Impairment of EQ-5D-5L Domains According to Allergic Rhinitis and Asthma Control: A MASK-air Real-World Study.

BACKGROUND: EQ-5D-5L (EuroQOL, 5 Domains, 5 Levels) is a widely used health-related quality-of-life instrument, comprising 5 domains. However, it is not known how each domain is impacted by rhinitis or asthma control. OBJECTIVE: To assess the association between rhinitis or asthma control and the different EQ-5D-5L domains using data from the MASK-air mHealth app. METHODS: In this cross-sectional study, we assessed data from all MASK-air users (2015-2021; 24 countries). For the levels of each EQ-5D-5L domain, we assessed rhinitis and asthma visual analog scales (VASs) and the combined symptom-medication score (CSMS). We built ordinal multivariable models assessing the adjusted association between VAS/CSMS values and the levels of each EQ-5D-5L domain. Finally, we compared EQ-5D-5L data from users with rhinitis and self-reported asthma with data from users with rhinitis alone. RESULTS: We assessed 5354 days from 3092 users. We observed an association between worse control of rhinitis or asthma (higher VASs and CSMS) and worse EQ-5D-5L levels. In multivariable models, all VASs and the CSMS were associated with higher levels of pain/discomfort and daily activities. For anxiety/depression, the association was mostly observed for rhinitis-related tools (VAS nose, VAS global, and CSMS), although the presence of self-reported asthma was also associated with worse anxiety/depression. Worse mobility ("walking around") was particularly associated with VAS asthma and with the presence of asthma. CONCLUSIONS: A worse rhinitis control and a worse asthma control are associated with higher EQ-5D-5L levels, particularly regarding pain/discomfort and activity impairment. Worse rhinitis control is associated with worse anxiety/depression, and poor asthma control with worse mobility.

The Correlation between the Results of the Sniffin' Sticks Test, Demographic Data, and Questionnaire of Olfactory Disorders in a Hungarian Population after a SARS-CoV-2 Infection.

BACKGROUND: After a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, smell disorders frequently occur, significantly affecting patients' quality of life (QoL). METHODS: 110 patients with persistent olfactory disorder after coronavirus infection were enrolled. These patients underwent chemosensory testing using the Sniffin' Sticks test, and completed the Questionnaire of Olfactory Disorders (QOD). RESULTS: 30% of the patients reported anosmia, and 70% reported hyposmia. Upon comparing subjective and chemosensory testing categories, good category matching was observed in 75.3% (i.e., anosmia based on both methods in 10 and hyposmia in 48 cases). Statistical analysis using the Chi-square test revealed a significant result (p = 0.001 *). Between the TDI (i.e., Threshold, Discrimination, Identification) results of the three subjective report groups (i.e., hyposmia, anosmia, and parosmia), no significant differences were observed. When the TDI and QOD results were compared, no consistent significant correlations were found in most TDI and QOD outcomes. Between the TDI and Scale 2 results, a significant, although slight correlation was observed by the Spearman's (rho = 0.213, p = 0.027 *) and Pearson's (rho = 0.201, p = 0.037 *) tests. CONCLUSIONS: The nonsignificant correlation between objective and subjective methods suggests that these results should be interpreted independently. Moreover, adequate management is essential even in mild cases.

Digitally-enabled, patient-centred care in rhinitis and asthma multimorbidity: The ARIA-MASK-air® approach.

MASK-air® , a validated mHealth app (Medical Device regulation Class IIa) has enabled large observational implementation studies in over 58,000 people with allergic rhinitis and/or asthma. It can help to address unmet patient needs in rhinitis and asthma care. MASK-air® is a Good Practice of DG Santé on digitally-enabled, patient-centred care. It is also a candidate Good Practice of OECD (Organisation for Economic Co-operation and Development). MASK-air® data has enabled novel phenotype discovery and characterisation, as well as novel insights into the management of allergic rhinitis. MASK-air® data show that most rhinitis patients (i) are not adherent and do not follow guidelines, (ii) use as-needed treatment, (iii) do not take medication when they are well, (iv) increase their treatment based on symptoms and (v) do not use the recommended treatment. The data also show that control (symptoms, work productivity, educational performance) is not always improved by medications. A combined symptom-medication score (ARIA-EAACI-CSMS) has been validated for clinical practice and trials. The implications of the novel MASK-air® results should lead to change management in rhinitis and asthma.

