Improvement of daily allergy control by sublingual immunotherapy: A MASK‐air® study

To the Editor, Allergen immunotherapy (AIT) is an effective treatment for allergic rhinitis and has been hypothesised as rapidly effective.1 Rush subcutaneous AIT to pollen and mites reduces skin test reactivity to allergens within days, in a dosedependent and timeindependent manner.2,3 Venom rush AIT is also effective within days. The tolerance of beekeepers to bee stings fades in some individuals and is also reinstalled after a few stings in a dosedependent and timeindependent manner.4 Finally, desensitisation to drug allergy is effective within hours and there is a refractory period after tolerance.5 These shortterm clinical sequences cannot be explained by an adaptive immune response (immunotherapy) but may be related to rapid and shortlasting cell downregulation responses (desensitisation).1,6 These considerations have prompted the hypothesis that sublingual immunotherapy (SLIT) may induce a rapid relief of allergic symptoms during the pollen season.1 While previous studies have found that SLIT is effective in the same allergy season as when first introduced,7 no study has ever assessed its efficacy on a daily basis. Therefore, in this study, we aimed to assess whether days of SLIT use were associated with better allergy control during the expected pollen season. Such analyses may hint at a potential shortterm effect of SLIT, to be assessed by proper studies. MASKair® is a free mobile app available in 27 countries. The app includes a daily monitoring questionnaire which can be answered on a daily basis. The questionnaire assesses (i) the daily severity and impact of allergy symptoms (through four mandatory visual analogue scales— VASs),8 (ii) the daily rhinitis and asthma medication used on that day by the patient and (iii) whether the patient used AIT on that day. Such information allows the computation of the combined symptommedication score (CSMS), assessing the daily control of allergic rhinitis.9 We included the daily monitoring data of European MASKair® users (i) aged between 16 years (or lower— not below 13 years— for countries with a lower age of digital consent) and 90 years, (ii) with a selfreported diagnosis of allergic rhinitis and (iii) on SLIT for grass pollen. We analysed the data provided during the months of May and June (assuming that they corresponded to the grass pollen season in Europe) from 2015 to 2021. We performed a crosssectional analysis, in which we studied all days reported between May and June for three different samples: (S1) all users under SLIT (of any type) for grass pollen; (S2) users taking SLIT tablets for grass pollen and (S3) users using SLIT (of any type) for grass pollen and reporting at least 1 day of AIT use during the studied period (to account for nonadherence and potential incorrect reporting of SLIT use). Sample 1 was used to assess a sufficientlypowered group. The robustness of the results of SLIT in S1 was assessed in S2 and S3, where different inclusion criteria were adopted. We performed this crosssectional analysis by building multivariable mixedeffects regression models to assess, for each sample, whether days of AIT use were associated with a better allergic rhinitis control (with the dependent variables being either the CSMS or the VAS quantifying the impact of global allergy symptoms— ‘VAS global’). In our models, we considered the clustering of observations by users, by country and by month of the year, setting these variables as random effects (i.e. we clustered observations by users, by the user's country and by the month of the year). In addition, results were further adjusted for the following independent variables which were included in our regression models: baseline domains impacted by allergic rhinitis, baseline symptoms of allergic rhinitis, patients' gender and age, selfreported diagnosis of asthma, occurrence of conjunctivitis and use of daily rhinitis or asthma medication in monotherapy or comedication. We also performed a longitudinal analysis, in which we analysed complete periods of 2 weeks (missing at most an average of 2 days per week) of patients using SLIT for grass pollen and reporting at least 1 day of AIT use during the same period. We performed the longitudinal study in a smaller subset of users, comparing days of AIT use versus days when AIT was not used on the CSMS and VAS global. For such comparisons, we built multivariable mixedeffects regression models similar to those applied in crosssectional analyses. When responding to the MASKair® daily questionnaire, it is not possible to skip any of the questions and data are saved only after the final answer. This precludes missing data within each questionnaire. Pvalues <.05 were considered statistically significant. A Holm– Bonferroni correction was applied to account for multiple


