly significant Triamcinolone 1 (0.8) discriminant validity of the DECA criteria for severity Fluticasone furoate 43 (33.6) was found when comparing these scores. The percent - Fluticasone/azelastine combination 41 (32.0) age of patients classify similarly regarding severity with AC: allergic conjunctivitis; AR: allergic rhinitis; DECA: Spanish document on the mARIA criteria and the DECA criteria also showed a allergic conjunctivitis; rTOSS: reflective total ocular symptom score; SD: standard good balance facing both systems (Fig. 2). deviation S ánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 5 of 9 Test–retest reliability Responsiveness Thirty-three patients had the same AC severity as assessed The magnitudes of the change in the PROs scores for by the VAS, resulting in a kappa value of 0.45 (72.7% agree- patients who worsened, improved or stayed the same ment) with the DECA severity criteria, and 56 patients for in their AC severity were significantly different regard - the ESPRINT-15 question 4, kappa value of 0.33 (62.5% ing rTOSS, VAS, the Efron hyperemia scale, and agreement), reflecting a fair test–retest reliability. ESPRINT-15 question 4 (Fig.  3a), suggesting that the Table 2 Mean (standard deviation) for  the  scores of  the  different validated patient reported outcomes assessed in the severity categories classified by using the DECA criteria DECA criteria p Mild Moderate Severe Ocular symptoms (0–3), mean (SD) Pruritus 0.77 (0.83) 1.61 (0.84) 1.89 (1.05) < 0.0001 Tearing 0.47 (0.78) 1.25 (0.89) 1.78 (1.09) < 0.0001 Redness 0.43 (0.68) 1.28 (1.01) 1.78 (0.83) < 0.0001 rTOSS score (0–9), mean (SD) 1.66 (1.98) 4.17 (2.28) 5.44 (2.65) < 0.0001 Ocular symptoms by VAS (0–10 cm), mean (SD) Pruritus 1.70 (2.17) 4.48 (2.94) 5.30 (2.86) < 0.0001 Tearing 1.45 (2.30) 3.80 (2.95) 4.79 (3.20) < 0.0001 Redness 1.35 (2.41) 3.94 (3.05) 4.56 (3.03) < 0.0001 VAS global score 1.82 (2.21) 4.87 (2.88) 6.14 (3.01) < 0.0001 Efron hyperemia scale (0–4), mean (SD) 0.10 (0.31) 0.93 (0.81) 1.20 (1.14) < 0.0001 ESPRINT‑15 (0–6), mean (SD) 1.39 (1.51) 3.32 (1.71) 4.10 (1.37) < 0.0001 Question 4* DECA: Spanish document on allergic conjunctivitis; ESPRINT‑15: Spanish allergic rhinitis quality of life questionnaire; rTOSS: reflective total ocular symptom score; VAS: visual analogue scale; SD: standard deviation *ESPRINT‑15 Question 4: “In the past 2 weeks, how much have you been bothered by itchy eyes or having to rub your eyes?” Fig. 2 Percentage of patients in each allergic conjunctivitis (AC) severity category using DECA criteria (mild, moderate, or severe) and for each allergic rhinitis (AR) severity category by mARIA Sánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 6 of 9 DECA criteria for severity showed good responsiveness were compared with the mARIA criteria. Although AR to detect changes on symptoms, ocular signs and quality severity and AC severity do not necessarily have to fol- of life. low parallel classifications, in our study we observe a good agreement between the two, suggesting that these Validation of the DECA criteria for AC control instruments are effective and can simplify and expedite Patients classified as controlled by the DECA criteria the classification of both diseases [25]. Additionally, we showed PROs scores significantly different from patients find it is highly useful to differentiate AC severity in three classified as uncontrolled, indicating a high discriminant categories (mild, moderate, and severe), as differentiating validity of the DECA criteria for AC control (Table 3). moderate to severe patients can reduce the heterogeneity Patients who did not report changes in AC control, in the higher severity status [14, 15]. when assessed by DECA criteria, between the basal and The capacity of the DECA criteria to discriminate follow-up visits (N = 15) showed a similar score in PROs patients according to the degree of AC control can be (Kappa value of 0.59; 80% agreement), proving a good observed in Table 3, clearly suggesting their validity. Lon- test–retest validity. gitudinal validity and responsiveness for the DECA crite- The changes in PROs scores for patients who changed ria severity and control were also acceptable and suggest their level of control assessed by DECA criteria were sig- that they could be useful in the evaluation and follow-up nificantly and relevantly higher than patients who do not, of treated patients. showing a good responsiveness (Fig. 3b). This validation study had some limitations. First, it only included patients with a diagnosis of moderate to severe Discussion AR or that patients with ocular symptoms alone were not This study successfully validated the DECA criteria for included. Second, a methodological limitation derives severity and control of AC according to the require- from the lack of a standard and normalized classification ments established in the COSMIN: discriminant validity, for eye symptoms related to AC. For this reason, in our test–retest reliability, and responsiveness [17]. The data validation we could only compare the DECA criteria with obtained in the CORINA study described here suggest other validated instruments previously applied to various that the DECA criteria could be used to rapidly assess AC aspects of symptom severity and quality of life formally severity and control of the disease in patients with AC designed for AR. We have also used the specific ocu - symptoms. lar items of the ESPRINT-15 and RCAT questionnaires Despite the increase in allergic eye diseases in recent (questions 4 and 3, respectively), but these items were not decades and the socioeconomic impact generated by AC designed to be used in isolation and therefore their reli- [3–5, 22], it is commonly accepted that AC is often under- ability has not been validated. Similarly, comparison with diagnosed and undertreated [6]. This could be due in part other classification schemes previously proposed before to the highly frequent comorbidity of AC with other more has not been possible, as they have not been validated. severe allergic diseases such as asthma [23]. In our study One of the strengths of this study is that it showed for we also observed this frequent comorbidity, as asthma the first time the validation of an instrument specific for was present in 41.4% of the patients and atopic dermatitis AC control, following the COSMIN recommendations in 10.9% (in addition to rhinitis which, for methodologi- for reliability, validity and responsiveness [17]. It has been cal reasons, was present in