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Effect of nasal irrigation on allergic rhinitis control in children; complementarity between CARAT and MASK outcomes

Effect of nasal irrigation on allergic rhinitis control in children; complementarity between... Background: Nasal irrigations (NI) are increasingly used as an over‑the ‑ counter adjunctive treatment for allergic rhinitis (AR), but clinical studies on their effectiveness are limited. Methods: An open‑label, controlled, non‑randomized, real‑life study was conducted to evaluate the effectiveness of NI with a new hypertonic solution as add‑ on treatment for AR. Children and adolescents with AR were prescribed symptomatic treatment. The active group also received an additional sea‑ water NI solution supplemented with algae extracts. The primary endpoint was symptom control, assessed by the control of allergic rhinitis and asthma test (CARAT ) questionnaires. Moreover, the MASK/Allergy Diary was used to track symptoms and daily medication use that were combined in a novel total symptom/medication score ( TSMS). Results: We assessed 76 patients. Overall, there was a significant improvement of CARAT results (median Z ‑score change of 1.1 in the active/NI group vs. 0.4 in the control group; p = 0.035). Among patients > 12 years old (n = 51), there was a significant improvement in CARAT10 results among participants receiving NI (21.0 to 25.5; p < 0.001), but not in the regular treatment group (21.5 to 24.0; p = 0.100). For children < 12 years old (n = 25), the ΝΙ group had sig‑ nificantly improved symptom control (CARATKids results: 5.0 to 2.0; p = 0.002), in contrast to the control group (4.0 to 2.5; p = 0.057). MASK data on allergic symptoms were comparable between groups. However, the NI group had lower TSMS, more days with < 20% symptoms and fewer days using symptomatic treatment (26.9% vs. 43.5%; p = 0.005). Conclusion: Addition of NI with a sea‑ water solution to regular treatment improved AR symptom control. CARAT questionnaires and MASK application can be useful outcome tools in real‑life studies. Keywords: Allergic rhinitis, Nasal irrigations, Sea‑ water solution, CARAT questionnaire, MASK/Allergy Diary app, Children and adolescents, Symptom score, Medication score, Undaria pinnatifida, Spirulina platensis Introduction particularly if not appropriately treated, AR may lead to Allergic rhinitis (AR) is a very common manifestation of decreased quality of life and may be complicated with respiratory allergy, with a prevalence of up to 20–25% in multi-morbidities such as otitis, sinusitis and asthma. In Western societies. Children are commonly affected and, fact, AR is considered one of the main predisposing fac- tors for the development of asthma [1, 2]. Symptomatic treatment consists of antihistamines and nasal steroids, while allergen immunotherapy is usually performed in *Correspondence: dmitsias@yahoo.com Allergy Department, 2nd Pediatric Clinic, Athens General Children’s more severe/persistent cases [3, 4]—in any case, AR Hospital “P&A Kyriakou”, University of Athens, Thivon and Levadias 1, usually requires chronic treatment, which raises safety Athens, Greece 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. Mitsias et al. Clin Transl Allergy (2020) 10:9 Page 2 of 11 concerns about protracted drug usage, leading to the runny and/or blocked nose, sneezing, nasal itch) for quest for non-pharmacological approaches [5, 6]. at least 6  months, observed between April 2017 and Among add-on treatments, nasal irrigation (NI) with August 2018. In all, skin prick tests and/or specific IgE saline solutions appears to be useful [7–11], as it does confirmed sensitization to at least one relevant aeroal - not need medical prescription and is considered safe lergen (using a standard panel consisting of seasonal for long-term use [7]. Normal saline is primarily used, and perennial allergens, including, but not exclusively, although studies have shown increased effectiveness with grasses, olive, birch, mugwort, ragweed, Parietaria hypertonic solutions [8, 9]. Its mechanisms of action and cypress pollen, Dermatophagoides pteronyssi- include direct mechanical cleansing of the mucosa from nus and farinae, Alternaria, cat and dog epithelia, and allergens or other particles, decrease of inflammatory cockroach). Exclusion criteria consisted of adenoidal and/or allergic mediators, and increase of mucociliary hyperplasia, septal deformity, polyps, infectious rhi- clearance. Meta-analyses suggest that NI can be used as nitis, vasomotor rhinitis, rhinitis medicamentosa, i.e. add-on to medical treatment [11]. However, in children, signs and symptoms indicative of non-allergic rhinitis NI is not yet part of the guideline recommendations, (e.g. not responsive to regular treatment, fever, apnoea, probably due to insufficient evidence of its pediatric decongestant overuse). We also excluded children at effectiveness. need of oral corticosteroids, at the time of presentation. Therefore, this study aimed to evaluate the effective - ness of NI as an add-on treatment for AR, using a new NI product based on sea-water supplemented with (1) Performance of the study extracts from the sea weeds Undaria pinnatifida and All children were prescribed indicated rhinitis treat- Spirulina platensis, and (2) dexpanthenol. This is the first ment, consisting of a second-generation antihistamine study using these compounds intranasally: Undaria pin- and/or nasal corticosteroid (CS) or CS + azelastine. natifida is a brown alga rich in fucoidans (i.e. sulfated All patients/parents were instructed in allergen avoid- polysaccharides) with anti-inflammatory and anti-aller - ance measures and in the nasal spray (and irrigation, gic properties [12, 13]; Spirulina platensis is a green alga if applicable) technique and were instructed to use whose active components are phycocyanins, which have pharmacological treatment for 10-15 consecutive days, multiple possible actions, including an anti-allergic effect resuming it in case of persisting symptoms. Mast cell in the respiratory epithelium [14, 15]; dexpanthenol, the stabilizing eye drops were prescribed for conjunctivitis alcoholic analogue of pantothenic acid, acts as a mucosal refractory to antihistamines, and asthma was treated moisturizer and hydrating agent [16]. To evaluate NI with inhaled CS or CS + long-acting β-agonist, accord- effectiveness (i.e. disease control, symptoms and use of ing to the guidelines. A follow-up visit was planned for medication), we used the Control of Allergic Rhinitis and 30  days later. Signed informed consent was obtained Asthma Test (CARAT) [17, 18] and the MASK/Allergy by all patients/parents. This study was approved by the Diary app, developed by the ARIA group [19]. Ethics Committee of the “P.& A. Kyriakou” Children’s Hospital. Methods Design of the study Intervention: nasal irrigations This was an open-label, controlled, real-life, non-ran - The active/NI group received a nasal spray consisting of domized, prospective quasi-experimental study. The sea-water hypertonic (2.3% NaCl) solution with extracts attending physician prescribed the treatment accord- from Undaria pinnatifida and Spirulina platensis algae ing to guidelines and the patient/caregiver chose to use and dexpanthenol (“Sinomarin + Algae Allergy Relief”, (or not) supplementary NI in addition to the prescribed available as over-the-counter). The patient/caregiver was treatment. Therefore, an active/NI group (standard AR instructed to use the product daily during the observa- therapy plus NI) was compared with a control group tion period according to the manufacturer’s instructions: (standard AR therapy only) regarding AR symptoms and 2 puffs/nostril 3 times/day for children < 12  years old; 4 medication use. puffs/nostril up to 5 times/day for children > 12 years old. Nasal irrigations were performed at least 15  min before Setting and patients potential inhaled CS use. However, adherence either to This study was performed at the Allergy Unit of the pharmacologic treatment or NI was not further enforced 2nd Pediatric Clinic, University of Athens, a tertiary or assessed. Nevertheless, prospective data on medica- referral center. We included all eligible and consenting tion use were gathered and analyzed through the MASK/ children and adolescents (6–19  years old) with symp- Allergy Diary as described in detail below. toms suggestive of AR (such as, but not exclusively, M itsias et al. Clin Transl Allergy (2020) 10:9 Page 3 of 11 Outcomes were defined as those with score < 20% (either for VAS/ CARAT questionnaires Symptom Score or TSMS) [23]. All patients/parents Control of allergic rhinitis and asthma test (CARAT) is a were trained to use MASK application and upload data brief self-administered questionnaire aiming to quantify accordingly. symptoms and control of AR and asthma. There are two versions of CARAT—(i) CARAT10 was used