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Immunotherapy
Immunotherapy
Immunotherapy
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10.1080/1750743X.2024.2347828
2347828
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Research Article
Research Article
Satisfaction, Qol and adherence of patients allergic to dust mites and/or pollens undergoing sublingual immunotherapy
https://orcid.org/0009-0003-3953-0009
Garrido-Fernández Sara * a b
Fernández Diego Gutierrez c
López Germán Sánchez d
del Mar Escribano Rodríguez Maria e
Delgado Víctor Matheu f
Iglesias-Souto Javier g
de Castro Gómez Cristina h
Bòria Elena Villarrubia i
https://orcid.org/0009-0001-1782-8643
Hernández-Peña Jenaro j
https://orcid.org/0000-0003-3600-8138
Sánchez-López Jaime k
a Servicio de Alergología, Hospital Universitario de Navarra (HUN), Navarra, 31008, Spain
b Instituto de Investigación Sanitaria de Navarra (IDISNA), Navarra, 31008, Spain
c Servicio de Alergología, Hospital Universitario Puerta del Mar, Cádiz, 11009, Spain
d Consulta privada de Alergología, Clínica Motril, Granada, 18600, Spain
e Centro Médico Adeslas, Granada, 18002, Spain
f Servicio de Alergología, Hospital Quironsalud Costa Adeje, Tenerife, 38660, Spain
g Servicio de Alergología, Hospital Universitario Hospiten Sur, Tenerife, 38660, Spain
h Servicio de Alergia, Centro Médico Adeslas, Córdoba, 14006, Spain
i Advanced Outcomes Research, S.L., 08015, Spain
j Servicio de Alergia, Hospital Central de la Defensa “Gómez Ulla”, Madrid, 28028, Spain
k Medical Department, Stallergenes Ibérica, Barcelona, 08005, Spain
* CONTACT: Tel.: +34 848 429 195; sgarridf@navarra.es
18 6 2024
2024
18 6 2024
16 10 693704
Aptara25 4 2024
17 6 2024
30 12 2023
08 4 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Aim: Sublingual immunotherapy (SLIT) changes history of allergic respiratory disease (ARD). However, adherence is a barrier for optimal outcomes.

Patients & methods: In the QUALI study, 859 patients with house-dust mite (HDM) and/or pollen induced ARD uncontrolled with symptomatic treatment and undergoing SLIT for at least 6 months or including one pre-coseason (pollen) were collected.

Results & conclusion: SLIT significantly improved allergic rhinoconjunctivitis (ARC) and asthma symptom control, leading to reduced medication, meaningful health-related quality of life gain, improved nasal, ocular and bronchial symptoms and everyday life activities. Patients were highly satisfied and most of them adhered to SLIT, being forgetfulness the main non-adherence motive. SLIT is a quick effective treatment against persistent moderate-to-severe symptoms in ARC and asthma but it should been improve forgetfulness, as non-adherence reason.

Plain Language Summary

Sublingual immunotherapy (SLIT) has really changed how we deal with allergic respiratory disease. But there's a catch: sticking to the treatment can be tough.

In the QUALI study, we looked at 859 patients dealing with dust mite and/or pollen allergies who were not getting relief from the usual treatments. We put them on SLIT for at least 6 months or during pollen season.

This treatment made a big difference. Symptoms got better, people needed less medication and they felt better in their day-to-day lives. Most patients were happy with the treatment and stuck to it well, but some forgot sometimes.

In short, SLIT works fast and works well for moderate to severe allergies and asthma. But we need to help people remember to stick with it.

Summary points

QUALI study is the largest multicenter retrospective cross-sectional study in Spain to provide comprehensive short-term real-life data of the impact, quality of life, satisfaction and adherence in the allergen immunotherapy field.

Nearly half of the sample are children and adolescents, where allergic rhinitis and asthma impacts with a high prevalence.

The study use complementary tools for a more precise adherence measurement, which is not a frequent practice among previous studies or clinical practice.

Significant proportion of patients progressed to a greater or even definite symptom control in terms of frequency and severity.

There was a reduction on the medication use for symptom relief.