all patients). Another possible suggested that measurements of disease control should reason for the underdiagnosis of AC could be the lack of be reproducible and easily implementable in everyday an unanimously agreed classification criteria. Addition - practice and focused on the disease’s impact in daily life ally, in most epidemiological studies on allergic diseases [9]. In this regard, the DECA criteria are designed to be the eye and nasal symptoms have been treated as a single a practical tool used by primary health practitioners and clinical entity [24]. For these reasons, in an effort to bring specialists alike. Further, the proposed clinical classifi - together the classification criteria of AC and AR and to cation of AC severity is consistent and complementary unify nomenclature on AC, the DECA consensus docu- with that currently in use for AR severity. The unifica - ment proposed a new classification of AC and also added a tion of criteria for the evaluation of severity and con- proposal for the definition of AC control [13]. trol is important in the development of diagnostic and In this study some relevant properties of the DECA cri- treatment guidelines for common use by primary care teria were assessed. The discriminant validity for disease physicians, allergists, and ophthalmologists, as a mul- severity, as shown in Table  2, reflected a high capacity tidisciplinary communication is necessary for the opti- to differentiate mild, moderate, and severe patients. The mal management of AC patients [1, 6, 9]. In this regard, extent by which AC is associated with AR could also be the validated instruments described here could also be observed when patient classification by the DECA criteria used to rapidly screen these patients with AC control S ánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 7 of 9 Fig. 3 Boxplots showing the DECA criteria score changes (median, 25th and 75th interquartile values) between visits for AC patients, which were categorized as worse, equal, or improved compared to baseline. a Comparisons for PROs evaluating severity. The differences are statistically significant for rTOSS (p < 0.0001), VAS (p < 0.0001), hyperemia scale (p < 0.0002), and ESPRINT‑15 question 4 (p < 0.0001). b Comparisons for PROs evaluating control. The differences were statistically significant for rTOSS (p < 0.0001), ESPRINT‑15 question 4 (p < 0.0001), and RCAT question 3 (p < 0.0002) problems and could help patients to communicate with Conclusion health care practitioners about their disease and their This study validated with good results the criteria for response to treatment. severity and control assessment proposed in DECA, making this a potentially useful tool for physicians and Sánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 8 of 9 Marañón, Madrid); Ignacio Dávila González (Hospital Clínico, Salamanca); Table 3 Mean (standard deviation) of  the  different Carmen Panizo Bravo (Hospital Nuestra Señora del Prado. Talavera de la Reina, validated patient reported outcomes for  controlled Toledo); Víctor Soriano Gomis (Hospital General Alicante); María José Barasona versus  not  controlled AC control assessed by  the  DECA Villarejo (Hospital Reina Sofía, Córdoba); José Luis Llorente Pendas and César criteria Alvarez Marcos (Hospital Central Asturias, Oviedo); Jesús Bonnin Otal (Hospital General de Elda, Alicante); Dolores Hernández Fernández de Rojas (Hospital DECA criteria p La Fe, Valencia); Francisco Vega de la Osada (Hospital Universitario La Princesa, Madrid); María Luisa González Gutiérrrez (Hospital Clínico San Carlos, Madrid); Controlled Not controlled Pedro Amaro Merino (Instituto Oto Vértigo, Madrid); Albert Roger (Centre Roger Asmología y Alergia, Barcelona); Magdalena Lluch Bernal (Hospital Uni‑ Ocular symptoms (0–3), mean (SD) versitario de La Paz, Madrid); Beatriz Parra (Hospital El Bierzo. Ponferrada, León). Pruritus 0.94 (0.86) 2.00 (0.71) < 0.0001 Authors’ contributions Tearing 0.65 (0.89) 1.62 (0.82) < 0.0001 All authors contributed to study design, data acquisition and data analysis; Redness 0.60 (0.81) 1.76 (0.99) < 0.0001 MCS‑H and AMN wrote the first draft of the manuscript; all authors partici‑ rTOSS score (0–9), mean (SD) 2.19 (2.25) 5.38 (1.97) < 0.0001 pated in the writing and approved the final version of the manuscript before submission. All authors read and approved the final manuscript. Ocular symptoms by VAS (0–10 cm), mean (SD) Pruritus 0.94 (0.86) 2.00 (0.71) < 0.0001 Funding Tearing 0.65 (0.89) 1.62 (0.82) < 0.0001 This study was funded by Meda Pharma SL (a Mylan company). Redness 0.60 (0.81) 1.76 (0.99) < 0.0001 Availability of data and materials ESPRINT‑15 (0–6), mean (SD) 1.75 (1.60) 4.33 (1.40) < 0.0001 Data is available from the corresponding author upon reasonable request. Question 4* RCAT (5‑1), mean (SD) 3.68 (1.13) 2.20 (0.96) < 0.0001 Ethics approval and consent to participate Question 3** The study was approved by the Ethics Committee for Clinical Research of the Hospital Clínic de Barcelona. All patients signed informed consent to DECA: Spanish document on allergic conjunctivitis; ESPRINT‑15: Spanish allergic participate. rhinitis quality of life questionnaire; RCAT: rhinitis control assessment test; rTOSS: reflective total ocular symptom score; VAS: visual analogue scale Consent for publication * ESPRINT‑15 Question 4: “In the past 2 weeks, how much have you been All participants signed their written consent for publication. bothered by itchy eyes or having to rub your eyes?” ** RCAT Question 3: “During the past week, how often did you have watery Competing interests eyes?” MCS‑H reports grants from MYLAN during the conduct of the study. Outside this study, she reports personal fees from MYLAN, Sanofi, Novartis, and Merck. AMN reports grants from MYLAN during the conduct of the study. Outside this study, she reports personal fees from GSK, AstraZeneca, Merck, and MYLAN. patients in the evaluation of eye symptoms and follow-up CC reports having served as a consultant to Mylan and AstraZeneca; having of therapies. been paid lecture fees by AstraZeneca, GSK, Mylan, and MSD; and grants from Roxall, Novartis, AstraZeneca, and Sanofi. AdC reports grants from MYLAN during the conduct of the study. Outside this study, he reports grants and Abbreviations personal fees from MYLAN, FAES Pharma, Novartis, Allakos, and Sanofi; and AC: Allergic conjunctivitis; AR: Allergic rhinitis; ARIA: Allergic rhinitis and its personal fees from ALK, GSK, and MSD. JS reports grants from MEDA during