by partici- pants > 12 years old, who filled it directly (as it has been Statistical analysis designed for adults and teenagers), and (ii) CARATKids, Continuous variables were described using medians which was used by participants aged 6–12 years old and and percentiles 25–75, while categorical variables were filled by them together with their parents. described with absolute frequencies and percentages. CARAT10 assesses the previous 4 weeks. The responses CARAT and MASK/Allergy Diary results were compared for all ten questions are on 4-point Likert scales, scor- using Wilcoxon’s rank-sum and Kruskal–Wallis tests ing from 0 to 3. The final score ranges from 0 to 30, with (continuous variables), and Pearson’s Chi squared test scores > 24 indicating good control of asthma and AR (categorical variables). Intention to treat analyses were [17], and four-point changes being considered clinically both performed altogether for participants of all ages, relevant [20]. CARAT10 has been translated and vali- and separately for children 6–12 and > 12 years old. dated to Greek (kindly provided by Prof. I. Tsiligianni). To perform a combined analysis on CARAT10 and CARATKids includes 13 “Yes/No” questions: affirma - CARATKids results, Z-scores were separately computed tive answers scored as 1 (corresponding to “symptom/ for CARAT10/CARATKids and, for each, both refer- item present”), while negative answers scored as 0 ence values and standard-deviations of all values (i.e. (“symptom/item not present”). Therefore, 13 points cor - those collected at first visit and at day 30) were consid - respond to a complete absence of control [18]. A version ered. Z-scores changes (i.e. Z-scores differences between translated by the authors was used. days 1 and 30) were compared between the active and control group using Mann–Whitney U test. Addition- ally, to test the consistency of our results, a non-para- MASK/Allergy Diary application metric ANCOVA was performed, with day 30 Z-scores Allergy diary is a free, on-line application for smart- as dependent variable and day 1 Z-scores as co-variate. phones, developed by MASK-rhinitis (Mobile Airways To assess whether CARAT10 and CARATKids results are Sentinel NetworK for AR) to evaluate AR symptoms and sufficiently similar to be assessed together, a meta-anal - disease control [19, 21, 22]. It contains four visual ana- ysis of standardized mean changes was performed—an logue scales (VAS) measuring nasal, ocular, asthma and I > 50% and a Cochran Q-test p-value < 0.10 were con- overall allergic symptoms. It is used prospectively and sidered to represent substantial heterogeneity. Statistical filled daily, allowing also for registering the medications analysis was accomplished with R software, version 3.5.0. used each day [23]. The application does not integrate Significance level was defined at 0.05. symptom and medication scores [24] and, therefore, we The RELEVANT criteria were considered in the design calculated a Total Symptom/Medication Score (TSMS) and reporting of this study [26]. RELEVANT is a recently based on equal weight, as suggested by EAACI [25]: developed tool by Respiratory Effectiveness Group (REG) Symptom Score+Medication Score TSMS = , where symptom and EAACI, designed to evaluate the quality of real-life score is the VAS 0-100 score, and Medication Score studies and whether they may be used in guidelines. is a 0-100 score with the following punctuation sys- tem depending on the AR medication taken: no medi- cation = 0 points; oral and/or topical (eyes or nose) Results H1antihistamines (H1A) = 100 × points; intranasal Overall, 89 children and adolescents with symptoms sug- CS (INS) with/without H1A = 100 × points; oral gestive of AR agreed to participate in this study. Seventy- CS (with/without INS and with/without H1A) = 100 six children (85%) returned for the second visit (for whom points. Of note, this approach is based on the clinical we present CARAT data) (Fig.  1). Of those, 53 children effects of pharmacotherapy on symptom reduction, but used NI (active group), while 23 did not use NI (control neither takes into account the use of specific medica - group). Children in the active/NI group, controls and tion (only the drug class) or daily dosing nor has yet drop-outs did not differ demographically, clinically or in been validated [25]. Therefore, apart from the 4 Symp - initial CARAT scores (Tables  1, 2). The MASK Allergy toms Scores (nasal, ocular, asthma and overall allergic Diary application was used by 78 children (88% accept- symptoms VAS), 4 TSMS (i.e. taking into account daily ance rate, average of 19.7 entries/child), corresponding to medication) were established. “Symptom-free days” 55 children in the active group and 23 controls. Mitsias et al. Clin Transl Allergy (2020) 10:9 Page 4 of 11 Children/adolescents aending the special clinic with indicaon of allergic rhinis n=433 Not assessed for eligibility Declined consent n=172 Assessed for eligibility Excluded n=261 Ineligible Non-allergic rhinisn=91 Possible local allergic rhinisn=17 Need for peros corcosteroidn=2 Eligible but not recruited Total recruited Refused to parcipate n=42 Unable to use applicaon n=20 n=89 Lost to follow-up (drop-outs) CARAT analysis Did not appear at re-evaluaon visit n=13 MASK analysis Could not use the applicaon n=8 Did not enter personal code n=3 Paents analyzed CARAT analysis n=76 MASK analysis n=78 Fig. 1 Flow chart of the selection process of included participants Disease control 21.5 (25–75 percentiles: 17.5–24.0) on day 1 (p = 0.100) CARAT10 (Fig.  2a). Moreover, the improvement of CARAT10 We assessed 51 participants aged > 12  years old, with score (i.e. the individual differences between day 1 and those on the NI group ending up with significantly day 30) was significantly higher for the active than for improved disease control compared to those on the the control group (median increase: 5.0 vs. 1.0, respec- control group. In fact, when we compared day 1 to day tively; p = 0.023) (Table  2). This difference surpassed 30 scores, for the active group, day30 median CARAT10 the limit of 3.5 that is considered by the CARAT devel- score was 25.5 (25–75 percentiles: 22.0–26.0), up from opers (also co-authors of the present study) to be the 21.0 (25–75 percentiles: 17.0–23.0) on day 1 (p < 0.001); minimal clinically relevant difference [20] and was on the other hand, for the control group, median day 30 achieved despite the fact that both groups had (i) simi- score was 24.0 (25–75 percentiles: 18.5–25.5), up from lar instructions in regard to regular pharmaceutical M itsias et al. Clin Transl Allergy (2020) 10:9 Page 5 of 11 Table 1 Characteristics of  the  recruited study participants, as  well as  of  the participants with  complete CARAT questionnaire and MASK/Allergy Diary results Recruited participants p-value * CARAT outcome group p-value * Allergy diary outcome p-value * (active/control group) (active/control group) group (active/control group) Total 89 (64/25) 76 (53/23) 78 (55/23) Age 0.592 1.000 0.520 > 12 years old 59(44/15) 51 (36/15) 50 (37/13) < 12 years old 30(20/10) 25 (17/8) 28 (18/10) Gender 0.578 0.427 0.485 Male 62 (43/19) 53 (35/18) 55 (37/18) Female 27 (21/6) 23 (18/5) 23 (18/5) Asthma 31 (24/7) 0.550 26 (19/7) 0.846 28 (22/6) 0.363 Sensitizations 0.929 0.873 0.819 1 20 (14/6) 14 (9/5) 17 (11/6) 2 31 (22/9) 27 (19/8) 28 (20/8) > 2 38 (28/10) 35 (25/10) 33 (24/9) * Pearson’s Chi square test Concurrent allergic asthma Table 2 CARATKids and  CARAT10 scores on  day 1, and  individual differences between  day 1 and  day 30: CARAT scores in day 1 did not differ significantly for active, control and drop-outs; by contrast, CARAT10 changes for each patient were significantly different between day 1 and day 30 Active (n: 53) Control (n: 23) Drop-outs (n: 13) p-value CARATKids (score range 0–13) n: 17 n: 8 n: 5 Day 1 5.0 (3.8–6.3) 4.0 (3.0–7.0) 5.0 (4.0–5.3) 0.878 * Day 1/day 30 difference − 3.0 (− 5.0 to 2.0) − 2.00 (− 4.0 to 0) 0.574 ** CARAT10 (score range: 0–30) n: 36 n: 15 n: 8 Day 1 21.0 (17.0–23.0) 21.5 (17.5–24.0) 19.0 (17.0–22.0) 0.536 * Day 1/day 30 difference 5.0 (0.8–6.3) 1.00 (0.5–2.5) 0.023 ** p-values < 0.05 are shown in italics Values shown as medians with 25–75 percentiles * Kruskal–Wallis test ** Wilcoxon’s rank-sum test Combined analysis of CARAT10 and CARATKids treatment, and (ii) similar severity of symptoms on day To analyze the results of all participants together, we computed Z-scores for CARAT10 and CARATKids. The active group presented a significantly higher improve - ment on its Z-score compared to the control group CARATKids (median improvement: 1.1 vs. 0.4 points, respectively; Twenty-five children < 12 years old completed the CAR- p = 0.035) (Fig. 3). These results were consistent to those ATKids questionnaire. Day 30 median CARATKids obtained when performing a non-parametric ANCOVA score for the active group was 2.0 (25–75 