Sublingual immunotherapy treatment led to a meaningful gain in health-related quality of life in terms of an important reduction of nasal, ocular and bronchial symptoms and in derived problems affecting their daily life.

Patients and investigators were remarkably satisfied.

Has been reported high adherence rates, being forgetfulness the main motive for non-adherence.

Practically none of the patients referred adverse events, and these were local and mostly mild.

A fast onset of action of allergen-specific immunotherapy is linked to adherence in sublingual immunotherapy.

Keywords: 

adherence
allergic rhinitis
quality of life
satisfaction
sublingual immunotherapy
Stallergenes Iberica supported and sponsored The study was supported and sponsored by Stallergenes Iberica (Barcelona, Spain).
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pmc1. Introduction

Allergic respiratory disease (ARD) is a frequent condition that causes major illness and disability worldwide [1]. It affects to a fifth of the Spanish population [2], being pollen the most common etiologic allergen followed by house-dust mite (HDM) [3,4]. Thus, the risk of disease progression, the increasing need of pharmacotherapy for symptom control and the impact in quality of life (QoL) of patients [4–6] require an integrated approach and greater awareness [7–9].

Allergen-specific immunotherapy (AIT) [10] via subcutaneous (SCIT) or sublingual (SLIT) routes is the only treatment able to modify the natural history of the allergic disease [9]. It may desensitize a patient, ameliorating symptoms, reducing symptomatic medication and mitigating disease burden [3,9,11–14]. AIT is recommended for short-term benefit on seasonal and perennial respiratory allergic disease, with grass AIT showing the strongest evidence for long-term benefit [11]. The efficacy and favorable safety profile of SLIT, along with needle avoidance plus self-administration at home, positions this therapy as the drug of choice for many patients, especially young children [9,12,13].

However, many gaps exist in the body of AIT evidence, including those around contraindications, adherence and use in children [11]. On one hand, AIT is underused in allergic asthma, both in children and adults, due to its contraindication in patients with uncontrolled asthma [11,15]. In cases of partially controlled asthma and poor adherence, caution is recommended [11]. In this sense, a minimum 3-year therapy is recommended for long-term benefits [9,16], but most patients discontinue within the first year [10,17–19]. Particularly in Spain, only two out of three HDM allergic patients adhered to SLIT treatment [20] Thus, as a long-term self-administered medication, adherence is a major barrier for optimal outcomes [3]. Despite teenagers showing the lowest compliance levels with the highest discontinuation rates [20], quantitative data on pediatric adherence remain scarce [21]. Adherence is influenced by patient satisfaction, motivated by improvement of symptoms and aspects of health-related quality of life (HRQoL) [22]. Given the ARD impact on patients' HRQoL [3,6,7], its evolution is an outcome of increasing interest [6,23,24]. Beyond evidence of clinical trials, real-world studies on SLIT are limited and manage heterogeneous data (allergen types, outcomes, subpopulations, follow-up periods, sample sizes, measure tools, etcetera) [3,14,18–20,25–28]. In addition, the adherence measured in controlled trials is usually good, but this does not reflect what happens in real life [29].

We hypothesized that those factors leading to symptom improvement in their variety of manifestations, satisfaction and quality of life will promote adherence and therefore effectiveness. The QUALI study was aimed at gaining immunotherapy real-world insights about the minimum period to benefit allergic patients undergoing SLIT treatment. Specifically, we investigated the potential factors contributing to the greater satisfaction, HRQoL and adherence of two well-defined populations: HDM-sensitized patients with respiratory disease subject to a minimum 6-month SLIT perennial regimen; and pollen-sensitized patients who completed a SLIT pre-coseasonal regimen. As children and adolescents bear the greatest burden of the allergic rhinitis (AR) rising trend [7], we also explored the degree of satisfaction of the pediatric subpopulation on SLIT. Finally, we collected safety data about the drug. To this end, we designed a cross-sectional real-life study with the participation of investigators from healthcare centers throughout Spain. We collected retrospective data on a large sample of patients at the medical visit following SLIT treatment, by using complementary measure tools and stratifying both by age and by the most common allergen types.

