Impact of liquid sublingual immunotherapy on asthma onset and progression in patients with allergic rhinitis: a nationwide population-based study (EfficAPSI study).

Background: The only disease-modifying treatment currently available for allergic rhinitis (AR) is allergen immunotherapy (AIT). The main objective of the EfficAPSI real-world study (RWS) was to evaluate the impact of liquid sublingual immunotherapy (SLIT-liquid) on asthma onset and evolution in AR patients. Methods: An analysis with propensity score weighting was performed using the EfficAPSI cohort, comparing patients dispensed SLIT-liquid with patients dispensed AR symptomatic medication with no history of AIT (controls). Index date corresponded to the first dispensation of either treatment. The sensitive definition of asthma event considered the first asthma drug dispensation, hospitalisation or long-term disease (LTD) for asthma, the specific one omitted drug dispensation and the combined one considered omalizumab or three ICS ± LABA dispensation, hospitalisation or LTD. In patients with pre-existing asthma, the GINA treatment step-up evolution was analysed. Findings: In this cohort including 112,492 SLIT-liquid and 333,082 controls, SLIT-liquid exposure was associated with a significant lower risk of asthma onset vs. control, according to all definitions (combined: HR [95% CI] = 0.62 [0.60-0.63], sensitive: 0.77 [0.76-0.78], and specific: 0.67 [0.61-0.72]). Exposure to SLIT was associated with a one-third reduction in GINA step-up regardless baseline steps. Interpretation: In this national RWS with the largest number of person-years of follow-up to date in the field of AIT, SLIT-liquid was associated with a significant reduction in the risk of asthma onset or worsening. The use of three definitions (sensitive or specific) and GINA step-up reinforced the rigorous methodology, substantiating SLIT-liquid evidence as a causal treatment option for patients with respiratory allergies. Funding: Stallergenes Greer.

Respiratory allergic diseases and allergen immunotherapy: A French patient survey before and during the COVID-19 pandemic.

Background: The COVID-19 pandemic brought unprecedented global disruption to both healthcare providers and patients with respiratory allergies. There are limited real-life data on the impact of the COVID-19 pandemic on the risk perception of patients with allergy treated with allergen immunotherapy (AIT). Objective: To understand the risk perception of allergic patients treated with sublingual immunotherapy (SLIT) before and during the pandemic, and their attitudes towards COVID-19 infection and vaccination. Methods: This was a non-interventional, cross-sectional survey conducted from October to November 2021 in France. Adult patients, who had been prescribed and had received a Stallergenes SLIT (liquid or liquid and tablets) before the pandemic (from August 1, 2018 to March 10, 2020) and during the pandemic (from March 11, 2020 to August 31, 2021), were identified from the Stallergenes named-patient products (NPP) database. Patients completed an online questionnaire. Data were analyzed descriptively. Results: A total of 5258 patients from all over France completed the questionnaire. Mean (±SD) age of the respondents was 39.3 (±13.0) years and 66.9% were female. Some of them (11.8%) were obese (BMI >30 kg/m2). Main allergic diseases were rhinitis (80.0% of patients) with or without conjunctivitis, and asthma (39.0%). More than half of the patients experienced moderate to severe (58.0%) and persistent allergic rhinitis profile (70.4%). Most patients were poly-allergic (72.7%), mostly to house dust mites (61.9%), grass pollens (61.5%), tree pollens (57.8%), and cat dander (37.2%). Only 14.1% of patients experienced an aggravation of their allergy symptoms during lockdown and 14.8% were infected with COVID-19, with hospitalization required for 1.8%. Only 3.1% of patients reported their SLIT initiation as being postponed due to the pandemic. SLIT was changed, temporarily interrupted or permanently discontinued during the pandemic in 21.9% of patients. Changes mainly concerned the maintenance dose for SLIT-liquid (63.2%). SLIT modification was due to COVID-19 infection in only 4.2%. Most patients did not feel vulnerable (53.1%), anxious (55.2%), at risk to present severe symptoms of COVID-19 (77.1%), or at risk to transmit coronavirus (80.4%). However, greater anxiety was reported in patients with allergic asthma (33.6%) or other respiratory disorders (50.4%). Patients who felt vulnerable partly assigned their vulnerability to their allergic disease (59.3%). Suffering from an allergic disease did not make patients feel more vulnerable to side effects of COVID-19 vaccine for 79.6% of them. Conclusion: Overall, most patients with allergy and under SLIT were not strongly concerned by the COVID-19 infection. SLIT did not have a negative impact on the COVID-19 symptoms.