percentiles: comparing day 30 Z-scores between the active and the 1.0–3.0), down from 5.0 (25–75 percentiles: 3.8–6.3) control group, adjusted for day 1 Z-scores (p = 0.004). Of on day 1 (p = 0.002); for the control group, the day 30 interest, the lower the initial Z-score (i.e. the lower the score was 2.5 (25–75 percentiles: 1.8–3.0), down from initial symptom control), the higher was the difference at 4.0 (25–75 percentiles: 3.0–7.0) on day 1 (p = 0.057) the end (i.e. the greater the benefit for the patient; Fig. 4). (Fig.  2b). However, the 30-day differences in CARAT - Finally, we performed a meta-analysis pooling CAR- Kids values between active and control groups were ATKids and CARAT10 results. The standardized mean not significantly different (median decrease of − 3.0 vs . change in CARAT results was significantly higher in the − 2.0; p = 0.574) (Table 2). Mitsias et al. Clin Transl Allergy (2020) 10:9 Page 6 of 11 Fig. 2 Initial (day 1) and final (day30) CARAT scores for (a) adolescents > 12 years old (CARAT10), and (b) children < 12 years old (CARATKids). Analysis was performed with Wilcoxon’s signed‑rank test active than in the control group (0.62, 95% CI 0.08–1.16; calculated Medication Score (median: 16.7 vs. 25.7, p = 0.024), with no heterogeneity observed (I = 0%; p = 0.006) (Table 5). p = 0.718) (Fig. 5). Discussion Symptoms and medication In this proof-of-concept study, a hypertonic sea-water There were no significant differences in symptom scores (2.3% NaCl) based solution supplemented with extracts as evaluated by the VAS. However, when TSMS was cal- from the sea weeds Undaria pinnatifida and Spirulina culated, significant differences emerged for all 4 param - platensis and dexpanthenol was found to be effective as eters (Table  3). When medication use was taken into an add-on treatment in symptom control of children with account (i.e. TSMS), children using NI were symptom- AR, suggesting that NI may improve AR control with free (days with < 20% on VAS) for significantly more days reduced use of medication. regarding all parameters except the ocular one (Table 4). The medications commonly used for AR have shown Interestingly, the improvement in the active group was by objective measures to be effective and safe even for achieved with less medication use: (i) children using ΝΙ prolonged use. However, regarding children, parents/ received the prescribed pharmacologic treatment for sig- caregivers are often skeptical and unwilling to follow nificantly less days, when compared to the control group long-term treatments, which results in considerably (median: 26.9% vs. 43.5% of the days, p = 0.005) and (ii) low adherence [27]. Nasal irrigations (particularly those the active group used less medication as judged by the with normal saline) have long been used to remove mucus from the upper respiratory tract, as they are safe, M itsias et al. Clin Transl Allergy (2020) 10:9 Page 7 of 11 Fig. 3 Dot plot for the Z‑scores of CARAT10/CARATKids results for active and control groups on day 1 and day 30 Fig. 4 Correlation of initial (day1) CARAT Z‑scores and 30‑ days Z‑score difference in the control group (a) and in the active group receiving nasal irrigations (b) Mitsias et al. Clin Transl Allergy (2020) 10:9 Page 8 of 11 Table 4 Percentage of  symptom-free days, regarding different types of symptoms Percentage (%) Active (n: 55) Control (n: 23) p-value * of symptom-free days Ocular symptoms 100.0 (85.2–100.0) 96.8 (81.0–100.0) 0.483 Nasal symptoms 67.7 (50.0–87.9) 68.0 (44.8–85.7) 0.896 Asthma symptoms 100.0 (87.5–100.0) 100.0 (96.6–100.0) 0.540 Overall allergic 69.6 (40.9–90.7) 75.0 (41.7–85.7) 0.906 symptoms 75.0 (53.7–85.7) 66.7 (46.2–77.3) 0.054 Ocular TSMS Nasal TSMS 64.5 (50.8–76.8) 44.0 (38.5–56.5) 0.019 Asthma TSMS 76.9 (61.8–85.0) 64.0 (42.9–76.2) 0.016 Overall allergic 65.4 (51.9–77.8) 42.9 (36.7–61.5) 0.012 TSMS p-values < 0.05 are shown in italics Values shown as medians with 25–75 percentiles Corresponding to < 20% on  visual analogue scales (VAS) for symptoms and  Total Symptom and Medication Score (TSMS) Fig. 5 Meta‑analysis of standardized mean changes (between day 1 * Wilcoxon’srank-sum test and day 30) of CARAT results, pooling CARATKids and CARAT10 results solutions (e.g. 2.3% NaCl) being apparently more effec - Table 3 Ocular, nasal, asthma and  overall allergic tive than normal saline solutions [8, 9, 30]. symptoms using Visual Analogue Scales (VAS) for  symptoms and  total symptom and  medication score This is the first study assessing the intranasal use of (TSMS) (i.e., considering medication use on  the  respective algae, with the species used being known for having, days) among other, anti-allergic effects [12–15]. It is also the first study in children and adolescents with parallel, two Active (n: 55) Control (n: 23) p-value* way evaluation of the effectiveness of NI; intention to Ocular symptoms 1.3 (0.1–8.5) 4.1 (0.2–10.3) 0.482 treat analysis was performed. Nasal symptoms 20.0 (9.2–27.6) 20.6 (9.0–28.7) 0.936 We used a combination approach to evaluate the Asthma symptoms 0.4 (0.0–9.5) 0.1 (0.0–3.0) 0.503 effectiveness of NI, namely involving the use of CARAT Overall allergic 18.0 (8.7–26.3) 18.6 (11.6–27.8) 0.701 questionnaires and MASK/Allergy Diary application. symptoms Concurrent use of data from many sources is encour- Ocular TSMS 9.5 (6.5–17.4) 15.7 (12.2–23.6) 0.019 aged so as to provide a wider angle of the impact of AR Nasal TSMS 18.8 (12.9–22.3) 23.6 (17.3–28.0) 0.046 in each patient [31]. CARAT gives a retrospective view Asthma TSMS 10.8 (6.6–16.8) 15.6 (11.1–20.4) 0.039 on the symptoms occurred over the last weeks, while the Overall allergic TSMS 17.6 (13.0–22.1) 23.6 (14.1–28.2) 0.035 MASK/Allergy Diary provides prospective daily data on p-values < 0.05 are shown in italics symptoms and on medication use, giving the opportu- Values shown as medians and 25–75 percentiles nity to longitudinally follow the course of AR. Although * Wilcoxon’s rank-sum test this study did not aim to formally compare CARAT and Mean daily VAS MASK/Allergy Diary outcomes, our results indicate that Mean daily TSMS these tools can be used in parallel, augmenting the ability to clinically assess AR activity. tolerable and more easily acceptable by parents/caregiv- According to our results, NI can be helpful as an ers. The effectiveness of NI not only includes mechanical add-on treatment in children with allergic rhinitis. removal of mucinous excretions, but also an increase of The effect seems to be more prominent in adolescents, mucociliary function, decreased interaction of allergens possibly reflecting several factors, including different with the nasal mucosa [8], and reduced release of inflam - pathophysiology, different volume of NI, difficulty in matory mediators such as histamine, prostaglandins and symptoms monitoring in younger patients, and—prob- leukotrienes and/or receptors (such as ICAM-1) [28]. ably most important—the smaller sample size regarding Studies have shown their efficacy in AR and sinusitis, and patients < 12 years old. meta-analyses support their use [11, 29], with hypertonic M itsias et al. Clin Transl Allergy (2020) 10:9 Page 9 of 11 Table 5 Medication use in  subjects using nasal irrigation (active group) and  in  the control group, as  assessed by the percentage of days on treatment and by the medication score Active (n: 55) Control (n: 23) p-value * Percentage (%) of days on treatment 0.005 Median (25–75 percentile) 26.9 (19.1–40.7) 43.5 (31.0–61.2) Medication score 0.006 Median (25–75 percentile) 16.7 (10.7–25.0) 25.7 (17.3–35.7) p-values < 0.05 are shown in italics Medication score 0–100 depending on the drugs taken * Wilcoxon’s rank-sum test When specific allergic symptoms were assessed there treatment modalities—our participants adhered variably was some discordance between CARAT (showing con- to prescribed pharmacological treatment but adhered siderable decrease between start and end of the evalua- well to more “natural” NI and still achieved improved tion) and the Allergy Diary (that showed no difference in symptom control. Such an insight would have been symptom score alone, according to VAS, in the longitudi- impossible in the context of a randomized control trial. nal follow-up). This may reflect a rapid improvement of Another limitation is that the TSMS presented herein, symptoms after the initial evaluation, leading to a dilu- based on MASK/Allergy Diary [23] and on the EAACI tion of the effect over a 30-day period. However, when Position Paper [25], had not been formally validated. medication use was integrated with VAS (i.e. TSMS), However, both VAS and a Combined Symptom/Medica- it became apparent that control patients regulate their tion Score were recently validated [33]. Therefore, given symptoms by treatment use [32] as they used more medi- the heterogeneity of the several scores that attempt to cation (antihistamines and/or nasal