2. Methods

2.1. Participants

The study population included patients ≥5 years old with house dust mite (HDM)- or pollen-induced allergic respiratory disease (ARD) uncontrolled with symptomatic treatment. Eligible patients were treated with a sublingual standardized liquid formulation with a concentration of 300 IR/ml (Stallergenes Iberica, Barcelona, Spain). In the case of HDM-induced allergy, patients were treated for at least 6 months on perennial regimen. In the case of pollen-induced allergy, patients received AIT in a pre-coseasonal regimen for one season. Patients were excluded if they had received any other type of AIT within the prior-5 years, were not able to answer the questionnaires, or were participating in another study.

2.3. Study design

A multicenter descriptive epidemiologic study was conducted with the participation of 48 investigators throughout Spain, who collected retrospective cross-sectional data from patients between May and November 2018.

Data were collected through a Case Report Form (CRF) filled in by patients and investigators, which included data from the patient medical record, and from clinical data obtained at the time of consultation. The CRF collected sociodemographic data, general clinical data and data related to the allergy and symptomatology, before and after SLIT. It also included data on perception of physicians and patients toward drug reduction for symptom relief.

Data on allergic symptoms covered AR symptoms: presence, frequency and severity, according to the Allergic Rhinitis and its impact on Asthma (ARIA-Valero) criteria [30]; conjunctivitis symptoms: presence, frequency and severity (DECA) [31]; and asthma-related symptoms: presence, severity (GEMA 4.2) [32] and asthma control (GINA) [33].

Adherence to SLIT was assessed using three complementary methods. Morisky-Green test [34], validated in its Spanish version by Val and collaborators [35] and applied recently to SLIT, is a structured four-item self-reported adherence measurement tool [20]. self-recording of compliance using the Haynes-Sackett test [36]; it test identifies compliant patients as those who answer negatively to the question: “Most people find difficulties to administer the medication in sublingual drops”. Do you find difficulties to take yours? And questionnaire to assess patient self-reported compliance with recommended doses [37]; it combines two questions about the difficulty to administrate the medication, and the missed doses in the prior month: subjects taking ≥80% of the overall prescription (doses and administrations) ≥21 days/month or >5 days/week were identified as compliant. Finally, through a self-report assessment form, non-compliant patients were asked about the main reasons for halting or not adhering to the treatment.

Satisfaction with SLIT was measured with a Visual Analog Scale (VAS) filled in by patients and investigators, and through the ESPIA questionnaire in adult population [38,39] and with an ad-hoc items in non-adult population.

Impact of ARD related symptoms and daily activities was measured through a VAS, scoring from 0 (not annoyed at all) to 10 (very annoying).

Global impact in quality of life was measured also with a VAS, scoring from 0 (very annoying) to 10 (not annoyed at all). Data related to the presence of adverse events were also recorded.

All the procedures followed the ethical standards of the Helsinki Declaration, and the ICH guidelines for Good Clinical Practice (GCP). The study was approved by the Research Ethics Committee of the Community Foral of Navarra (EO18/1). Written informed consent was obtained from participating patients, their parents, or legal representatives.

2.4. Sample size calculation & statistical analyzes

Based on epidemiological data [2,40], we estimated as 15.2% the proportion of patients with pollen-induced allergic rhinoconjunctivitis (ARC) in Spain, and 9.3% the proportion with HDM-induced ARC. Consequently, a sample of 2369 individuals (1447 with pollen allergy, and 949 with dust-mite allergy) was needed to obtain a 2.1% of accuracy with bilateral contrast and 20% of statistical power and estimate the ARC patient rate with a 95% confidence interval. A 22.5% of missing data was assumed based on CITARA study on adherence with SLIT22. Finally, 859 evaluable patients were enrolled (35,8% of planned sample size); sample that shows 76% of statistical power, enough for data statistical analysis.

The sample was stratified by prescribed allergen – ‘dust mite’, ‘pollen’ or ‘overall sample’, and by age – ‘children’ (5–12 years), ‘adolescents’ (13–17 years) and ‘adults’ (≥18 years). All patients completed age-specific questionnaires. Categorical variables were described as number and percentage of subjects in each category and continuous variables, as mean plus standard deviation. Two-sided non-parametric tests (Kolmogorov-Smirnov with 95% IC) were conducted to assess normal distribution for the variables. For statistical inferences, bivariate and multivariate parametric (Chi Square, t-Student, ANOVA, etc.), or non-parametric (Fischer, Mann-Whitney, Kruskal-Wallis, etc.) bilateral tests (95% IC) were used where corresponded. Lost or missing data at the time of the analyzes were handled according to the requirements of each statistical method. Interpolation and extrapolation methods were not used to estimate missing data in any of the cases.