impact on asthma; COSMIN: Consensus‑based standards for the selection of the conduct of the study; grants and personal fees from SANOFI; and personal health measurement instruments; DECA: Consensus document on allergic fees from GSK, NOVARTIS, ASTRA ZENECA, MUNDIPHARMA, and FAES FARMA, conjunctivitis (Spanish acronym for “Documento de consenso sobre conjunti‑ outside the submitted work. JM reports personal fees and other from SANOFI‑ vitis alérgica”); ESPRINT‑15: Spanish allergic rhinitis quality of life questionnaire; GENZYME & REGENERON, NOVARTIS; grants and personal fees from MYLAN‑ mARIA: Modified allergic rhinitis and its impact on asthma; PRO: Patient ‑ MEDA Pharma and URIACH Group; and personal fees from Mitsubishi‑ Tanabe, reported outcome; QoL: Quality of life; RCAT : Rhinitis control assessment test; Menarini, UCB, AstraZeneca, GSK, and MSD, outside the submitted work. AV rTNSS: Reflective total nasal symptom score; rTOSS: Reflective total ocular reports grants from MEDA during the conduct of the study. symptom score; VAS: Visual analogic scale. Author details Acknowledgements Department of Allergy, Hospital Universitario Virgen Macarena, Seville, Spain. The authors wish to thank Francisco López de Saro, PhD ( Trialance SCCL) Department of Allergy, Hospital El Tomillar, Dos Hermanas, Seville, Spain. 3 4 for medical writing assistance in the preparation of this article. The authors Doctor Relimpio 6, 3B, 41003 Seville, Spain. Department of Allergy, Hospital thank the participation in this study of María Teresa Dordal Culla (Hospital de Clínico‑Instituto de Investigación Sanitaria de Aragón, Zaragoza, Spain. Badalona, Barcelona); Encarnación Antón Casas (Hospital Marqués Valdecilla, Rhinology & Asthma Unit; Department of Otorhinolaryngology, Hospital Santander); Javier Montoro (Hospital Arnau de Vilanova, Valencia); Ignacio Jau‑ Universitario de Jerez, Cádiz, Spain. Department of Allergy, Fundación Jimé‑ regui Presa and Ignacio Antepara (Hospital de Basurto, Bilbao); Manuel Alcán‑ nez Díaz, Madrid, Spain. Department of Medicine, Universidad Autónoma de tara Villar (private practice, Jaén); Elisa Gómez Torrijos (Hospital Universitario Madrid, Madrid, Spain. CIBERES, Instituto de Salud Carlos III, Madrid, Spain. Ciudad Real); Julio Delgado Romero (Hospital Virgen Macarena, Sevilla); Enric Rhinology Unit & Smell Clinic, Department of Otorhinolaryngology, Hospital Figuerola Massana (Hospital Universitario Juan XXIII, Tarragona); Ramona Soler Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), (Hospital Universitaroi Son Espases, Palma de Mallorca); Miguel Armengot Universitat de Barcelona, Barcelona, Spain. Department of Pneumology Carceller (Hospital General Valencia); María Salas Cassinello (Hospital Carlos and Allergy, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Haya, Málaga); Javier Fernández Arbeiza (Complejo Hospitalario, Cáceres); Sunyer (IDIBAPS), Barcelona, Spain. Alfonso Malet Casajuana (Private practice, Malet, Barcelona); Víctor Matheu Delgado (Hospital Quirón, Tenerife); Ruperto González (Clinic Alergocan, Received: 30 July 2020 Accepted: 8 October 2020 Tenerife); José Miguel Villacampa (Hospital de Collado‑ Villaba‑IDC, Madrid); María Cesárea Sánchez (Hospital Juan Ramón Jiménez, Complejo Hospital‑ ario de Huelva); Manuel de Barrio Fernández (Hospital Universitario Gregorio S ánchez‑Hernández  et al. Clin Transl Allergy (2020) 10:43 Page 9 of 9 References 15. Valero A, Ferrer M, Baro E, Sastre J, Navarro AM, Marti‑ Guadano E, et al. 1. Dupuis P, Prokopich CL, Hynes A, Kim H. A contemporary look at allergic Discrimination between moderate and severe disease may be used conjunctivitis. Allergy Asthma Clin Immunol. 2020;16:5. in patients with either treated or untreated allergic rhinitis. Allergy. 2. Ojeda P, Sastre J, Olaguibel JM, Chivato T. Alergologica 2015: a National 2010;65:1609–13. 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Ophthalmic Epidemiol. 2005;12:233–42. to Spanish and validation of the Rhinitis Control Assessment Test (RCAT ) 5. Pitt AD, Smith AF, Lindsell L, Voon LW, Rose PW, Bron AJ. Economic and questionnaire. J Investig Allergol Clin Immunol. 2020;30:175–81. quality‑ of‑life impact of seasonal allergic conjunctivitis in Oxfordshire. 19. Nathan RA, Dalal AA, Stanford RH, Meltzer EO, Schatz M, Derebery J, et al. Ophthalmic Epidemiol. 2004;11:17–33. Qualitative development of the rhinitis control assessment test (RCAT ), an 6. Bielory L, Delgado L, Katelaris CH, Leonardi A, Rosario N, Vichyanoud P. instrument for evaluating rhinitis symptom control. Patient. 2010;3:91–9. ICON: diagnosis and management of allergic conjunctivitis. Ann Allergy 20. Valero A, Alonso J, Antepara I, Baro E, Colas C, del Cuvillo A, et al. Asthma Immunol. 2020;124:118–34. Development and validation of a new Spanish instrument to measure 7. 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Allergy Clin Immunol. 2011;11:471–6. 10. Bousquet J, Arnavielhe S, Bedbrook A, Fonseca J, Morais Almeida M, Todo 23. Neto HJ, Rosario NA, Westphal GL, Riedi CA, Santos HL. Allergic conjunc‑ Bom A, et al. The allergic rhinitis and its impact on asthma (ARIA) score of tivitis in asthmatic children: as common as underreported. Ann Allergy allergic rhinitis using mobile technology correlates with quality of life: the Asthma Immunol. 2010;105:399–400. MASK study. Allergy. 2018;73:505–10. 24. Sánchez M, Fernández Parra B, Matheu V, Navarro A, Ibáñez M, Dávila I, 11. Brozek JL, Bousquet J, Agache I, Agarwal A, Bachert C, Bosnic‑Anticevich et al. Allergic conjunctivitis. J Allergy Clin Immunol. 2011;21:1–19. S, et al. Allergic rhinitis and its impact on Asthma (ARIA) guidelines‑2016 25. Gradman J, Wolthers OD. Allergic conjunctivitis in children with asthma, revision. J Allergy Clin Immunol. 2017;140:950–8. rhinitis and eczema in a secondary outpatient clinic. Pediatr Allergy 12. Leonardi A, Bogacka E, Fauquert JL, Kowalski ML, Groblewska A, Jedrze‑ Immunol. 2006;17:524–6. jczak‑ Czechowicz M, et al. Ocular allergy: recognizing and diagnosing hypersensitivity disorders of the ocular surface. Allergy. 2012;67:1327–37. Publisher’s Note 13. Sánchez‑Hernández MC, Montero J, Rondón C, Benitez del Castillo JM, Springer Nature remains neutral with regard to jurisdictional claims in pub‑ Velázquez E, Herreras JM, et al. Consensus document on allergic conjunc‑ lished maps and institutional affiliations. tivitis (DECA). J Investig Allergol Clin Immunol. 2015;25:94–106. 14. Valero A, Ferrer M, Sastre J, Navarro AM, Monclus L, Marti‑ Guadano E, et al. A new criterion by which to discriminate between patients with moder‑ ate allergic rhinitis and patients with severe allergic rhinitis based on the allergic rhinitis and its impact on asthma severity items. J Allergy Clin Immunol. 2007;120:359–65. Ready to submit your research ? 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Validation of the DECA criteria for allergic conjunctivitis severity and control