steroids); this was merge symptoms and medication, the use of a simple, not the case of the active group, whose patients managed commonly used Medication Score as the one suggested to have less symptoms with less pharmacologic treat- in this study should be encouraged. It appears, therefore, ments. Therefore, our newly suggested MASK/Allergy that the use of a novel TSMS concept deserves further Diary-based TSMS appears to be a good descriptor of consideration. respiratory allergy control. Of note, as with all Medica- Another limitation stems from the impossibility of tion Scores used up to date, there is no differentiation knowing whether the observed beneficial effect of NI can between specific compounds of the same class (i.e. differ - be attributed to the hypertonic sea-water, the “active” ent H1A and/or intranasal CS). Accordingly, to track effi - compounds, or both; in fact, the increasing number of cacy differences among drugs of the same class was out products with different compositions available prompts of the scope of our study. the need for studies separating class effect from indi - Our results may suggest that TSMS complements vidual product effects. However, assessing that would CARAT, as we observed lower use of pharmaceutical require a much larger sample and a different study treatment concurrent with an improvement of disease design, which would be practically impossible to perform control in the NI group. This is one of the first studies taking into account the logistical considerations of a real- using the Allergy Diary for a longitudinal cohort study, life study. Additionally, further studies are required to in what appears to be a valuable tool, with unexplored assess adults and patients with other rhinitis phenotypes, potential. to whom our results cannot be generalized. By contrast, as this study was performed during a 14-month period Limitations and included both seasonal and perennial AR, it is pos- Our study has some limitations, as it was non-rand- sible that the presented results maybe generalized to dif- omized and assessed a relatively small sample (particu- ferent AR triggers. larly for the lower age group). In fact, the low number In summary, ΝΙ with sea-water, supplemented with sea of children < 12  years old might explain why some dif- weed extracts and dexpanthenol, was found to be effec - ferences in that group were not found to be statistically tive as an add-on therapy for children and adolescents significant. In addition, blinding in our study was not with AR. Improved symptom control was achieved with feasible and the placebo effect of NI cannot be excluded. reduced medication use in a real-life setting. Additional However, while the evidence level is not that of a rand- studies are needed to evaluate the potential role of NI omized trial, our conclusions offer insight into the use in the algorithm for AR treatment. In this context, tools of medication and real-life effectiveness of different such as the CARAT questionnaires and the MASK/ Mitsias et al. Clin Transl Allergy (2020) 10:9 Page 10 of 11 Received: 11 October 2019 Accepted: 5 March 2020 Allergy Diary, particularly when used together, can col- lect important data and guide future guidelines. Abbreviations References AR: Allergic rhinitis; NI: Nasal irrigations; CARAT : Control of Allergic Rhinitis and 1. Asher MI, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland SK, Asthma Test; MASK: Mobile Airways Sentinel Network; TSMS: Total Symptom et al. Worldwide time trends in the prevalence of symptoms of asthma, and Medication Score; RELEVANT: REal Life EVidence AssessmeNt Tool. allergic rhinoconjunctivitis, and eczema in childhood: ISAAC phases one and three repeat multi‑ country cross‑sectional surveys. Lancet. Acknowledgements 2006;368(9537):733–43. Not applicable. 2. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic rhinitis and its impact on asthma (ARIA) 2008 update(in col‑ Authors’ contributions laboration with the World Health Organization, GA2LEN and AllerGen). DIM was the main contributor on the conception, design of the study, acquisi‑ Allergy. 2008;63(Suppl. 86):8–160. tion and interpretation of data and prepared the manuscript. MVD substan‑ 3. Roberts G, Xatzipsalti M, Borrego LM, Custovic A, Halken S, Hellings PW, tially contributed to data acquisition. JL analyzed the data. KA provided the et al. Paediatric rhinitis: position paper of the European academy of nasal irrigations’ solution and contributed to the conception of the study. BS‑P allergy and clinical immunology. Allergy. 2013;68(9):1102–16. analyzed and interpreted the data and substantively revised the draft. JAF 4. Bousquet J, Pfaar O, Togias A, Schünemann HJ, Ansotegui I, Papadopoulos analyzed and interpreted the data and substantively revised the draft. JB sub‑ NG, et al. 2019 ARIA care pathways for allergen immunotherapy. Allergy. stantively revised the draft. NGP contributed on the conception and design of 2019;74(11):2087–102. the study and substantively revised the draft. All authors have approved the 5. Passalacqua G, Bousquet PJ, Carlsen KH, Kemp J, Lockey RF, Nigge‑ submitted version. They have also agreed that they are personally accountable mann B, et al. ARIA update: I‑systematic review of complementary and for their own contribution and ensure that questions related to the accuracy alternative medicine for rhinitis and asthma. J Allergy Clin Immunol. or integrity of any part of the work, even for those not personally involved, are 2006;117(5):1054–62. appropriately investigated, resolved, and the resolution is documented in the 6. Qiu J, Grine K. Complementary and alternative treatment for allergic literature. All authors read and approved the final manuscript. conditions. Prim Care. 2016;43(3):519–26. 7. Over‑the ‑ counter Nasal Products for Sinus Congestion: a review of the Funding clinical effectiveness. Ottawa: Canadian agency for drugs and technolo ‑ Research grant was offered from Gerolymatos Int.S.A. for the performance gies in health; 2016. https ://cadth .ca/over‑count er‑nasal ‑produ cts‑sinus of this study. The funder had no influence in the study design, execution or ‑conge stion ‑revie w‑clini cal‑effec tiven ess. interpretation of results. 8. Keojampa BK, Nguyen MH, Ryan MW. Eec ff ts of buffered saline solution on nasal mucociliary clearance and nasal airway patency. Otolaryngol Availability of data and materials Head Neck Surg. 2004;131(5):679–82. The datasets used and/or analyzed during the current study are available from 9. Marchisio P, Varricchio A, Baggi E, Bianchini S, Capasso ME, Torretta S, et al. the corresponding author on reasonable request. Hypertonic saline is more effective than normal saline in seasonal allergic rhinitis in children. Int J Immunopathol Pharmacol. 2012;25(3):721–30. Ethics approval and consent to participate 10. Jung M, Lee JY, Ryu G, Lee KE, Hong SD, Choi J, et al. Beneficial effect This study was approved by the Ethics Committee of the “P. & A. Kyriakou” of nasal saline irrigation in children with allergic rhinitis and asthma: a Children’s Hospital, #91, 24‑2‑2017. The informed consent included informa‑ randomized clinical trial. Asian Pac J Allergy Immunol. 2019. https ://doi. tion regarding the compound, its use and that it is accepted by the National org/10.12932 /ap‑07091 8‑0403. Drug Organization. 11. Head K, Snidvongs K, Glew S, Scadding G, Schilder AG, Philpott C, et al. Saline irrigation for allergic rhinitis. Cochrane Database Syst Rev. Consent for publication 2018;6:CD012597. Not applicable. 12. Maruyama H, Tamauchi H, Hashimoto M, Nakano T. Suppression of Th2 immune responses by mekabu fucoidan from Undaria pinnatifida sporo ‑ Competing interests phylls. Int Arch Allergy Immunol. 2005;137(4):289–94. DIM has received honoraria from Gerolymatos Int.S.A. MVD and JL have no 13. Iwamoto K, Hiragun T, Takahagi S, Yanase Y, Morioke S, Mihara S, et al. declared conflicts of interest. KA is a consultant/scientific advisory board Fucoidan suppresses IgE production in peripheral blood mononu‑ member for Gerolymatos Int.S.A. BS‑P has no declared conflicts of interest. clear cells from patients with atopic dermatitis. Arch Dermatol Res. JAF is the leading author of CARAT10 and CARATKids and is a member of 2011;303(6):425–31. the MASK/Allergy Diary research group. JB is the Director of the Fondation 14. Kim HM, Lee EH, Cho HH, Moon YH. Inhibitory effect of mast cell‑ MCVIA‑LR that owns the Allergy Diary mobile application. He reports personal mediated immediate‑type allergic reactions in rats by spirulina. Biochem and/or consultancy fees and/or honoraria for meeting lectures or is member Pharmacol. 