Improvement of daily allergy control by sublingual immunotherapy: A MASK-air® study
To the Editor, Allergen immunotherapy (AIT) is an effective treatment for allergic rhinitis and has been hypothesised as rapidly effective. 1 Rush subcutaneous AIT to pollen and mites reduces skin test reactivity to allergens within days, in a dose-dependent and time-independent manner. 2,3 Venom rush AIT is also effective within days. The tolerance of beekeepers to bee stings fades in some individuals and is also re-installed after a few stings in a dose-dependent and timeindependent manner. 4 Finally, desensitisation to drug allergy is effective within hours and there is a refractory period after tolerance. 5 These short-term clinical sequences cannot be explained by an adaptive immune response (immunotherapy) but may be related to rapid and short-lasting cell downregulation responses (desensitisation). 1,6 These considerations have prompted the hypothesis that sublingual immunotherapy (SLIT) may induce a rapid relief of allergic symptoms during the pollen season. 1 While previous studies have found that SLIT is effective in the same allergy season as when first introduced, 7 no study has ever assessed its efficacy on a daily basis. Therefore, in this study, we aimed to assess whether days of SLIT use were associated with better allergy control during the expected pollen season. Such analyses may hint at a potential shortterm effect of SLIT, to be assessed by proper studies.
MASK-air® is a free mobile app available in 27 countries. The app includes a daily monitoring questionnaire which can be answered on a daily basis. The questionnaire assesses (i) the daily severity and impact of allergy symptoms (through four mandatory visual analogue scales-VASs), 8 (ii) the daily rhinitis and asthma medication used on that day by the patient and (iii) whether the patient used AIT on that day. Such information allows the computation of the combined symptom-medication score (CSMS), assessing the daily control of allergic rhinitis. 9 We included the daily monitoring data of European MASK-air® users (i) aged between 16 years (or lower-not below 13 years-for countries with a lower age of digital consent) and 90 years, (ii) with a self-reported diagnosis of allergic rhinitis and (iii) on SLIT for grass pollen. We analysed the data provided during the months of May and June (assuming that they corresponded to the grass pollen season in Europe) from 2015 to 2021. We performed a cross-sectional analysis, in which we studied all days reported between May and June for three different samples: (S1) all users under SLIT (of any type) for grass pollen; (S2) users taking SLIT tablets for grass pollen and (S3) users using SLIT (of any type) for grass pollen and reporting at least 1 day of AIT use during the studied period (to account for non-adherence and potential incorrect reporting of SLIT use). Sample 1 was used to assess a sufficiently-powered group. The robustness of the results of SLIT in S1 was assessed in S2 and S3, where different inclusion criteria were adopted. We performed this cross-sectional analysis by building multivariable mixed-effects regression models to assess, for each sample, whether days of AIT use were associated with a better allergic rhinitis control (with the dependent variables being either the CSMS or the VAS quantifying the impact of global allergy symptoms-'VAS global'). In our models, we considered the clustering of observations by users, by country and by month of the year, setting these variables as random effects (i.e. we clustered observations by users, by the user's country and by the month of the year). In addition, results were further adjusted for the following independent variables which were included in our regression models: baseline domains impacted by allergic rhinitis, baseline symptoms of allergic rhinitis, patients' gender and age, self-reported diagnosis of asthma, occurrence of conjunctivitis and use of daily rhinitis or asthma medication in monotherapy or co-medication.
We also performed a longitudinal analysis, in which we analysed complete periods of 2 weeks (missing at most an average of 2 days per week) of patients using SLIT for grass pollen and reporting at least 1 day of AIT use during the same period. We performed the longitudinal study in a smaller subset of users, comparing days of AIT use versus days when AIT was not used on the CSMS and VAS global.
For such comparisons, we built multivariable mixed-effects regression models similar to those applied in cross-sectional analyses.
When responding to the MASK-air® daily questionnaire, it is not possible to skip any of the questions and data are saved only after the final answer. This precludes missing data within each ques-analyses. Additional information about study methods and findings is available in the following repository: https://github.com/Berna rdoSo usaPi nto/Impro vemen t-of-daily -aller gy-contr ol-by-subli ngual -immun other apy-A-MASK-air-study MASK-air® is CE1-registered and complies with the General Data Protection Regulation. All data were anonymised prior to the study. Users agreed to having their data analysed for scientific purposes in the Terms of Use. An independent review board approval was not required for this study.
In the cross-sectional analysis, we studied 3968 days from 171 patients in S1. Immunotherapy was reported in 2380 (60.0%) days.

Key messages
• mHealth-based real-world data allow rhinitis control to be monitored in patients using sublingual immunotherapy (SLIT).
• Days with SLIT use were associated with better rhinitis control than days without SLIT use.
• Our results raise the hypothesis (to be subsequently tested) that SLIT may be rapidly effective.

TA B L E 1
Multivariable mixed-effects regression models assessing the association between use of immunotherapy for grass pollen and allergic rhinitis control.  This study using MASK-air® real-world data suggests that in patients under SLIT during the pollen season, AIT may have a very short-term effect. In particular, in patients under SLIT, days with AIT were associated with better allergy control than those without AIT.
However, real-world data are only hypothesis-generating (considering the study design, we should be particularly careful when dealing with temporality) and such hypotheses require confirmation by future well-designed and sufficiently-powered trials.
This study has several strengths, including its multinational scope and the large volume of data analysed. In addition, the CSMS and MASK-air® VASs display medium-high validity, reliability and responsiveness. 8,9 Finally, we analysed three samples in crosssectional analyses and performed a longitudinal analysis, observing robust results.

Association with VAS globalregression coefficient (95%CI) [p-value]
C. Sublingual immunotherapy for grass pollen users reporting AIT use for at least 1 day an optimal control versus those who have just started using SLIT.
(iii) The grass pollen season has been roughly estimated, considering the period of May-June. (iv) We did not consider the different SLIT products in this study. These different products display highly variable standardisation, allergen content and clinical documentation of efficacy and safety. Such a limitation, however, has been partly overcome by the assessment of S2, as, in Europe, there are only a limited set of available products for grass pollen SLIT tablets.
The results of this study raise the hypothesis that SLIT may have a short-term effectiveness. If confirmed in future studies, this may provide a novel strategy in patients allergic to pollens who are F I G U R E 1 Regression coefficients for users under sublingual immunotherapy (SLIT) for grass pollen, on the association between immunotherapy or medication in the CSMS and VAS global. CSMS, Combined symptom-medication score; VAS global, Visual analogue scale on global allergy symptoms.