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10.1186/s13601-020-00349-4
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Abstract

Background: Allergic conjunctivitis (AC) is usually associated to allergic rhinitis (AR), but the severity and control of ocular symptoms should be assessed independently to improve diagnosis and treatment. The criteria from the Spanish consensus document on allergic conjunctivitis (DECA) aimed to be used as a patient‑reported instrument for AC management. Here we validate these criteria for classifying AC severity and defining its control following COSMIN guidelines recommendations. Methods: Patients with moderate or severe AR [reflective total nasal symptom score (rTNSS) score ≥ 8] and concomi‑ tant AC were recruited from hospitals in Spain. Patients were classified according to the severity of ocular symptoms as mild, moderate, or severe, and classified with respect to control as controlled and non‑ controlled, using the DECA criteria. To validate these criteria, comparisons with the validated modified allergic rhinitis and its impact on asthma (mARIA), reflective total ocular symptom score (rTOSS), rhinitis control assessment test (RCAT ), ESPRINT ‑15 question‑ naires, a conjunctival hyperemia scale and a visual analogue scale ( VAS) for ocular symptoms were performed. Results: A total of 128 patients participated in the validation. Mean age was 34.4 ± 12.1 years; 72.7% were women. The DECA criteria showed a good discriminant validity, reflecting a high capacity to differentiate between mild, mod‑ erate, and severe patients, and controlled from uncontrolled patients. A strong association between AC and AR was reflected in the comparison between the DECA and the mARIA criteria (p < 0.0001). The DECA criteria for severity and control presented satisfactory properties for longitudinal validity and responsiveness. Conclusions: Validation of the DECA criteria for severity and control of AC suggested that it can be useful in the evaluation of eye symptoms and follow‑up of therapies. Keywords: Allergic conjunctivitis, Allergic rhinoconjunctivitis, Conjunctivitis classification, Control, Ocular allergy Introduction allergic disorders in most patients, but the ocular symp- Allergic conjunctivitis (AC) is an immunological hyper- toms can be present without nasal involvement in 2–7% sensitivity disorder of the ocular conjunctiva, predomi- of AC patients [2, 3]. AC is a highly prevalent disease, nantly mediated by an IgE mechanism [1]. AC occurs affecting up to 40% of the adult population [1]. The most concomitantly with allergic rhinitis (AR) and other frequent symptoms are pruritus, tearing, and conjuncti- val hyperemia. These symptoms can cause a significant impact on quality of life (QoL), affecting sleep and result - *Correspondence: anam.navarro.sspa@juntadeandalucia.es ing in emotional problems and impairment of activities of M. Cesárea Sánchez‑Hernández and Ana M. Navarro contributed equally daily living or social functions, such as work productivity as first authors Joaquim Mullol and Antonio Valero contributed equally with senior or performance at school [4, 5]. AC is often underdiag- responsibilities nosed and undertreated, as only a small proportion of Department of Allergy, Hospital El Tomillar, Dos Hermanas, Seville, Spain patients (~ 10%) with AC symptoms seek medical advice Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Sánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 2 of 9 [6]. Failure to recognize and treat ocular symptoms asso- classification, control and treatment of patients with AC ciated with AR can increase the burden of the disease [13]. This consensus (henceforth named DECA, for its substantially for allergy patients. acronym in Spanish) was based on the modified ARIA To better understand disease progression and to help (mARIA) classification of AR [14] adapted to AC (Fig.  1). assessing the effectiveness of treatment pathways, in The mARIA criteria classified patients as mild (when no the last two decades the concepts of ‘disease severity’ items are affected), moderate (involvement of 1, 2 or 3 and ‘disease control’ have been established for chronic items) and severe (involvement of the 4 items) in both allergic diseases [7]. Thus, several patient-reported out - untreated and treated patients [14, 15]. Accordingly, in come (PRO) instruments have been developed to meas- the DECA classification three levels of severity were pro - ure severity and control of AR [8, 9]. A successful and posed (mild, moderate, severe) and the criteria for fre- widely discussed initiative was the allergic rhinitis and quency were retained (intermittent/persistent). its impact on asthma (ARIA) approach, which classified The novel DECA criteria for control were based on the patients according to severity and, more recently, also to analysis of control criteria proposed for various allergic control [8, 10, 11]. The original ARIA document classi - diseases [13]. AC was classified as controlled or uncon - fied AR severity based on the impact of AR on 4 items: trolled based on 3 evaluation criteria: occurrence and sleep, activities/leisure/sports, work productivity/school frequency of ocular symptoms, a VAS score, and the performance and bothersome symptoms [8]. Based on degree of conjunctiva hyperemia as determined by the the original ARIA criteria, a severity classification for AC Efron scale [16]. patients based on ocular symptoms was also proposed The objective of this study was to validate the DECA [12]. criteria for classifying severity and control in AC patients, In 2015, experts from the Spanish Societies of Aller- following the recommendations from the Consensus- gology and Ophthalmology proposed a consensus of based Standards for the Selection of Health Measure- basic criteria that could be useful for both specialists ment Instruments (COSMIN) initiative [17], in a sample and primary care physicians to facilitate the diagnosis, Fig. 1 The criteria from the Spanish consensus document on allergic conjunctivitis (DECA). a Criteria for severity; b Criteria for control S ánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 3 of 9 of AC patients included in an observational study on the severity or control. These patients were defined as those control of allergic rhinitis in Spain (CORINA) study. who had < 1.2 changes in the VAS score or ≤ 1 point in ESPRINT-15 question 4. Methods 3. Responsiveness was assessed comparing the magni- This study was part of a larger observational, prospective, tude of the change in the different PROs (rTOSS, VAS, and multicenter real-life study to assess the epidemiol- the Efron scale, and ESPRINT-15 question 4 for severity ogy of patients with moderate and severe AR in Spain and rTOSS, ESPRINT-15 question 4, and RCAT question in terms of control (CORINA), carried out between 3 for control) for three options of change in severity and November 2015 and October 2016. Research was per- control: worse, equal and improved. formed by allergists and/or otorhinolaryngologists work- ing at reference hospitals and health centers throughout Patient‑reported outcomes and assessments Spain. To avoid a possible bias due to seasonality, each The values of all the study variables were extracted from researcher included no more than 4 consecutive patients the patients’ medical records and from the study ques- meeting the inclusion criteria each month until reach- tionnaires filled out during the visits. Data was collected ing the target figure of 15 patients per investigator. The on demography, concomitant diseases and medication study was non-interventional as the clinical decision use, etiology of allergic sensitization, and severity and to prescribe treatments for the management of AC was control of AC. made according to the usual clinical practice and was AC symptoms evaluated were pruritus, tearing and prior and independent of any consideration of the pos- redness. Each of the symptoms was evaluated on a scale sible participation of patients in this study. During the between 0 (no symptom) and 3 (severe symptom) and study, patients received standard medical care without on a VAS (0–10  cm; 0 = no symptoms, 10 = maximum analytical tests or other clinical procedures specific to the severity). Conjunctive hyperemia was measured with study. All included patients had to sign informed consent the grading scale by Efron (0–4; 0 = normal, 4 = severe) and be able to attend the follow-up visit. The study was [16]. The rTOSS was calculated as the sum to the indi - approved by the Ethics Committee for Clinical Research vidual score at 3 symptoms, with a maximum score of 9. of the Hospital Clínic de Barcelona. Question 3 of the Spanish-validated RCAT was used to evaluate control: “During the past week, how often did Patient population and study design you have watery eyes?” (5–1; 5 = never, 1 = extremely The inclusion criteria were age ≥ 18 years and a diagnosis often) [18, 19]. Question 4 of the Spanish version of the of AC according to the criteria in the DECA document ESPRINT-15 questionnaire was used to evaluate affec - [13] (Fig.  1). All patients had moderate or severe AR tation of quality of life: “In the past 2  weeks, how much according to mARIA criteria [14], with a reflective total have you been bothered by itchy eyes or having to rub nasal symptom score (rTNSS) of ≥ 8 (scale 0–12). your eyes?” (0–6; 0 = not at all; 6 = extremely) [20, 21]. The patients made a first visit (baseline visit) and a AC severity was classified according to the DECA cri - second visit 4–5  weeks later (follow-up visit). We fol- teria based on the impact on 4 items: bothersome symp- lowed COSMIN recommendations, as this international toms, affectation of vision, interference with academic consensus established how to measure and evaluate in a or work tasks, or interference with daily activities, read- uniform and consensual way the different health instru - ing and/or sport (Fig.  1a) [13]. Based on these criteria, ments [17]. According to COSMIN, the DECA severity patients were classified as mild (no items affected), mod - and control criteria were validated for: erate (involvement of 1, 2 or 3 items) and severe (involve- 1. Discriminant validity was evaluated by comparing ment of the 4 items). AC was also classified according to differences in the reflective total ocular symptom score its duration in intermittent (up to 4 days/week or up to 4 (rTOSS), the rTNSS, question 3 of the rhinitis control consecutive weeks) or persistent (more than 4 days/week assessment test (RCAT), a visual analogue scale (VAS), and more than 4 consecutive weeks). hyperemia scale and question 4 from the ESPRINT-15 The degree of AC control was assessed, according to the questionnaire between patients classified in the differ - DECA criteria, by symptoms, VAS and the Efron scale for ent categories of severity or control using DECA criteria. conjunctival hyperemia (Fig.  1b) [13]. AC was consid- Also, the percentage of patients classified in each cat - ered controlled if there were no symptoms or they were egory of severity using mARIA criteria was assessed for not bothersome 2 or more days per week, VAS < 5  cm each category of AC severity by the DECA criteria. and hyperemia scale was 0–1. It was considered uncon- 2. Test–retest reliability was evaluated by analyzing trolled if at least one of the following items was observed: the score agreement (kappa coefficient) in the basal and symptoms with any intensity 2 or more days per week, follow-up visits in those patients reporting equal AC VAS ≥ 5 cm and/or hyperemia scale was 2–4. Sánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 4 of 9 Statistical methods Table 1 Baseline characteristics of  the  patients included For the statistical analysis, the package SAS version in  the  DECA criteria for  AC severity and  control validation study (N = 128) 9.2 for Windows was used. The mean, median, stand - ard deviation, minimum and maximum, 25th and 75th Age, years, mean (SD) 34.4 (12.1) percentiles, and the number of valid cases were used Gender, female, N (%) 93 (72.7) for the description of continuous variables. The num - Allergic comorbidities, N (%) ber and percentage of patients per response category AR 128 (100.0) was used for categorical variables. Prior to performing Asthma 53 (41.4) parametric tests, we applied statistical techniques to Atopic dermatitis 14 (10.9) ensure compliance with the assumptions. In case the Urticaria 11 (8.6) established assumptions were not met, non-parametric Contact dermatitis 4 (3.1) tests were employed. A level of statistical significance Food allergy 4 (3.1) (p-value) of < 0.05 was used for all statistical tests. Other 14 (10.9) Type of AC sensitization, N (%) Perennial 40 (32.5) Results Seasonal 31 (25.2) The CORINA study recruited 252 patients [18]. Of Both 52 (42.3) these, 198 (78.6%) presented with AC symptoms in rTOSS score, mean (SD) 5.4 (2.3) the basal visit, and 128 patients (50.8%) in the follow- Hyperemia (Efron scale), N (%) Normal 26 (20.3) up visit. The validation of the DECA criteria for sever - Trace 62 (48.4) ity and control was performed on this sample of 128 Mild 29 (22.7) patients with AC symptoms and who attended both Moderate 11 (8.6) the baseline and the follow-up visits. Table  1 shows AC duration, N (%) the baseline characteristics of the patients included Intermittent 44 (34.4) in this study. The mean age of the AC patients was Persistent 84 (65.6) 34.4 ± 12.1  years and 72.7% were women. The mean Items reported (DECA), N (%) time elapsed between the date of diagnosis and the Bothersome symptoms 116 (90.6) study was 6.3 ± 9.7  years. At the basal visit, 94.5% of Aec ff ting vision 39 (30.5) patients presented pruritus, 85.9% tearing, and 85.9% Interference with academic or work tasks 54 (42.2) redness. All patients presented moderate or severe Interference with daily activity, reading, sport 66 (51.6) AR (100%) and 41.4% had concomitant asthma, 10.9% Severity (DECA criteria), N (%) atopic dermatitis, and 3.1% food allergy. The most fre - Mild (no items affected) 10 (7.8) quent allergen sensitizations were to dust mites (57.7%) Moderate (1–3 items affected) 93 (72.7) and grass pollens (45.5%), while 63% of the patients Severe (4 items affected) 25 (19.5) presented polysensitization. Regarding type of AC sen- Control (DECA criteria), N (%) sitization, for 25.2% of the patients it was seasonal, for Controlled 27 (21.1) 32.5% perennial, and for 42.3% both. Table 1 shows the Not controlled 101 (78.9) treatment followed by the patients at baseline, which Ophthalmic treatments at baseline, N (%) the specialist adjusted according to current guidelines Azelastine 34 (26.6) at baseline, modifying it in 63.3% of cases and initiating Ketotifen 11 (8.6) it in 20.3%. Olopatadine 3 (2.3) Levocabastine 1 (0.8) Others 1 (0.8) Validation of the DECA criteria for AC severity Nasal treatments at baseline, N (%) Discriminant validity Budesonide 2 (1.6) Table  2 shows the scores of the different validated PROs Fluticasone 12 (9.4) when assessed according to the severity categories Mometasone 22 (17.2) defined by using the DECA criteria. A highly significant Triamcinolone 1 (0.8) discriminant validity of the DECA criteria for severity Fluticasone furoate 43 (33.6) was found when comparing these scores. The percent - Fluticasone/azelastine combination 41 (32.0) age of patients classify similarly regarding severity with AC: allergic conjunctivitis; AR: allergic rhinitis; DECA: Spanish document on the mARIA criteria and the DECA criteria also showed a allergic conjunctivitis; rTOSS: reflective total ocular symptom score; SD: standard good balance facing both systems (Fig. 2). deviation S ánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 5 of 9 Test–retest reliability Responsiveness Thirty-three patients had the same AC severity as assessed The magnitudes of the change in the PROs scores for by the VAS, resulting in a kappa value of 0.45 (72.7% agree- patients who worsened, improved or stayed the same ment) with the DECA severity criteria, and 56 patients for in their AC severity were significantly different regard - the ESPRINT-15 question 4, kappa value of 0.33 (62.5% ing rTOSS, VAS, the Efron hyperemia scale, and agreement), reflecting a fair test–retest reliability. ESPRINT-15 question 4 (Fig.  3a), suggesting that the Table 2 Mean (standard deviation) for  the  scores of  the  different validated patient reported outcomes assessed in the severity categories classified by using the DECA criteria DECA criteria p Mild Moderate Severe Ocular symptoms (0–3), mean (SD) Pruritus 0.77 (0.83) 1.61 (0.84) 1.89 (1.05) < 0.0001 Tearing 0.47 (0.78) 1.25 (0.89) 1.78 (1.09) < 0.0001 Redness 0.43 (0.68) 1.28 (1.01) 1.78 (0.83) < 0.0001 rTOSS score (0–9), mean (SD) 1.66 (1.98) 4.17 (2.28) 5.44 (2.65) < 0.0001 Ocular symptoms by VAS (0–10 cm), mean (SD) Pruritus 1.70 (2.17) 4.48 (2.94) 5.30 (2.86) < 0.0001 Tearing 1.45 (2.30) 3.80 (2.95) 4.79 (3.20) < 0.0001 Redness 1.35 (2.41) 3.94 (3.05) 4.56 (3.03) < 0.0001 VAS global score 1.82 (2.21) 4.87 (2.88) 6.14 (3.01) < 0.0001 Efron hyperemia scale (0–4), mean (SD) 0.10 (0.31) 0.93 (0.81) 1.20 (1.14) < 0.0001 ESPRINT‑15 (0–6), mean (SD) 1.39 (1.51) 3.32 (1.71) 4.10 (1.37) < 0.0001 Question 4* DECA: Spanish document on allergic conjunctivitis; ESPRINT‑15: Spanish allergic rhinitis quality of life questionnaire; rTOSS: reflective total ocular symptom score; VAS: visual analogue scale; SD: standard deviation *ESPRINT‑15 Question 4: “In the past 2 weeks, how much have you been bothered by itchy eyes or having to rub your eyes?” Fig. 2 Percentage of patients in each allergic conjunctivitis (AC) severity category using DECA criteria (mild, moderate, or severe) and for each allergic rhinitis (AR) severity category by mARIA Sánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 6 of 9 DECA criteria for severity showed good responsiveness were compared with the mARIA criteria. Although AR to detect changes on symptoms, ocular signs and quality severity and AC severity do not necessarily have to fol- of life. low parallel classifications, in our study we observe a good agreement between the two, suggesting that these Validation of the DECA criteria for AC control instruments are effective and can simplify and expedite Patients classified as controlled by the DECA criteria the classification of both diseases [25]. Additionally, we showed PROs scores significantly different from patients find it is highly useful to differentiate AC severity in three classified as uncontrolled, indicating a high discriminant categories (mild, moderate, and severe), as differentiating validity of the DECA criteria for AC control (Table 3). moderate to severe patients can reduce the heterogeneity Patients who did not report changes in AC control, in the higher severity status [14, 15]. when assessed by DECA criteria, between the basal and The capacity of the DECA criteria to discriminate follow-up visits (N = 15) showed a similar score in PROs patients according to the degree of AC control can be (Kappa value of 0.59; 80% agreement), proving a good observed in Table 3, clearly suggesting