1998;55(7):1071–6. of advisory boards of Chiesi, Cipla, Hikma, Menarini, Mundipharma, Mylan, 15. Chang CJ, Yang YH, Liang YC, Chiu CJ, Chu KH, Chou HN, et al. A novel Novartis, Sanofi‑Aventis, Takeda, Teva, Uriach and has shares in Kyomed, all phycobiliprotein alleviates allergic airway inflammation by modulating outside the submitted work. NGP has received honoraria from AZ, BI, GSK, immune responses. Am J Respir Crit Care Med. 2011;183(1):15–25. Medscape, HAL Allergy B.V., Novartis Pharma AG, Menarini, Mylan, and Danone 16. Ebner F, Heller A, Rippke F, Tausch I. Topical use of dexpanthenol in skin Nutricia Research. disorders. Am J Clin Dermatol. 2002;3(6):427–33. 17. Fonseca JA, Nogueira‑Silva L, Morais‑Almeida M, Azevedo L, Sa‑Sousa A, Author details Branco‑Ferreira M, et al. Validation of a questionnaire (CARAT10) to assess Allergy Department, 2nd Pediatric Clinic, Athens General Children’s Hospital rhinitis and asthma in patients with asthma. Allergy. 2010;65(8):1042–8. “P&A Kyriakou”, University of Athens, Thivon and Levadias 1, Athens, Greece. 18. Linhares DV, da Fonseca JA, Borrego LM, Matos A, Pereira AM, Sa‑Sousa A, 2 3 Gerolymatos Int.S.A., Krioneri, Greece. CINTESIS, Center for Research et al. Validation of control of allergic rhinitis and asthma test for children in Health Technology and Information Systems, Faculty of Medicine, University (CARATKids)—a prospective multicenter study. Pediatr Allergy Immunol. of Porto, Porto, Portugal. MEDCIDS, Department of Community Medicine, 2014;25(2):173–9. Information and Health Decision Sciences, Faculty of Medicine, University 19. Bousquet J, Arnavielhe S, Bedbrook A, Bewick M, Laune D, Mathieu‑Dupas of Porto, Porto, Portugal. MACVIA‑France, Fondation Partenariale FMC VIA‑LR, E, et al. MASK 2017: ARIA digitally‑ enabled, integrated, person‑ centred Montpellier, France. Division of Infection, Immunity & Respiratory Medicine, care for rhinitis and asthma multi‑morbidity using real‑ world‑ evidence. Royal Manchester Children’s Hospital, University of Manchester, Manchester, Clin Transl Allergy. 2018;8:45. UK. M itsias et al. Clin Transl Allergy (2020) 10:9 Page 11 of 11 20. van der Leeuw S, van der Molen T, Dekhuijzen PN, Fonseca JA, van 28. Di Lorenzo G, Drago A, Esposito Pellitteri M, Candore G, Colombo A, Ger‑ Gemert FA, Gerth Wijk van R, et al. The minimal clinically important dif‑ vasi F, et al. Measurement of inflammatory mediators of mast cells and ference of the control of allergic rhinitis and asthma test (CARAT ): cross‑ eosinophils in native nasal lavage fluid in nasal polyposis. Int Arch Allergy cultural validation and relation with pollen counts. NPJ Prim Care Respir Immunol. 2001;125(2):164–75. Med. 2015;25:14107. 29. Nguyen SA, Psaltis AJ, Schlosser RJ. Isotonic saline nasal irrigation is an 21. Bousquet J, Bedbrook A, Czarlewski W, Onorato GL, Arnavielhe S, Laune D, effective adjunctive therapy to intranasal corticosteroid spray in allergic et al. Guidance to 2018 good practice: ARIA digitally‑ enabled, inte‑ rhinitis. Am J Rhinol Allergy. 2014;28(4):308–11. grated, person‑ centered care for rhinitis and asthma. Clin Transl Allergy. 30. Garavello W, Di Berardino F, Romagnoli M, Sambataro G, Gaini RM. 2019;9:16. Nasal rinsing with hypertonic solution: an adjunctive treatment for 22. Bousquet JJ, Schunemann HJ, Togias A, Erhola M, Hellings PW, Zuberbier pediatric seasonal allergic rhinoconjunctivitis. Int Arch Allergy Immunol. T, et al. Next‑ generation ARIA care pathways for rhinitis and asthma: a 2005;137(4):310–4. model for multimorbid chronic diseases. Clin Transl Allergy. 2019;9:44. 31. Bousquet J, Schunemann HJ, Fonseca JA, Samolinski B, Bachert 23. Caimmi D, Baiz N, Tanno LK, Demoly P, Arnavielhe S, Murray R, et al. Valida‑ C, Canonica GW, et al. MACVIA‑ARIA Sentinel NetworK for allergic tion of the MASK‑rhinitis visual analogue scale on smartphone screens to rhinitis(MASK‑rhinitis): the new generation guideline implementation. assess allergic rhinitis control. Clin Exp Allergy. 2017;47(12):1526–33. Allergy. 2015;70(11):1372–92. 24. Bousquet PJ, Combescure C, Neukirch F, Klossek JM, Mechin H, Daures JP, 32. Bedard A, Basagana X, Anto JM, Garcia‑Aymerich J, Devillier P, Arna‑ et al. Visual analog scales can assess the severity of rhinitis graded accord‑ vielhe S, et al. Mobile technology offers novel insights on control and ing to ARIA guidelines. Allergy. 2007;62(4):367–72. treatment of allergic rhinitis. The MASK study. J Allergy Clin Immunol. 25. Pfaar O, Demoly P, Gerth Wijk van R, Bonini S, Bousquet J, Canonica GW, 2019;144(1):135–43. et al. Recommendations for the standardization of clinical outcomes 33. Bedard A, Anto JM, Fonseca JA, Arnavielhe S, Bachert C, Bedbrook A, et al. used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an Correlation between work impairment, scores of rhinitis severity and EAACI Position Paper. Allergy. 2014;69(7):854–67. asthma using the MASK‑air App. Allergy. 2020. https ://doi.org/10.1111/ 26. Roche N, Campbell JD, Krishnan JA, Brusselle G, Chisholm A, Bjermer L, all.14204 . et al. Quality standards in respiratory real‑life effectiveness research: the REal Life Evidence AssessmeNt Tool (RELEVANT ): report from the respira‑ Publisher’s Note tory effectiveness Group ‑European academy of allergy and clinical immu‑ Springer Nature remains neutral with regard to jurisdictional claims in pub‑ nology task force. Clin Transl Allergy. 2019;9:20. lished maps and institutional affiliations. 27. Baiardini I, Novakova S, Mihaicuta S, Oguzulgen IK, Canonica GW. Adher‑ ence to treatment in allergic respiratory diseases. 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Effect of nasal irrigation on allergic rhinitis control in children; complementarity between CARAT and MASK outcomes

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10.1186/s13601-020-00313-2
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Abstract

Background: Nasal irrigations (NI) are increasingly used as an over‑the ‑ counter adjunctive treatment for allergic rhinitis (AR), but clinical studies on their effectiveness are limited. Methods: An open‑label, controlled, non‑randomized, real‑life study was conducted to evaluate the effectiveness of NI with a new hypertonic solution as add‑ on treatment for AR. Children and adolescents with AR were prescribed symptomatic treatment. The active group also received an additional sea‑ water NI solution supplemented with algae extracts. The primary endpoint was symptom control, assessed by the control of allergic rhinitis and asthma test (CARAT ) questionnaires. Moreover, the MASK/Allergy Diary was used to track symptoms and daily medication use that were combined in a novel total symptom/medication score ( TSMS). Results: We assessed 76 patients. Overall, there was a significant improvement of CARAT results (median Z ‑score change of 1.1 in the active/NI group vs. 0.4 in the control group; p = 0.035). Among patients > 12 years old (n = 51), there was a significant improvement in CARAT10 results among participants receiving NI (21.0 to 25.5; p < 0.001), but not in the regular treatment group (21.5 to 24.0; p = 0.100). For children < 12 years old (n = 25), the ΝΙ group had sig‑ nificantly improved symptom control (CARATKids results: 5.0 to 2.0; p = 0.002), in contrast to the control group (4.0 to 2.5; p = 0.057). MASK data on allergic symptoms were comparable between groups. However, the NI group had lower TSMS, more days with < 20% symptoms and fewer days using symptomatic treatment (26.9% vs. 43.5%; p = 0.005). Conclusion: Addition of NI with a sea‑ water solution to regular treatment improved AR symptom control. CARAT questionnaires and MASK application can be useful outcome tools in real‑life studies. Keywords: Allergic rhinitis, Nasal irrigations, Sea‑ water solution, CARAT questionnaire, MASK/Allergy Diary app, Children and adolescents, Symptom score, Medication score, Undaria pinnatifida, Spirulina platensis Introduction particularly if not appropriately treated, AR may lead to Allergic rhinitis (AR) is a very common manifestation of decreased quality of life and may be complicated with respiratory allergy, with a prevalence of up to 20–25% in multi-morbidities such as otitis, sinusitis and asthma. In Western societies. Children are commonly affected and, fact, AR is considered one of the main predisposing fac- tors for the development of asthma [1, 2]. Symptomatic treatment consists of antihistamines and nasal steroids, while allergen immunotherapy is usually performed in *Correspondence: dmitsias@yahoo.com Allergy Department, 2nd Pediatric Clinic, Athens General Children’s more severe/persistent cases [3, 4]—in any case, AR Hospital “P&A Kyriakou”, University of Athens, Thivon and Levadias 1, usually requires chronic treatment, which raises safety Athens, Greece 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. Mitsias et al. Clin Transl Allergy (2020) 10:9 Page 2 of 11 concerns about protracted drug usage, leading to the runny and/or blocked nose, sneezing, nasal itch) for quest for non-pharmacological approaches [5, 6]. at least 6  months, observed between April 2017 and Among add-on treatments, nasal irrigation (NI) with August 