Statistical analysis was performed with the SPSS software following the good biometric practice.

3. Results

3.1. Patients

We enrolled 859 evaluable patients (54.0% adults, 10.1% adolescents, 35.9% children) with pollen- and/or HDM-induced ARD (Table 1). The two subpopulations differentiated by prescribed allergen group, ‘HDM’ (N = 431) and ‘Pollen’ (N = 428), showed similar age and sex distribution (Supplementary Table S1). Half of the patients were monosensitized (Table 1), mostly to HDM versus pollens (71.2 vs. 30.8%, Supplementary Table S1).

Table 1. Demographic and clinical data of the study population.

Demographic data	Overall (N = 859)	
Age, years, mean (SD)	24.9 (17.6)	
Age range, n (%)†
  Adults
  Adolescents
  Children	
464 (54.0)
87 (10.1)
308 (35.9)	
Sex, n (%)
  Men
  Women	
454 (52.9)
405 (47.1)	
Allergy-related clinical data	Overall (N = 859)	
Allergen sensitization profile, n (%)
  Monosensitized
  Polisensitized
  NA	
439 (51.1)
408 (47.5)
12 (1.4)	
Months on SLIT at the time of consultation, mean (SD)	8.6 (1.9)	
Allergen extract(s) used in AIT, n (%)
  D. pteronyssinus + D. farinae
  D. Pteronyssinus
  D. pteronyssinus + D. farinae + B. tropicalis
  5 Grass + Olea
  Olea europea
  5 Grass
  Cupressaceae
  Parietaria
  Artemisia
  Birch (Betula)	
323 (37.6)
100 (11.6)
8 (0.9)
157 (18.3)
119 (13.9)
91 (10.6)
42 (4.9)
16 (1.9)
2 (0.2)
1 (0.1)	
AIT regimen, n (%)
  Perennial
  Pre-Coseasonal	
457 (53.2)
402 (46.8)	
† Children (5–12 years), adolescents (13–17 years) and adults (≥18 years).

AIT: Allergen immunotherapy; NA: Not available; SD: Standard deviation; SLIT: Sublingual immunotherapy.

At the time of consultation, mean duration of immunotherapy was 8.6 months (Table 1 & Supplementary Table S1). Regarding SLIT composition, the most frequent within the HDM group corresponded to D. pteronyssinus + D. farinae (50/50), while in the pollen group it was the 5 Grasses + Olea europea (50/50) mix (Supplementary Table S1).

3.2. Allergic symptoms & medication use

The analysis of clinical data before (baseline) and after SLIT administration (at the visit) revealed a relevant symptom improvement, paired to an agreement between patients and investigators on the lower use of symptomatic medication after SLIT.

With respect to AR, we observed a significant decrease in the frequency and intensity of symptoms reported by patients. In particular, persistent rhinitis decreased from 92% to 34%, while severe rhinitis cases almost disappeared after SLIT (Figure 1A; p < 0.0001 for all comparisons). In addition, 20.0% of the patients with AR did not report nasal symptoms after SLIT (p < 0.0001) (Figure 1A).

Figure 1. Allergic respiratory disease evolution following sublingual immunotherapy. Evolution of symptoms following SLIT use regarding allergic rhinitis (A), conjunctivitis (B) and asthma (C). Data are displayed as percentage of patients with symptoms. Allergic rhinitis type, conjunctivitis severity and asthma severity were graded according to ARIA-VALERO30, DECA31 and GEMA32 criteria, respectively. A significance level of p < 0.0001 was obtained for all comparisons between groups in AR, conjunctivitis and asthma.

ARIA: Allergic rhinitis and its impact on asthma; CE: Corticosteroid; GEMA: Spanish Asthma Management Guideline; GINA: Global Strategy for Asthma Management; SLIT: Sublingual immunotherapy.