Cutoff Values of MASK-air Patient-Reported Outcome Measures.

BACKGROUND: In clinical and epidemiological studies, cutoffs of patient-reported outcome measures can be used to classify patients into groups of statistical and clinical relevance. However, visual analog scale (VAS) cutoffs in MASK-air have not been tested. OBJECTIVE: To calculate cutoffs for VAS global, nasal, ocular, and asthma symptoms. METHODS: In a cross-sectional study design of all MASK-air participants, we compared (1) approaches based on the percentiles (tertiles or quartiles) of VAS distributions and (2) data-driven approaches based on clusters of data from 2 comparators (VAS work and VAS sleep). We then performed sensitivity analyses for individual countries and for VAS levels corresponding to full allergy control. Finally, we tested the different approaches using MASK-air real-world cross-sectional and longitudinal data to assess the most relevant cutoffs. RESULTS: We assessed 395,223 days from 23,201 MASK-air users with self-reported allergic rhinitis. The percentile-oriented approach resulted in lower cutoff values than the data-driven approach. We obtained consistent results in the data-driven approach. Following the latter, the proposed cutoff differentiating "controlled" and "partly-controlled" patients was similar to the cutoff value that had been arbitrarily used (20/100). However, a lower cutoff was obtained to differentiate between "partly-controlled" and "uncontrolled" patients (35 vs the arbitrarily-used value of 50/100). CONCLUSIONS: Using a data-driven approach, we were able to define cutoff values for MASK-air VASs on allergy and asthma symptoms. This may allow for a better classification of patients with rhinitis and asthma according to different levels of control, supporting improved disease management.

Consistent trajectories of rhinitis control and treatment in 16,177 weeks: The MASK-air® longitudinal study.

INTRODUCTION: Data from mHealth apps can provide valuable information on rhinitis control and treatment patterns. However, in MASK-air®, these data have only been analyzed cross-sectionally, without considering the changes of symptoms over time. We analyzed data from MASK-air® longitudinally, clustering weeks according to reported rhinitis symptoms. METHODS: We analyzed MASK-air® data, assessing the weeks for which patients had answered a rhinitis daily questionnaire on all 7 days. We firstly used k-means clustering algorithms for longitudinal data to define clusters of weeks according to the trajectories of reported daily rhinitis symptoms. Clustering was applied separately for weeks when medication was reported or not. We compared obtained clusters on symptoms and rhinitis medication patterns. We then used the latent class mixture model to assess the robustness of results. RESULTS: We analyzed 113,239 days (16,177 complete weeks) from 2590 patients (mean age ± SD = 39.1 ± 13.7 years). The first clustering algorithm identified ten clusters among weeks with medication use: seven with low variability in rhinitis control during the week and three with highly-variable control. Clusters with poorly-controlled rhinitis displayed a higher frequency of rhinitis co-medication, a more frequent change of medication schemes and more pronounced seasonal patterns. Six clusters were identified in weeks when no rhinitis medication was used, displaying similar control patterns. The second clustering method provided similar results. Moreover, patients displayed consistent levels of rhinitis control, reporting several weeks with similar levels of control. CONCLUSIONS: We identified 16 patterns of weekly rhinitis control. Co-medication and medication change schemes were common in uncontrolled weeks, reinforcing the hypothesis that patients treat themselves according to their symptoms.

Comparison of rhinitis treatments using MASK-air® data and considering the minimal important difference.