2018. In all, skin prick tests and/or specific IgE saline solutions appears to be useful [7–11], as it does confirmed sensitization to at least one relevant aeroal - not need medical prescription and is considered safe lergen (using a standard panel consisting of seasonal for long-term use [7]. Normal saline is primarily used, and perennial allergens, including, but not exclusively, although studies have shown increased effectiveness with grasses, olive, birch, mugwort, ragweed, Parietaria hypertonic solutions [8, 9]. Its mechanisms of action and cypress pollen, Dermatophagoides pteronyssi- include direct mechanical cleansing of the mucosa from nus and farinae, Alternaria, cat and dog epithelia, and allergens or other particles, decrease of inflammatory cockroach). Exclusion criteria consisted of adenoidal and/or allergic mediators, and increase of mucociliary hyperplasia, septal deformity, polyps, infectious rhi- clearance. Meta-analyses suggest that NI can be used as nitis, vasomotor rhinitis, rhinitis medicamentosa, i.e. add-on to medical treatment [11]. However, in children, signs and symptoms indicative of non-allergic rhinitis NI is not yet part of the guideline recommendations, (e.g. not responsive to regular treatment, fever, apnoea, probably due to insufficient evidence of its pediatric decongestant overuse). We also excluded children at effectiveness. need of oral corticosteroids, at the time of presentation. Therefore, this study aimed to evaluate the effective - ness of NI as an add-on treatment for AR, using a new NI product based on sea-water supplemented with (1) Performance of the study extracts from the sea weeds Undaria pinnatifida and All children were prescribed indicated rhinitis treat- Spirulina platensis, and (2) dexpanthenol. This is the first ment, consisting of a second-generation antihistamine study using these compounds intranasally: Undaria pin- and/or nasal corticosteroid (CS) or CS + azelastine. natifida is a brown alga rich in fucoidans (i.e. sulfated All patients/parents were instructed in allergen avoid- polysaccharides) with anti-inflammatory and anti-aller - ance measures and in the nasal spray (and irrigation, gic properties [12, 13]; Spirulina platensis is a green alga if applicable) technique and were instructed to use whose active components are phycocyanins, which have pharmacological treatment for 10-15 consecutive days, multiple possible actions, including an anti-allergic effect resuming it in case of persisting symptoms. Mast cell in the respiratory epithelium [14, 15]; dexpanthenol, the stabilizing eye drops were prescribed for conjunctivitis alcoholic analogue of pantothenic acid, acts as a mucosal refractory to antihistamines, and asthma was treated moisturizer and hydrating agent [16]. To evaluate NI with inhaled CS or CS + long-acting β-agonist, accord- effectiveness (i.e. disease control, symptoms and use of ing to the guidelines. A follow-up visit was planned for medication), we used the Control of Allergic Rhinitis and 30  days later. Signed informed consent was obtained Asthma Test (CARAT) [17, 18] and the MASK/Allergy by all patients/parents. This study was approved by the Diary app, developed by the ARIA group [19]. Ethics Committee of the “P.& A. Kyriakou” Children’s Hospital. Methods Design of the study Intervention: nasal irrigations This was an open-label, controlled, real-life, non-ran - The active/NI group received a nasal spray consisting of domized, prospective quasi-experimental study. The sea-water hypertonic (2.3% NaCl) solution with extracts attending physician prescribed the treatment accord- from Undaria pinnatifida and Spirulina platensis algae ing to guidelines and the patient/caregiver chose to use and dexpanthenol (“Sinomarin + Algae Allergy Relief”, (or not) supplementary NI in addition to the prescribed available as over-the-counter). The patient/caregiver was treatment. Therefore, an active/NI group (standard AR instructed to use the product daily during the observa- therapy plus NI) was compared with a control group tion period according to the manufacturer’s instructions: (standard AR therapy only) regarding AR symptoms and 2 puffs/nostril 3 times/day for children < 12  years old; 4 medication use. puffs/nostril up to 5 times/day for children > 12 years old. Nasal irrigations were performed at least 15  min before Setting and patients potential inhaled CS use. However, adherence either to This study was performed at the Allergy Unit of the pharmacologic treatment or NI was not further enforced 2nd Pediatric Clinic, University of Athens, a tertiary or assessed. Nevertheless, prospective data on medica- referral center. We included all eligible and consenting tion use were gathered and analyzed through the MASK/ children and adolescents (6–19  years old) with symp- Allergy Diary as described in detail below. toms suggestive of AR (such as, but not exclusively, M itsias et al. Clin Transl Allergy (2020) 10:9 Page 3 of 11 Outcomes were defined as those with score < 20% (either for VAS/ CARAT questionnaires Symptom Score or TSMS) [23]. All patients/parents Control of allergic rhinitis and asthma test (CARAT) is a were trained to use MASK application and upload data brief self-administered questionnaire aiming to quantify accordingly. symptoms and control of AR and asthma. There are two versions of CARAT—(i) CARAT10 was used by partici- pants > 12 years old, who filled it directly (as it has been Statistical analysis designed for adults and teenagers), and (ii) CARATKids, Continuous variables were described using medians which was used by participants aged 6–12 years old and and percentiles 25–75, while categorical variables were filled by them together with their parents. described with absolute frequencies and percentages. CARAT10 assesses the previous 4 weeks. The responses CARAT and MASK/Allergy Diary results were compared for all ten questions are on 4-point Likert scales, scor- using Wilcoxon’s rank-sum and Kruskal–Wallis tests ing from 0 to 3. The final score ranges from 0 to 30, with (continuous variables), and Pearson’s Chi squared test scores > 24 indicating good control of asthma and AR (categorical variables). Intention to treat analyses were [17], and four-point changes being considered clinically both performed altogether for participants of all ages, relevant [20]. CARAT10 has been translated and vali- and separately for children 6–12 and > 12 years old. dated to Greek (kindly provided by Prof. I. Tsiligianni). To perform a combined analysis on CARAT10 and CARATKids includes 13 “Yes/No” questions: affirma - CARATKids results, Z-scores were separately computed tive answers scored as 1 (corresponding to “symptom/ for CARAT10/CARATKids and, for each, both refer- item present”), while negative answers scored as 0 ence values and standard-deviations of all values (i.e. (“symptom/item not present”). Therefore, 13 points cor - those collected at first visit and at day 30) were consid - respond to a complete absence of control [18]. A version ered. Z-scores changes (i.e. Z-scores differences between translated by the authors was used. days 1 and 30) were compared between the active and control group using Mann–Whitney U test. Addition- ally, to test the consistency of our results, a non-para- MASK/Allergy Diary application metric ANCOVA was performed, with day 30 Z-scores Allergy diary is a free, on-line application for smart- as dependent variable and day 1 Z-scores as co-variate. phones, developed by MASK-rhinitis (Mobile Airways To assess whether CARAT10 and CARATKids results are Sentinel NetworK for AR) to evaluate AR symptoms and sufficiently similar to be assessed together, a meta-anal - disease control [19, 21, 22]. It contains four visual ana- ysis of standardized mean changes was performed—an logue scales (VAS) measuring nasal, ocular, asthma and I > 50% and a Cochran Q-test p-value < 0.10 were con- overall allergic symptoms. It is used prospectively and sidered to represent substantial heterogeneity. Statistical filled daily, allowing also for registering the medications analysis was accomplished with R software, version 3.5.0. used each day [23]. The application does not integrate Significance level was defined at 0.05. symptom and medication scores [24] and, therefore, we The RELEVANT criteria were considered in the design calculated a Total Symptom/Medication Score (TSMS) and reporting of this study [26]. RELEVANT is a recently based on equal weight, as suggested by EAACI [25]: developed tool by Respiratory Effectiveness Group (REG) Symptom Score+Medication Score TSMS = , where symptom and EAACI, designed to evaluate the quality of real-life score is the VAS 0-100 score, and Medication Score studies and whether they may be used in guidelines. is a 0-100 score with the following punctuation sys- tem depending on the AR medication taken: no medi- cation = 0 points; oral and/or topical (eyes or nose) Results