Symptoms of conjunctivitis followed a similar trend, with a significant decrease both in frequency and intensity of symptoms (Figure 1B; p < 0.0001 for all comparisons). Nearly half of the persistent cases (58% reduction from the basal score) and almost all the severe cases were missing after SLIT use (Figure 1B; p < 0.0001 for all comparisons). This improvement trend was also true for the number of patients with concurrent asthma and for those with exacerbations requiring corticoids. Likewise, SLIT led to a greater degree of asthma control (Figure 1C; p < 0.0001).

3.3. Health-related quality of life of patients undergoing SLIT treatment

Changes in symptoms and medication intake after SLIT were accompanied by a significant gain in the global health-related quality of life (HRQoL) scores, both in the overall sample (+44.2%) and in the subgroup of patients with asthma, as reflected by patients' assessment (+31.0%, p ≤ 0.005; Figure 2A).

Figure 2. Evolution of health-related quality of life of patients undergoing sublingual immunotherapy treatment. (A) Global assessment of HRQoL in the overall sample and in the group of patients with asthma. QoL scores range from 0 (very annoying) to 10 (not annoyed at all) (VAS scale). Patients reported significant HRQoL gains with SLIT. (B) Evolution of ARC symptoms affecting HRQoL. (C) Evolution of asthma symptoms affecting HRQoL. For B and C, VAS scale ranged between 0 = “No bother at all” and 10 = “Maximum inconvenience”. Differences in each item's assessment before and after SLIT were significant (p ≤ 0.005). ♦ Clinical ARC (B) or asthma (C) symptoms Clinical derived symptoms related to activities and daily life (B) or to places and limitations (C).

ARC: Allergic rhinoconjunctivitis; HRQoL: Health-related quality of life; SLIT: Sublingual immunotherapy; VAS: Visual analog scale.

When screened separately nasal and ocular symptoms affecting quality of life (nasal congestion, rhinorrhoea, sneezing, nasal itch, eyes itch, watery eyes, red eyes and swollen eyes), all symptoms significantly decreased after sublingual immunotherapy SLIT (black vs white markers in Figure 2B, p ≤ 0.005), in a range from 52 to 62.5%. A similar patient improvement across all analyzed ARC-derived problems ranged between 56.5 and 61.4% (gray vs. white corresponding markers, Figure 2B). This pattern was also true for patients with asthma, who experienced a significant decrease (approximately 60%) in all respiratory symptoms that affect QoL (black vs white markers in Figure 2C; p ≤ 0.005), ranging from 52.9 to 68%. For asthma-derived problems (gray vs corresponding white markers, Figure 2C), improvement was around 35% as regard to sites/environment (34–38.8%) and ranged between 52.2 and 64.6% for the rest of derived problems (fear of lack of medication, sleep limitation, etc.).

3.4. AIT satisfaction in adults

In a 0–100 scale, both physicians and patients reported high global satisfaction mean scores (standard deviation [SD]) with SLIT (79.4 [17.8] y 77.3 [20.8], respectively). To use objective parameters, we stratified the sample by age groups. Adult subjects completed the validated ESPIA questionnaire [38], where they reported being remarkably satisfied with SLIT (ESPIA mean [SD] overall score: 72.6 [22.4], Figure 3). The questionnaire's scores for the four dimensions (Figure 3) exhibited a low dispersion, ranging from 71 to 77: ‘overall satisfaction’ dimension scored the highest one (77 [22.3]), and ‘activities and environment’, the lowest one (71 [23.7]).

Figure 3. Satisfaction of adult patients with sublingual immunotherapy: ESPIA questionnaire scores. The ESPIA questionnaire (Justicia 2011, 2016) is a multi-response 16-item scale (Likert type with 5 answer options) that rates satisfaction of adult patients undergoing allergen immunotherapy. Overall and dimension scores (perceived efficacy, activities and environment, cost-benefit balance, overall satisfaction) range from 0 (low satisfaction) to 100 (high satisfaction).

ESPIA: Satisfaction scale for patients receiving allergen immunotherapy.