their validity. Lon- test–retest validity. gitudinal validity and responsiveness for the DECA crite- The changes in PROs scores for patients who changed ria severity and control were also acceptable and suggest their level of control assessed by DECA criteria were sig- that they could be useful in the evaluation and follow-up nificantly and relevantly higher than patients who do not, of treated patients. showing a good responsiveness (Fig. 3b). This validation study had some limitations. First, it only included patients with a diagnosis of moderate to severe Discussion AR or that patients with ocular symptoms alone were not This study successfully validated the DECA criteria for included. Second, a methodological limitation derives severity and control of AC according to the require- from the lack of a standard and normalized classification ments established in the COSMIN: discriminant validity, for eye symptoms related to AC. For this reason, in our test–retest reliability, and responsiveness [17]. The data validation we could only compare the DECA criteria with obtained in the CORINA study described here suggest other validated instruments previously applied to various that the DECA criteria could be used to rapidly assess AC aspects of symptom severity and quality of life formally severity and control of the disease in patients with AC designed for AR. We have also used the specific ocu - symptoms. lar items of the ESPRINT-15 and RCAT questionnaires Despite the increase in allergic eye diseases in recent (questions 4 and 3, respectively), but these items were not decades and the socioeconomic impact generated by AC designed to be used in isolation and therefore their reli- [3–5, 22], it is commonly accepted that AC is often under- ability has not been validated. Similarly, comparison with diagnosed and undertreated [6]. This could be due in part other classification schemes previously proposed before to the highly frequent comorbidity of AC with other more has not been possible, as they have not been validated. severe allergic diseases such as asthma [23]. In our study One of the strengths of this study is that it showed for we also observed this frequent comorbidity, as asthma the first time the validation of an instrument specific for was present in 41.4% of the patients and atopic dermatitis AC control, following the COSMIN recommendations in 10.9% (in addition to rhinitis which, for methodologi- for reliability, validity and responsiveness [17]. It has been cal reasons, was present in all patients). Another possible suggested that measurements of disease control should reason for the underdiagnosis of AC could be the lack of be reproducible and easily implementable in everyday an unanimously agreed classification criteria. Addition - practice and focused on the disease’s impact in daily life ally, in most epidemiological studies on allergic diseases [9]. In this regard, the DECA criteria are designed to be the eye and nasal symptoms have been treated as a single a practical tool used by primary health practitioners and clinical entity [24]. For these reasons, in an effort to bring specialists alike. Further, the proposed clinical classifi - together the classification criteria of AC and AR and to cation of AC severity is consistent and complementary unify nomenclature on AC, the DECA consensus docu- with that currently in use for AR severity. The unifica - ment proposed a new classification of AC and also added a tion of criteria for the evaluation of severity and con- proposal for the definition of AC control [13]. trol is important in the development of diagnostic and In this study some relevant properties of the DECA cri- treatment guidelines for common use by primary care teria were assessed. The discriminant validity for disease physicians, allergists, and ophthalmologists, as a mul- severity, as shown in Table  2, reflected a high capacity tidisciplinary communication is necessary for the opti- to differentiate mild, moderate, and severe patients. The mal management of AC patients [1, 6, 9]. In this regard, extent by which AC is associated with AR could also be the validated instruments described here could also be observed when patient classification by the DECA criteria used to rapidly screen these patients with AC control S ánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 7 of 9 Fig. 3 Boxplots showing the DECA criteria score changes (median, 25th and 75th interquartile values) between visits for AC patients, which were categorized as worse, equal, or improved compared to baseline. a Comparisons for PROs evaluating severity. The differences are statistically significant for rTOSS (p < 0.0001), VAS (p < 0.0001), hyperemia scale (p < 0.0002), and ESPRINT‑15 question 4 (p < 0.0001). b Comparisons for PROs evaluating control. The differences were statistically significant for rTOSS (p < 0.0001), ESPRINT‑15 question 4 (p < 0.0001), and RCAT question 3 (p < 0.0002) problems and could help patients to communicate with Conclusion health care practitioners about their disease and their This study validated with good results the criteria for response to treatment. severity and control assessment proposed in DECA, making this a potentially useful tool for physicians and Sánchez‑Hernández et al. Clin Transl Allergy (2020) 10:43 Page 8 of 9 Marañón, Madrid); Ignacio Dávila González (Hospital Clínico, Salamanca); Table 3 Mean (standard deviation) of  the  different Carmen Panizo Bravo (Hospital Nuestra Señora del Prado. Talavera de la Reina, validated patient reported outcomes for  controlled Toledo); Víctor Soriano Gomis (Hospital General Alicante); María José Barasona versus  not  controlled AC control assessed by  the  DECA Villarejo (Hospital Reina Sofía, Córdoba); José Luis Llorente Pendas and César criteria Alvarez Marcos (Hospital Central Asturias, Oviedo); Jesús Bonnin Otal (Hospital General de Elda, Alicante); Dolores Hernández Fernández de Rojas (Hospital DECA criteria p La Fe, Valencia); Francisco Vega de la Osada (Hospital Universitario La Princesa, Madrid); María Luisa González Gutiérrrez (Hospital Clínico San Carlos, Madrid); Controlled Not controlled Pedro Amaro Merino (Instituto Oto Vértigo, Madrid); Albert Roger (Centre Roger Asmología y Alergia, Barcelona); Magdalena Lluch Bernal (Hospital Uni‑ Ocular symptoms (0–3), mean (SD) versitario de La Paz, Madrid); Beatriz Parra (Hospital El Bierzo. Ponferrada, León). Pruritus 0.94 (0.86) 2.00 (0.71) < 0.0001 Authors’ contributions Tearing 0.65 (0.89) 1.62 (0.82) < 