H1antihistamines (H1A) = 100 × points; intranasal Overall, 89 children and adolescents with symptoms sug- CS (INS) with/without H1A = 100 × points; oral gestive of AR agreed to participate in this study. Seventy- CS (with/without INS and with/without H1A) = 100 six children (85%) returned for the second visit (for whom points. Of note, this approach is based on the clinical we present CARAT data) (Fig.  1). Of those, 53 children effects of pharmacotherapy on symptom reduction, but used NI (active group), while 23 did not use NI (control neither takes into account the use of specific medica - group). Children in the active/NI group, controls and tion (only the drug class) or daily dosing nor has yet drop-outs did not differ demographically, clinically or in been validated [25]. Therefore, apart from the 4 Symp - initial CARAT scores (Tables  1, 2). The MASK Allergy toms Scores (nasal, ocular, asthma and overall allergic Diary application was used by 78 children (88% accept- symptoms VAS), 4 TSMS (i.e. taking into account daily ance rate, average of 19.7 entries/child), corresponding to medication) were established. “Symptom-free days” 55 children in the active group and 23 controls. Mitsias et al. Clin Transl Allergy (2020) 10:9 Page 4 of 11 Children/adolescents aending the special clinic with indicaon of allergic rhinis n=433 Not assessed for eligibility Declined consent n=172 Assessed for eligibility Excluded n=261 Ineligible Non-allergic rhinisn=91 Possible local allergic rhinisn=17 Need for peros corcosteroidn=2 Eligible but not recruited Total recruited Refused to parcipate n=42 Unable to use applicaon n=20 n=89 Lost to follow-up (drop-outs) CARAT analysis Did not appear at re-evaluaon visit n=13 MASK analysis Could not use the applicaon n=8 Did not enter personal code n=3 Paents analyzed CARAT analysis n=76 MASK analysis n=78 Fig. 1 Flow chart of the selection process of included participants Disease control 21.5 (25–75 percentiles: 17.5–24.0) on day 1 (p = 0.100) CARAT10 (Fig.  2a). Moreover, the improvement of CARAT10 We assessed 51 participants aged > 12  years old, with score (i.e. the individual differences between day 1 and those on the NI group ending up with significantly day 30) was significantly higher for the active than for improved disease control compared to those on the the control group (median increase: 5.0 vs. 1.0, respec- control group. In fact, when we compared day 1 to day tively; p = 0.023) (Table  2). This difference surpassed 30 scores, for the active group, day30 median CARAT10 the limit of 3.5 that is considered by the CARAT devel- score was 25.5 (25–75 percentiles: 22.0–26.0), up from opers (also co-authors of the present study) to be the 21.0 (25–75 percentiles: 17.0–23.0) on day 1 (p < 0.001); minimal clinically relevant difference [20] and was on the other hand, for the control group, median day 30 achieved despite the fact that both groups had (i) simi- score was 24.0 (25–75 percentiles: 18.5–25.5), up from lar instructions in regard to regular pharmaceutical M itsias et al. Clin Transl Allergy (2020) 10:9 Page 5 of 11 Table 1 Characteristics of  the  recruited study participants, as  well as  of  the participants with  complete CARAT questionnaire and MASK/Allergy Diary results Recruited participants p-value * CARAT outcome group p-value * Allergy diary outcome p-value * (active/control group) (active/control group) group (active/control group) Total 89 (64/25) 76 (53/23) 78 (55/23) Age 0.592 1.000 0.520 > 12 years old 59(44/15) 51 (36/15) 50 (37/13) < 12 years old 30(20/10) 25 (17/8) 28 (18/10) Gender 0.578 0.427 0.485 Male 62 (43/19) 53 (35/18) 55 (37/18) Female 27 (21/6) 23 (18/5) 23 (18/5) Asthma 31 (24/7) 0.550 26 (19/7) 0.846 28 (22/6) 0.363 Sensitizations 0.929 0.873 0.819 1 20 (14/6) 14 (9/5) 17 (11/6) 2 31 (22/9) 27 (19/8) 28 (20/8) > 2 38 (28/10) 35 (25/10) 33 (24/9) * Pearson’s Chi square test Concurrent allergic asthma Table 2 CARATKids and  CARAT10 scores on  day 1, and  individual differences between  day 1 and  day 30: CARAT scores in day 1 did not differ significantly for active, control and drop-outs; by contrast, CARAT10 changes for each patient were significantly different between day 1 and day 30 Active (n: 53) Control (n: 23) Drop-outs (n: 13) p-value CARATKids (score range 0–13) n: 17 n: 8 n: 5 Day 1 5.0 (3.8–6.3) 4.0 (3.0–7.0) 5.0 (4.0–5.3) 0.878 * Day 1/day 30 difference − 3.0 (− 5.0 to 2.0) − 2.00 (− 4.0 to 0) 0.574 ** CARAT10 (score range: 0–30) n: 36 n: 15 n: 8 Day 1 21.0 (17.0–23.0) 21.5 (17.5–24.0) 19.0 (17.0–22.0) 0.536 * Day 1/day 30 difference 5.0 (0.8–6.3) 1.00 (0.5–2.5) 0.023 ** p-values < 0.05 are shown in italics Values shown as medians with 25–75 percentiles * Kruskal–Wallis test ** Wilcoxon’s rank-sum test Combined analysis of CARAT10 and CARATKids treatment, and (ii) similar severity of symptoms on day To analyze the results of all participants together, we computed Z-scores for CARAT10 and CARATKids. The active group presented a significantly higher improve - ment on its Z-score compared to the control group CARATKids (median improvement: 1.1 vs. 0.4 points, respectively; Twenty-five children < 12 years old completed the CAR- p = 0.035) (Fig. 3). These results were consistent to those ATKids questionnaire. Day 30 median CARATKids obtained when performing a non-parametric ANCOVA score for the active group was 2.0 (25–75 percentiles: comparing day 30 Z-scores between the active and the 1.0–3.0), down from 5.0 (25–75 percentiles: 3.8–6.3) control group, adjusted for day 1 Z-scores (p = 0.004). Of on day 1 (p = 0.002); for the control group, the day 30 interest, the lower the initial Z-score (i.e. the lower the score was 2.5 (25–75 percentiles: 1.8–3.0), down from initial symptom control), the higher was the difference at 4.0 (25–75 percentiles: 3.0–7.0) on day 1 (p = 0.057) the end (i.e. the greater the benefit for the patient; Fig. 4). (Fig.  2b). However, the 30-day differences in CARAT - Finally, we performed a meta-analysis pooling CAR- Kids values between active and control groups were ATKids and CARAT10 results. The standardized mean not significantly different (median decrease of − 3.0 vs . change in CARAT results was significantly higher in the − 2.0; p = 0.574) (Table 2). Mitsias et al. Clin Transl Allergy (2020) 10:9 Page 6 of 11 Fig. 2 Initial (day 1) and final (day30) CARAT scores for (a) adolescents > 12 years old (CARAT10), and (b) children < 12 years old (CARATKids). Analysis was performed with Wilcoxon’s signed‑rank test active than in the control group (0.62, 95% CI 0.08–1.16; calculated Medication Score (median: 16.7 vs. 25.7, p = 0.024), with no heterogeneity observed (I = 0%; p = 0.006) (Table 5). p = 0.718) (Fig. 5). Discussion Symptoms and medication In this proof-of-concept study, a hypertonic sea-water There were no significant differences in symptom scores (2.3% NaCl) based solution supplemented with extracts as evaluated by the VAS. However, when TSMS was cal- from the sea weeds Undaria pinnatifida and Spirulina culated, significant differences emerged for all 4 param - platensis and dexpanthenol was found to be effective as eters (Table  3). When medication use was taken into an add-on treatment in symptom control of children with account (i.e. TSMS), children using NI were symptom- AR, suggesting that NI may improve AR control with free (days with < 20% on VAS) for significantly more days reduced use of medication. regarding all parameters except the ocular one (Table 4). The medications commonly used for AR have shown Interestingly, the improvement in the active group was by objective measures to be effective and safe even for achieved with less medication use: (i) children using ΝΙ prolonged use. However, regarding children, parents/ received the prescribed pharmacologic treatment for sig- caregivers are often skeptical and unwilling to follow nificantly less days, when compared to the control group long-term treatments, which results in considerably (median: 26.9% vs. 43.5% of the days, p = 0.005) and (ii) low adherence [27]. Nasal irrigations (particularly those the active group used less medication as judged by the with normal saline) have long been used to remove mucus from the upper respiratory tract, as they are safe, M itsias et al. Clin Transl Allergy (2020) 10:9 Page 7 of 11 Fig. 3 Dot plot for the Z‑scores of CARAT10/CARATKids results for active and control groups on day 1 and day 30 Fig. 4 Correlation of initial (day1) CARAT Z‑scores and 30‑ days Z‑score difference in the control group (a) and in the active group receiving nasal irrigations (b) Mitsias et al. Clin Transl Allergy (2020) 10:9 Page 8 of 11 Table 4 Percentage of  symptom-free days, regarding different types of symptoms Percentage (%) Active (n: 55) Control (n: 23) p-value * of symptom-free days Ocular symptoms 100.0 (85.2–100.0) 96.8 (81.0–100.0) 0.483 Nasal symptoms 67.7 (50.0–87.9) 68.0 (44.8–85.7) 0.896 Asthma