3.5. AIT satisfaction in children/adolescents

By completing specific ad-hoc questionnaires, adolescents (Supplementary Table S2) and children (Supplementary Table S3) reported being satisfied with the treatment. Most of them experienced a reduction of symptoms within the two preceding months, which 42.5% of adolescents described it as ‘rather reduced’ and other 41.4% as ‘greatly reduced’ (Supplementary Table S2), whereas 72.4% of children asserted ‘having fewer symptoms’ (Supplementary Table S3). Two out of three cases in each group (63.2% of adolescents and 62.7% of children) reported that immunotherapy had eased their life. Additionally, the majority (71.3 and 75.7%, respectively) acknowledged that AIT had greatly improved their quality of life and assured being satisfied with their health status after SLIT treatment (80.5 and 75.3%, respectively). For this reason, more than 80% of the pediatric population believed they would recommend this AIT to other people. There were almost no differences between allergen subgroups.

3.6. Adherence to SLIT

Almost all patients admitted not having experienced difficulties to swallow the SLIT drops (92.5%, Table 2). The great majority of patients could be identified as compliant both when using the Haynes-Sackett test (91.3%) or the self-reported compliance with recommended doses (86.6%). Among non-compliant patients in the latter test (11.3%) – those who breached the prescription guidelines in >20% of dose administrations – the main reason was ‘forgetting some doses’, with a mean frequency of 1.4 days/month (Table 2). This was also true in the allergen subgroups (Supplementary Table S4).

Table 2. Adherence of patients to sublingual immunotherapy.

Adherence	Overall (N = 859)	
Did you have difficulty swallowing the AIT in sublingual drops?§, n (%)
  Yes
  No
  NA	
41 (4.8)
795 (92.5)
23 (2.7)	
Days the patient forgot taking the AIT in the last month§, mean (SD)	1.4 (2.9)	
Morisky-Green test†, n (%)
  Non-compliant
  Compliant
  NA	
342 (39.8)
506 (58.9)
11 (1.3)	
Haynes-Sackett test‡, n (%)
  Non-compliant
  Compliant
  NA	
49 (5.7)
784 (91.3)
26 (3.0)	
Compliance with recommended doses¶, n (%)
  Non-compliant
  Compliant
  NA	
97 (11.3)
744 (86.6)
18 (2.1)	
Major reason for non-compliance with recommended doses n (% of 97 non-compliant cases)#
  Forgetting some doses
  Lack of clinical improvement
  Duration of treatment
  Clinical improvement
  Side effects
  Fear of side effects
  Complex administration schedule
  Cost of treatment
  Other reasons	
60 (61.9)
6 (6.2)
5 (5.2)
4 (4.1)
3 (3.1)
2 (2.1)
2 (2.1)
1 (1.0)
1 (1.0)	
† Morisky-Green test.

‡ The Haynes-Sackett test.

§ Self-reported compliance questionnaire.

¶ Subjects taking ≥80% of the overall prescription (doses and administrations) ≥21 days/month or >5 days/week were identified as compliant.

# Due to some missing cases, some percentages do not add up to 100.

AIT: Allergen-specific immunotherapy; NA: Not available (does not know/does not reply); SD: Standard deviation.

3.7. Safety

SLIT was safe in both adults and children. Almost all patients (97.3%) referred not having experienced any adverse event (AEs; Table 3). Only 2.7% of patients were affected: by a local event (oropharyngeal itching) in 91% of the cases, and by gastrointestinal events and rhinoconjunctivitis in the rest of cases, mostly mild (87%) or moderate (n = 3). Just three patients (13%) within the pollen group, required SLIT discontinuation (Table 3 & Supplementary Table S5), but the rest did not require additional measures nor a dose adjustment. Causality of ARs was confirmed in 50% of patients sensitized to pollens and in 36.4% sensitized to HDM (Supplementary Table S5).

Table 3. Safety profile of the sublingual immunotherapy.