BACKGROUND: Different treatments exist for allergic rhinitis (AR), including pharmacotherapy and allergen immunotherapy (AIT), but they have not been compared using direct patient data (i.e., "real-world data"). We aimed to compare AR pharmacological treatments on (i) daily symptoms, (ii) frequency of use in co-medication, (iii) visual analogue scales (VASs) on allergy symptom control considering the minimal important difference (MID) and (iv) the effect of AIT. METHODS: We assessed the MASK-air® app data (May 2015-December 2020) by users self-reporting AR (16-90 years). We compared eight AR medication schemes on reported VAS of allergy symptoms, clustering data by the patient and controlling for confounding factors. We compared (i) allergy symptoms between patients with and without AIT and (ii) different drug classes used in co-medication. RESULTS: We analysed 269,837 days from 10,860 users. Most days (52.7%) involved medication use. Median VAS levels were significantly higher in co-medication than in monotherapy (including the fixed combination azelastine-fluticasone) schemes. In adjusted models, azelastine-fluticasone was associated with lower average VAS global allergy symptoms than all other medication schemes, while the contrary was observed for oral corticosteroids. AIT was associated with a decrease in allergy symptoms in some medication schemes. A difference larger than the MID compared to no treatment was observed for oral steroids. Azelastine-fluticasone was the drug class with the lowest chance of being used in co-medication (adjusted OR = 0.75; 95% CI = 0.71-0.80). CONCLUSION: Median VAS levels were higher in co-medication than in monotherapy. Patients with more severe symptoms report a higher treatment, which is currently not reflected in guidelines.

Allergen immunotherapy in MASK-air users in real-life: Results of a Bayesian mixed-effects model.

BACKGROUND: Evidence regarding the effectiveness of allergen immunotherapy (AIT) on allergic rhinitis has been provided mostly by randomised controlled trials, with little data from real-life studies. OBJECTIVE: To compare the reported control of allergic rhinitis symptoms in three groups of users of the MASK-air® app: those receiving sublingual AIT (SLIT), those receiving subcutaneous AIT (SCIT), and those receiving no AIT. METHODS: We assessed the MASK-air® data of European users with self-reported grass pollen allergy, comparing the data reported by patients receiving SLIT, SCIT and no AIT. Outcome variables included the daily impact of allergy symptoms globally and on work (measured by visual analogue scales-VASs), and a combined symptom-medication score (CSMS). We applied Bayesian mixed-effects models, with clustering by patient, country and pollen season. RESULTS: We analysed a total of 42,756 days from 1,093 grass allergy patients, including 18,479 days of users under AIT. Compared to no AIT, SCIT was associated with similar VAS levels and CSMS. Compared to no AIT, SLIT-tablet was associated with lower values of VAS global allergy symptoms (average difference = 7.5 units out of 100; 95% credible interval [95%CrI] = -12.1;-2.8), lower VAS Work (average difference = 5.0; 95%CrI = -8.5;-1.5), and a lower CSMS (average difference = 3.7; 95%CrI = -9.3;2.2). When compared to SCIT, SLIT-tablet was associated with lower VAS global allergy symptoms (average difference = 10.2; 95%CrI = -17.2;-2.8), lower VAS Work (average difference = 7.8; 95%CrI = -15.1;0.2), and a lower CSMS (average difference = 9.3; 95%CrI = -18.5;0.2). CONCLUSION: In patients with grass pollen allergy, SLIT-tablet, when compared to no AIT and to SCIT, is associated with lower reported symptom severity. Future longitudinal studies following internationally-harmonised standards for performing and reporting real-world data in AIT are needed to better understand its 'real-world' effectiveness.

Behavioural patterns in allergic rhinitis medication in Europe: A study using MASK-air® real-world data.

BACKGROUND: Co-medication is common among patients with allergic rhinitis (AR), but its dimension and patterns are unknown. This is particularly relevant since AR is understood differently across European countries, as reflected by rhinitis-related search patterns in Google Trends. This study aims to assess AR co-medication and its regional patterns in Europe, using real-world data. METHODS: We analysed 2015-2020 MASK-air® European data. We compared days under no medication, monotherapy and co-medication using the visual analogue scale (VAS) levels for overall allergic symptoms ('VAS Global Symptoms') and impact of AR on work. We assessed the monthly use of different medication schemes, performing separate analyses by region (defined geographically or by Google Trends patterns). We estimated the average number of different drugs reported per patient within 1 year. RESULTS: We analysed 222,024 days (13,122 users), including 63,887 days (28.8%) under monotherapy and 38,315 (17.3%) under co-medication. The median 'VAS Global Symptoms' was 7 for no medication days, 14 for monotherapy and 21 for co-medication (p < .001). Medication use peaked during the spring, with similar patterns across different European regions (defined geographically or by Google Trends). Oral H1 -antihistamines were the most common medication in single and co-medication. Each patient reported using an annual average of 2.7 drugs, with 80% reporting two or more. CONCLUSIONS: Allergic rhinitis medication patterns are similar across European regions. One third of treatment days involved co-medication. These findings suggest that patients treat themselves according to their symptoms (irrespective of how they understand AR) and that co-medication use is driven by symptom severity.

Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19.

In this article, we propose that differences in COVID-19 morbidity may be associated with transient receptor potential ankyrin 1 (TRPA1) and/or transient receptor potential vanilloid 1 (TRPV1) activation as well as desensitization. TRPA1 and TRPV1 induce inflammation and play a key role in the physiology of almost all organs. They may augment sensory or vagal nerve discharges to evoke pain and several symptoms of COVID-19, including cough, nasal obstruction, vomiting, diarrhea, and, at least partly, sudden and severe loss of smell and taste. TRPA1 can be activated by reactive oxygen species and may therefore be up-regulated in COVID-19. TRPA1 and TRPV1 channels can be activated by pungent compounds including many nuclear factor (erythroid-derived 2) (Nrf2)-interacting foods leading to channel desensitization. Interactions between Nrf2-associated nutrients and TRPA1/TRPV1 may be partly responsible for the severity of some of the COVID-19 symptoms. The regulation by Nrf2 of TRPA1/TRPV1 is still unclear, but suggested from very limited clinical evidence. In COVID-19, it is proposed that rapid desensitization of TRAP1/TRPV1 by some ingredients in foods could reduce symptom severity and provide new therapeutic strategies.

Hungarian adaptation and launch of the 2019 ARIA care pathways of allergic rhinitis in Hungary / A 2019. évi ARIA kezelési irányelvek magyar adaptációja és a hazai alkalmazás lehetoségei allergiás rhinitisben.

Összefoglaló. Az allergiás betegségekben szenvedo emberek száma világszerte, köztük Magyarországon is növekszik. Az egészségügyi ellátórendszerek azon dolgoznak, hogy minél hatékonyabban tudják felhasználni a rendelkezésre álló forrásokat. Az Allergic Rhinitis and its Impact on Asthma (ARIA) szervezet célja az allergiás náthában szenvedo betegek ellátásának javítása, szakmai ajánlások készítése, aktualizálása. Ennek egyik módja integrált betegellátási utak kidolgozása. Célunk ezek hazai elérhetové tétele, az ajánlások széles köru elterjesztése az Európai Unió (EU) többi tagállamához hasonlóan Magyarországon is. Az ARIA más nemzetközi innovatív szervezetek bevonásával olyan integrált betegellátási utakat fejlesztett ki, amelyek allergiás nátha, esetleg társbetegsége, az asztma esetén támogatják a kezelést. Ezeket újgenerációs irányelvek kidolgozása útján alkották, amelyekhez felhasználták a mobiltechnológiából és pollenkamra-vizsgálatokból származó valós evidenciákat is. A gyógyszeres terápia optimalizálásához a vizuális analóg skálán alapuló, úgynevezett Mobil Légúti Figyelo Hálózat algoritmusát digitalizálták, és valós evidenciák felhasználásával tovább finomították. Allergén immunterápiára az ARIA a világon elsoként dolgozott ki integrált betegellátási utakat 2019-ben. A kezelési irányelvekhez való adherenciaszint alacsony, a betegek a tüneteik erossége alapján módosítják a kezelést. A flutikazon-propionát-azelasztin kombináció hatása erosebb az intranasalis kortikoszteroidokénál, míg az utóbbi hatásosabb az oralis H1-antihisztaminoknál. A mobiltelefonokban tárolt elektronikus napló vagy más 'mobile health' (mHealth) eszközök használata segíti a betegek kiválasztását allergén immunterápiára. Az ARIA által javasolt algoritmus megfelelonek mutatkozott az allergiás rhinitis kezelésére, ezért ezek az irányelvek bekerülnek integrált betegellátási utakba, és részét fogják képezni az EU Egészségügyi és Élelmiszer-biztonsági Foigazgatósága digitalizált, személyközpontú gondozási anyagainak. Az allergén immunterápia hatékony az inhalatív allergének által okozott allergiás betegségekben, alkalmazását azonban korlátozni kell gondosan válogatott betegekre. Orv Hetil. 2020; 161(49): 2059-2071. Summary. The number of allergic patients is increasing all over the world, also in Hungary. Delivering effective and cost-effective health care is essential for all health care systems. ARIA (Allergic Rhinitis and its Impact on Asthma) aims to improve the care of patients who suffer from allergic rhinitis by setting up guidelines and updating them. Development of ICPs (integrated care pathways) can play an essential role in attaining this goal. Our aim is to make ICP-s developed by ARIA available also in Hungary, as is already the case in other countries of the European Union (EU). Together with other international initiatives, ARIA has worked out digitally-enabled ICPs to support care in allergic rhinitis and comorbid asthma. ICPs are based on new-generation guidelines using RWE (real-world evidence) from chamber studies and mobile technology. The MASK (Mobile Airways Sentinel NetworK) algorithm - based on visual analogue scale - was digitalized to support pharmacotherapy, and was refined by using RWE. ARIA was the first to develop ICPs for allergen immunotherapy (AIT) in 2019. Based on MASK data, patients did not follow guidelines and their adherence to treatment was poor. Patients would modify their treatments, depending on the disease control. The effect of fluticasone propionate-azelastine combination is superior to intranasal corticosteroids which are superior to oral H1-antihistamines. Electronic diaries obtained from cell phones and other 'mobile health' (mHealth) devices help select patients for AIT. The ARIA algorithm for AR was found appropriate and no change is necessary. These guidelines will inform ICPs and will be included in the DG Santé digitally-enabled, person-centred care system. AIT is an effective treatment for allergic diseases caused by inhaled allergens. Its use should, however, be restricted to carefully selected patients. Orv Hetil. 2020; 161(49): 2059-2071.