symptoms 100.0 (87.5–100.0) 100.0 (96.6–100.0) 0.540 Overall allergic 69.6 (40.9–90.7) 75.0 (41.7–85.7) 0.906 symptoms 75.0 (53.7–85.7) 66.7 (46.2–77.3) 0.054 Ocular TSMS Nasal TSMS 64.5 (50.8–76.8) 44.0 (38.5–56.5) 0.019 Asthma TSMS 76.9 (61.8–85.0) 64.0 (42.9–76.2) 0.016 Overall allergic 65.4 (51.9–77.8) 42.9 (36.7–61.5) 0.012 TSMS p-values < 0.05 are shown in italics Values shown as medians with 25–75 percentiles Corresponding to < 20% on  visual analogue scales (VAS) for symptoms and  Total Symptom and Medication Score (TSMS) Fig. 5 Meta‑analysis of standardized mean changes (between day 1 * Wilcoxon’srank-sum test and day 30) of CARAT results, pooling CARATKids and CARAT10 results solutions (e.g. 2.3% NaCl) being apparently more effec - Table 3 Ocular, nasal, asthma and  overall allergic tive than normal saline solutions [8, 9, 30]. symptoms using Visual Analogue Scales (VAS) for  symptoms and  total symptom and  medication score This is the first study assessing the intranasal use of (TSMS) (i.e., considering medication use on  the  respective algae, with the species used being known for having, days) among other, anti-allergic effects [12–15]. It is also the first study in children and adolescents with parallel, two Active (n: 55) Control (n: 23) p-value* way evaluation of the effectiveness of NI; intention to Ocular symptoms 1.3 (0.1–8.5) 4.1 (0.2–10.3) 0.482 treat analysis was performed. Nasal symptoms 20.0 (9.2–27.6) 20.6 (9.0–28.7) 0.936 We used a combination approach to evaluate the Asthma symptoms 0.4 (0.0–9.5) 0.1 (0.0–3.0) 0.503 effectiveness of NI, namely involving the use of CARAT Overall allergic 18.0 (8.7–26.3) 18.6 (11.6–27.8) 0.701 questionnaires and MASK/Allergy Diary application. symptoms Concurrent use of data from many sources is encour- Ocular TSMS 9.5 (6.5–17.4) 15.7 (12.2–23.6) 0.019 aged so as to provide a wider angle of the impact of AR Nasal TSMS 18.8 (12.9–22.3) 23.6 (17.3–28.0) 0.046 in each patient [31]. CARAT gives a retrospective view Asthma TSMS 10.8 (6.6–16.8) 15.6 (11.1–20.4) 0.039 on the symptoms occurred over the last weeks, while the Overall allergic TSMS 17.6 (13.0–22.1) 23.6 (14.1–28.2) 0.035 MASK/Allergy Diary provides prospective daily data on p-values < 0.05 are shown in italics symptoms and on medication use, giving the opportu- Values shown as medians and 25–75 percentiles nity to longitudinally follow the course of AR. Although * Wilcoxon’s rank-sum test this study did not aim to formally compare CARAT and Mean daily VAS MASK/Allergy Diary outcomes, our results indicate that Mean daily TSMS these tools can be used in parallel, augmenting the ability to clinically assess AR activity. tolerable and more easily acceptable by parents/caregiv- According to our results, NI can be helpful as an ers. The effectiveness of NI not only includes mechanical add-on treatment in children with allergic rhinitis. removal of mucinous excretions, but also an increase of The effect seems to be more prominent in adolescents, mucociliary function, decreased interaction of allergens possibly reflecting several factors, including different with the nasal mucosa [8], and reduced release of inflam - pathophysiology, different volume of NI, difficulty in matory mediators such as histamine, prostaglandins and symptoms monitoring in younger patients, and—prob- leukotrienes and/or receptors (such as ICAM-1) [28]. ably most important—the smaller sample size regarding Studies have shown their efficacy in AR and sinusitis, and patients < 12 years old. meta-analyses support their use [11, 29], with hypertonic M itsias et al. Clin Transl Allergy (2020) 10:9 Page 9 of 11 Table 5 Medication use in  subjects using nasal irrigation (active group) and  in  the control group, as  assessed by the percentage of days on treatment and by the medication score Active (n: 55) Control (n: 23) p-value * Percentage (%) of days on treatment 0.005 Median (25–75 percentile) 26.9 (19.1–40.7) 43.5 (31.0–61.2) Medication score 0.006 Median (25–75 percentile) 16.7 (10.7–25.0) 25.7 (17.3–35.7) p-values < 0.05 are shown in italics Medication score 0–100 depending on the drugs taken * Wilcoxon’s rank-sum test When specific allergic symptoms were assessed there treatment modalities—our participants adhered variably was some discordance between CARAT (showing con- to prescribed pharmacological treatment but adhered siderable decrease between start and end of the evalua- well to more “natural” NI and still achieved improved tion) and the Allergy Diary (that showed no difference in symptom control. Such an insight would have been symptom score alone, according to VAS, in the longitudi- impossible in the context of a randomized control trial. nal follow-up). This may reflect a rapid improvement of Another limitation is that the TSMS presented herein, symptoms after the initial evaluation, leading to a dilu- based on MASK/Allergy Diary [23] and on the EAACI tion of the effect over a 30-day period. However, when Position Paper [25], had not been formally validated. medication use was integrated with VAS (i.e. TSMS), However, both VAS and a Combined Symptom/Medica- it became apparent that control patients regulate their tion Score were recently validated [33]. Therefore, given symptoms by treatment use [32] as they used more medi- the heterogeneity of the several scores that attempt to cation (antihistamines and/or nasal steroids); this was merge symptoms and medication, the use of a simple, not the case of the active group, whose patients managed commonly used Medication Score as the one suggested to have less symptoms with less pharmacologic treat- in this study should be encouraged. It appears, therefore, ments. Therefore, our newly suggested MASK/Allergy that the use of a novel TSMS concept deserves further Diary-based TSMS appears to be a good descriptor of consideration. respiratory allergy control. Of note, as with all Medica- Another limitation stems from the impossibility of tion Scores used up to date, there is no differentiation knowing whether the observed beneficial effect of NI can between specific compounds of the same class (i.e. differ - be attributed to the hypertonic sea-water, the “active” ent H1A and/or intranasal CS). Accordingly, to track effi - compounds, or both; in fact, the increasing number of cacy differences among drugs of the same class was out products with different compositions available prompts of the scope of our study. the need for studies separating class effect from indi - Our results may suggest that TSMS complements vidual product effects. However, assessing that would CARAT, as we observed lower use of pharmaceutical require a much larger sample and a different study treatment concurrent with an improvement of disease design, which would be practically impossible to perform control in the NI group. This is one of the first studies taking into account the logistical considerations of a real- using the Allergy Diary for a longitudinal cohort study, life study. Additionally, further studies are required to in what appears to be a valuable tool, with unexplored assess adults and patients with other rhinitis phenotypes, potential. to whom our results cannot be generalized. By contrast, as this study was performed during a 14-month period Limitations and included both seasonal and perennial AR, it is pos- Our study has some limitations, as it was non-rand- sible that the presented results maybe generalized to dif- omized and assessed a relatively small sample (particu- ferent AR triggers. larly for the lower age group). In fact, the low number In summary, ΝΙ with sea-water, supplemented with sea of children < 12  years old might explain why some dif- weed extracts and dexpanthenol, was found to be effec - ferences in that group were not found to be statistically tive as an add-on therapy for children and adolescents significant. In addition, blinding in our study was not with AR. Improved symptom control was achieved with feasible and the placebo effect of NI cannot be excluded. reduced medication use in a real-life setting. Additional However, while the evidence level is not that of a rand- studies are needed to evaluate the potential role of NI omized trial, our conclusions offer insight into the use in the algorithm for AR treatment. In this context, tools of medication and real-life effectiveness of different such as the CARAT questionnaires and the MASK/ Mitsias et al. Clin Transl Allergy (2020) 10:9 Page 10 of 11 Received: 11 October 2019 Accepted: 5 March 2020 Allergy Diary, particularly when used together, can col- lect important data and guide future guidelines. Abbreviations References AR: Allergic rhinitis; NI: Nasal irrigations; CARAT : Control of Allergic Rhinitis and 1. Asher MI, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland SK, Asthma Test; MASK: Mobile Airways Sentinel Network; TSMS: Total Symptom et al. 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