Safety	Overall N = 859	
The patient experienced an adverse reaction, n (%)
  Yes
  No	
23 (2.7)
836 (97.3)	
Type of adverse reactions, n (%)
  Local
  Systemic	
21 (91.3)
2 (8.7)	
Severity of adverse reactions, n (%)
  Mild
  Moderate
  Severe	
20 (87.0)
3 (13.0)
0 (0.0)	
Actions taken with the product, n (%)
  None
  Discontinuation
  No dosage changes
  Other	
13 (56.5)
3 (13.0)
4 (17.4)
3 (13.0)	
Causality of adverse reaction, n (%)
  Certain/definite/true
  Probable
  Possible
  Improbable
  NA	
10 (43.5)
6 (26.1)
5 (21.7)
1 (4.35)
1 (4.35)	
NA: Not available (does not know/does not reply).

4. Discussion

To our knowledge, QUALI study is the largest multicenter retrospective cross-sectional study in Spain to provide comprehensive short-term real-life data of the impact, quality of life, satisfaction and adherence of patients over 5 years undergoing high-dose SLIT for HDM- and/or pollen-induced ARD. Despite the poor baseline symptom control and the short-course of SLIT treatment – at least 6 months on perennial regimen or over one pre-coseason, respectively, a significant proportion of patients progressed to a greater or even definite symptom control in terms of frequency and severity. In line with this, most physicians and patients agreed there was a reduction on the medication use for symptom relief.

SLIT treatment led to a meaningful gain in HRQoL. Patients experienced an important reduction of nasal, ocular and bronchial symptoms and in derived problems affecting their daily life. Patients and investigators were remarkably satisfied regardless of the allergy type. Furthermore, most children and adolescents recognized that immunotherapy had greatly improved their QoL, assuring being satisfied with their health status after SLIT. Using complementary instruments, we reported high adherence rates, being forgetfulness the main motive for non-adherence. Practically none of the patients referred adverse events and the few of them (2.7%) were local and mostly mild.

We characterized the wide age-ranged population according to well-delimited scales of presence, frequency, severity and control of ARC and/or asthma symptoms [30–33]. In our descriptive analysis of SLIT short-term action, relevant changes took place in the evolution of symptoms, symptomatic medication intake and burdensome symptoms affecting QoL. Increasingly more real-life studies evaluate long-term evolution of symptoms, and only a few provide short-term data. However, patients are influenced by symptomatic treatment, and perception of poor efficacy motivates non-compliance to SLIT [18], while self-perception of improvement (severity in particular) or medication reduction after 12 months are associated with a higher compliance [20]. Related to short therapy courses, a retrospective study in pediatric patients with HDM-induced AR showed reduction of allergy severity and medication consumption after six-month of AIT course of treatment [25]. However, the investigators did not find a reduction in the consumption of asthma medication within that short period or in subsequent visits, nor a temporal improvement in asthma severity [25]. They attributed this to the good asthma control at baseline, which might refrain patients from obtaining additional benefits [41]. In our case half of our asthmatic population (48.4%) presented poor-to-moderate asthma control at baseline, and our results reveal improvement both in asthma severity and control within the short-term.

Two studies [22,42] highlighted the importance of early immunotherapy to prevent progression and mitigate allergic disease impact on patients' well-being and QoL. This is particularly relevant in patients with comorbid asthma, whose QoL is severely burdened [6,23]. Self-perception of beneficial effects since the very beginning may boost satisfaction and adherence to treatment. However, data on self-perception of AIT beneficial effects are scarce [22], particularly in the short-term treatment in real-world practice of pediatric patients with concurrent asthma. In our study, a SLIT short course led to significant high ratings in all HRQoL dimensions independently of the comorbid asthma; and conferred patients a positive evolution of troublesome symptoms, and derived symptoms affecting QoL. Our results are consistent with other studies in our environment, Confirming that SLIT can reduce the impact on work/academic performance and HRQoL of patients allergic to HDM and/or pollen in Spain [3,43].

Patient satisfaction reflects their perception of symptoms and QoL improvement, influencing immunotherapy success by adhering to treatment [22]. Our high satisfaction scores are consistent with those reported by other studies with short SLIT courses in the real-world setting. A recent study reported excellent ratings for each dimension and overall score of the ESPIA questionnaire in patients over five with rhinitis and/or asthma undergoing a minimum 4-month HDM-SLIT treatment [24]. Another study stated similar levels of satisfaction with pollen SLIT among patients of all ages in a pre-coseasonal regimen over two seasons in Spain [43].