Association of PPAR polymorphisms with cytokine levels in allergic rhinitis.

Our aim was to study the association of Pro12Ala and exon6 C161T polymorphisms of PPARgamma and intron7 G/C polymorphisms of PPAR-alpha with clinical symptoms, peak nasal inspiratory flow values, serum soluble TNF-alpha, TNF-R1, Fas, Fas ligand and IgE concentrations in patients with seasonal allergic rhinitis during and after pollen season. We performed a follow-up study of 66 Hungarian patients with seasonal allergic rhinitis and 180 healthy referent subjects. We used PCR-RFLP technique and ELISA. The distribution of mutant alleles of PPAR-gamma and -alpha did not differ in patients and referent subjects. Patients carrying the mutant 12Ala, exon6 161T alleles of PPAR-gamma and intron7 C allele of PPAR-alpha had significantly higher clinical symptom score values, TNF-alpha and IgE levels and lower peak nasal inspiratory flow values during and after pollen season. The results indicated that nuclear receptors PPAR-gamma and PPAR-alpha are involved in the regulation of inflammatory mediator production in patients with seasonal allergic rhinitis and polymorphisms of the receptors are very likely to contribute to the heterogeneity of clinical and immunological parameters of allergic patients.

Association of TLR-4 and TNF-alpha polymorphisms with clinical symptoms and cytokine levels in patients with allergic rhinitis.

Our objective was to determine the frequency of TNF-alpha -238, -308 G/A promoter and TLR-4 299 D/G and 399 T/I polymorphisms in healthy population and in patients with seasonal allergic rhinitis, and to examine its influences on serum TNF-alpha, TNF receptor-1, Fas, Fas-ligand, IgE levels and on clinical symptoms. A pilot study was performed in 66 patients with seasonal allergic rhinitis to ragweed pollen and 161 non-allergic subjects using PCR-RFLP technique and ELISA. Carriers of the -238A and -308G alleles have significantly higher TNF-alpha and IgE levels, clinical score values and lower peak nasal flow (PNIF) values during and after ragweed pollen season. Patients with the 299G/399I alleles of the TLR-4 gene have significantly lower TNF-alpha, Fas, FasL and IgE levels, clinical scores and higher PNIF values during and after pollen season. The -238A and -308G polymorphisms of the TNF-alpha promoter and 299D/399T polymorphisms of the TLR-4 gene are associated with more pronounced clinical symptoms, higher cytokine and IgE levels, and low PNIF values. These polymorphisms are very likely to contribute to the heterogeneity of clinical and laboratory parameters of patients.