0.0001 All authors contributed to study design, data acquisition and data analysis; Redness 0.60 (0.81) 1.76 (0.99) < 0.0001 MCS‑H and AMN wrote the first draft of the manuscript; all authors partici‑ rTOSS score (0–9), mean (SD) 2.19 (2.25) 5.38 (1.97) < 0.0001 pated in the writing and approved the final version of the manuscript before submission. All authors read and approved the final manuscript. Ocular symptoms by VAS (0–10 cm), mean (SD) Pruritus 0.94 (0.86) 2.00 (0.71) < 0.0001 Funding Tearing 0.65 (0.89) 1.62 (0.82) < 0.0001 This study was funded by Meda Pharma SL (a Mylan company). Redness 0.60 (0.81) 1.76 (0.99) < 0.0001 Availability of data and materials ESPRINT‑15 (0–6), mean (SD) 1.75 (1.60) 4.33 (1.40) < 0.0001 Data is available from the corresponding author upon reasonable request. Question 4* RCAT (5‑1), mean (SD) 3.68 (1.13) 2.20 (0.96) < 0.0001 Ethics approval and consent to participate Question 3** The study was approved by the Ethics Committee for Clinical Research of the Hospital Clínic de Barcelona. All patients signed informed consent to DECA: Spanish document on allergic conjunctivitis; ESPRINT‑15: Spanish allergic participate. rhinitis quality of life questionnaire; RCAT: rhinitis control assessment test; rTOSS: reflective total ocular symptom score; VAS: visual analogue scale Consent for publication * ESPRINT‑15 Question 4: “In the past 2 weeks, how much have you been All participants signed their written consent for publication. bothered by itchy eyes or having to rub your eyes?” ** RCAT Question 3: “During the past week, how often did you have watery Competing interests eyes?” MCS‑H reports grants from MYLAN during the conduct of the study. Outside this study, she reports personal fees from MYLAN, Sanofi, Novartis, and Merck. AMN reports grants from MYLAN during the conduct of the study. Outside this study, she reports personal fees from GSK, AstraZeneca, Merck, and MYLAN. patients in the evaluation of eye symptoms and follow-up CC reports having served as a consultant to Mylan and AstraZeneca; having of therapies. been paid lecture fees by AstraZeneca, GSK, Mylan, and MSD; and grants from Roxall, Novartis, AstraZeneca, and Sanofi. AdC reports grants from MYLAN during the conduct of the study. Outside this study, he reports grants and Abbreviations personal fees from MYLAN, FAES Pharma, Novartis, Allakos, and Sanofi; and AC: Allergic conjunctivitis; AR: Allergic rhinitis; ARIA: Allergic rhinitis and its personal fees from ALK, GSK, and MSD. JS reports grants from MEDA during impact on asthma; COSMIN: Consensus‑based standards for the selection of the conduct of the study; grants and personal fees from SANOFI; and personal health measurement instruments; DECA: Consensus document on allergic fees from GSK, NOVARTIS, ASTRA ZENECA, MUNDIPHARMA, and FAES FARMA, conjunctivitis (Spanish acronym for “Documento de consenso sobre conjunti‑ outside the submitted work. JM reports personal fees and other from SANOFI‑ vitis alérgica”); ESPRINT‑15: Spanish allergic rhinitis quality of life questionnaire; GENZYME & REGENERON, NOVARTIS; grants and personal fees from MYLAN‑ mARIA: Modified allergic rhinitis and its impact on asthma; PRO: Patient ‑ MEDA Pharma and URIACH Group; and personal fees from Mitsubishi‑ Tanabe, reported outcome; QoL: Quality of life; RCAT : Rhinitis control assessment test; Menarini, UCB, AstraZeneca, GSK, and MSD, outside the submitted work. AV rTNSS: Reflective total nasal symptom score; rTOSS: Reflective total ocular reports grants from MEDA during the conduct of the study. symptom score; VAS: Visual analogic scale. Author details Acknowledgements Department of Allergy, Hospital Universitario Virgen Macarena, Seville, Spain. The authors wish to thank Francisco López de Saro, PhD ( Trialance SCCL) Department of Allergy, Hospital El Tomillar, Dos Hermanas, Seville, Spain. 3 4 for medical writing assistance in the preparation of this article. The authors Doctor Relimpio 6, 3B, 41003 Seville, Spain. Department of Allergy, Hospital thank the participation in this study of María Teresa Dordal Culla (Hospital de Clínico‑Instituto de Investigación Sanitaria de Aragón, Zaragoza, Spain. Badalona, Barcelona); Encarnación Antón Casas (Hospital Marqués Valdecilla, Rhinology & Asthma Unit; Department of Otorhinolaryngology, Hospital Santander); Javier Montoro (Hospital Arnau de Vilanova, Valencia); Ignacio Jau‑ Universitario de Jerez, Cádiz, Spain. Department of Allergy, Fundación Jimé‑ regui Presa and Ignacio Antepara (Hospital de Basurto, Bilbao); Manuel Alcán‑ nez Díaz, Madrid, Spain. Department of Medicine, Universidad Autónoma de tara Villar (private practice, Jaén); Elisa Gómez Torrijos (Hospital Universitario Madrid, Madrid, Spain. CIBERES, Instituto de Salud Carlos III, Madrid, Spain. Ciudad Real); Julio Delgado Romero (Hospital Virgen Macarena, Sevilla); Enric Rhinology Unit & Smell Clinic, Department of Otorhinolaryngology, Hospital Figuerola Massana (Hospital Universitario Juan XXIII, Tarragona); Ramona Soler Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), (Hospital Universitaroi Son Espases, Palma de Mallorca); Miguel Armengot Universitat de Barcelona, Barcelona, Spain. Department of Pneumology Carceller (Hospital General Valencia); María Salas Cassinello (Hospital Carlos and Allergy, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Haya, Málaga); Javier Fernández Arbeiza (Complejo Hospitalario, Cáceres); Sunyer (IDIBAPS), Barcelona, Spain. Alfonso Malet Casajuana (Private practice, Malet, Barcelona); Víctor Matheu Delgado (Hospital Quirón, Tenerife); Ruperto González (Clinic Alergocan, Received: 30 July 2020 Accepted: 8 October 2020 Tenerife); José Miguel Villacampa (Hospital de Collado‑ Villaba‑IDC, Madrid); María Cesárea Sánchez (Hospital Juan Ramón Jiménez, Complejo Hospital‑ ario de Huelva); Manuel de Barrio Fernández (Hospital Universitario Gregorio S ánchez‑Hernández  et al. Clin Transl Allergy (2020) 10:43 Page 9 of 9 References 15. Valero A, Ferrer M, Baro E, Sastre J, Navarro AM, Marti‑ Guadano E, et al. 1. Dupuis P, Prokopich CL, Hynes A, Kim H. A contemporary look at allergic Discrimination between moderate and severe disease may be used conjunctivitis. Allergy Asthma Clin Immunol. 2020;16:5. in patients with either treated or untreated allergic rhinitis. Allergy. 2. Ojeda P, Sastre J, Olaguibel JM, Chivato T. Alergologica 2015: a National 2010;65:1609–13. 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Published: Oct 23, 2020

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