The more satisfied a patient is, the more likely they will adhere to their treatment [39]. Most patients in our study adhere to SLIT, as regards of the Haynes-Sackett test (91.3%) or the self-reported compliance with recommended doses (86.6%). As in other studies [18,20], we detected variations depending on the method to test adherence. Thus, Morisky-Green [18] test yielded lower adherence rates (60%), in agreement with the figures obtained by Malet [20] (50.9%). Studies report a good compliance to SLIT, ranging from 75 to 90% [44]. In our real practice, adherence to SLIT is quite good, as our patients lie on the top of those figures.

The main non-compliance reason was ‘forgetting some doses’ (approximately 62% of non-compliant patients, 7% of the study population). Non-compliance reasons may differ across environments and countries. The findings that cost of medication is not relevant in our country [29] may reveal other priorities in Spanish patients. This might explain the high rank reached in the cost-benefit balance item of our ESPIA questionnaire.

Parallel to the high compliance rates, our data yielded low discontinuation rates (13%) within both allergen subpopulations (n = 3, all pollen cases). Other real-word studies reported higher rates within the first year of treatment (22% [20], 51% [18], 54% [19]). However, a study demonstrated a clear inverse correlation between compliance and SLIT treatment duration [18].

Several studies have associated the reduction of symptomatic medication consumption [20,29] and the decrease of frequency and severity of allergic symptoms [20] with compliance. These factors probably play a role in our study contributing to the high levels registered of satisfaction, quality of life and compliance.

We are aware of some limitations, as 859 evaluable patients were enrolled out of the 2396 planned sample size (35.8%). However the statistical power of final sample (76%) is enough could proceed to the analysis. Also, while retrospective nature might entail a recall bias, the close follow-up from prospective studies may push patients to be compliant while doses' counts provide objective compliance. Finally, while comparison between populations on differential regimens is challenging, it elicited relevant information. Related to the strengths, we provide real-life adherence data on one of the largest populations in the allergen immunotherapy field. Moreover, nearly half of our population are children and adolescents, where allergic rhinitis and asthma impacts with a high prevalence. Another asset is the use of complementary tools for a more precise adherence measurement, which is not a frequent practice among previous studies or clinical practice [20]. The large sample size may help minimize the potential bias overestimating adherence data.

5. Conclusion

Treatment with a sublingual standardized allergen immunotherapy in liquid formulation at 300 IR/ml has shown to be effective in a real-life setting to reduce allergic rhinitis-, conjunctivitis- and asthma-associated symptoms and to improve quality of life in a short-term evaluation period. This, together with the high level of satisfaction identified with the therapy and a high rate of adherence indicates that a fast onset of action of AIT is linked to adherence in SLIT.

Supplementary Material

Supplementary Tables S1-S5

Acknowledgments

The authors thank the investigators/research co-ordinators participating in the study. We extend our appreciation to the patients with ARC who participated in the study.

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/1750743X.2024.2347828

Author contributions

All authors have made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. S Garrido-Fernández, E Villarrubia Bòriai and J Sánchez-López drafted the work or revising it critically for important intellectual content. All authors approved the final version to be published.

Financial disclosure

The study was supported and sponsored by Stallergenes Iberica (Barcelona, Spain). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

J Hernández-Peñaj reports that he grant or contract from ASAC PHARMA as a external consultant and with Stallergenes Greer for lectures, presentations, speakers bureaus, manuscript writing or educational events. J Sánchez López is full-time employee at Stallergenes Iberica (Barcelona, Spain). The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing support was provided by C Gutiérrez Viloria (medical writer, Spain) and was funded by Stallergenes Ibérica (Barcelona, Spain).

Writing disclosure

The authors acknowledge C Gutiérrez Viloria (medical writer, Spain) for writing assistance with the preparation of this manuscript. The assistance was funded by Stallergenes Ibérica (Barcelona, Spain).

Ethical conduct of research

All the procedures followed the ethical standards of the Helsinki Declaration, and the ICH guidelines for Good Clinical Practice (GCP). The study was approved by the Research Ethics Committee of the Community Foral of Navarra (EO18/1). Written informed consent was obtained from participating patients, their parents, or legal representatives.
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