Plasma tissue factor activity in lung cancer patients predicts venous thromboembolism and poor overall survival.

Background: Biomarkers to identify lung cancer (LC) patients with high risk of venous thromboembolism (VTE) are needed. Objectives: To evaluate the usefulness of plasma tissue factor activity (TFA) and D-dimer levels for the prediction of VTE and overall survival in patients with LC. Methods: In a prospective multicenter observational cohort of consecutive LC patients, TFA and D-dimer levels were measured at diagnosis before any cancer treatment (V1) and between 8 and 12 weeks after diagnosis (V2). Results: Among 302 patients, 38 (12.6%) experienced VTE within the first year after diagnosis. V1-TFA and V1-D-dimer levels were significantly (P = .02) higher in patients who presented VTE within 3 months than in patients without VTE: V1-TFA was 2.02 (25th-75th percentiles, 0.20-4.01) vs 0.49 (0.20-3.09) ng/mL and V1-D-dimer was 1.42 (0.64-4.40) vs 0.69 (0.39-1.53) µg/mL, respectively. Cutoffs of 1.92 ng/mL for TFA and 1.26 µg/mL for D-dimer could discriminate both groups of patients. In multivariate analysis, V1-TFA > 1.92 ng/mL was the only significant predictor of VTE risk at 1 year (hazard ratio, 2.10; 95% CI, 1.06-4.16; P = .03). V2-TFA, quantified in 251 patients, decreased significantly compared with V1-TFA (0.20 vs 0.56 ng/mL, P < .05), but a V2-TFA level > 0.77 ng/mL could predict VTE in the following 3 months. Median overall survival was worse for patients with V1-TFA > 1.92 ng/mL (14.6 vs 23.8 months) and V1-D-dimer > 1.26 µg/mL (13.8 vs 24 months, P < .001). Conclusion: High plasma TFA levels are associated with the occurrence of VTE within the next 3 months after each visit (V1 or V2) and poor survival.

Efficacy of 300 IR house dust mite immunotherapy as a function of disease activity: Tertile analysis in clinical trials.

BACKGROUND: The symptoms of house dust mite (HDM)-induced allergic rhinitis (AR) vary with changes in exposure related to the weather or the domestic environment. In allergen immunotherapy (AIT) studies, a certain level of AR disease activity is necessary to demonstrate treatment efficacy; the latter can be underestimated if a substantial proportion of the patient population is weakly symptomatic. OBJECTIVE: To better estimate the real treatment effect of a HDM sublingual AIT (SLIT) tablet, we analysed the results of natural field studies in detail by applying a tertile approach. METHODS: We used data from three randomised, controlled trials (RCT) in a total of 2585 patients with AR treated with the 300 index of reactivity (IR) HDM SLIT-tablet or placebo. The study centres were grouped into tertiles according to the level of combined symptom and medication scores in patients in the placebo group. In each tertile, the difference between SLIT and placebo was assessed through an analysis of covariance. RESULTS: In the three RCTs, combined scores were found to be similar in the SLIT and placebo groups in the low tertiles. The treatment effect of the 300 IR HDM tablet increased in the medium and high tertiles, with notably significant differences versus placebo in the highest tertile and greater (ranging from -21% to -39%) than in the entire study population (-13% to -20%). The positive relationship between treatment efficacy and the combined score in each tertile was independent of the RCT and the score used. CONCLUSION AND CLINICAL RELEVANCE: Application of the tertile approach to AIT studies in a field in which many variables interact strongly might provide more accurate and meaningful measurements of efficacy and benefit for patients, better reflecting their real-life condition.

Residual reversibility in COPD patients already on long-acting bronchodilator: The OscilloRevers Study.

BACKGROUND: Dyspnea is a complex symptom of chronic obstructive pulmonary disease (COPD) which is not strongly correlated with lung function measures. Long-acting bronchodilators (LAB) may reduce this dyspnea, but some patients report persistent chronic dyspnea despite this treatment. This study aims to assess residual reversibility and clinical response after short-acting bronchodilator (SAB) in COPD patients already treated by LAB and reporting persistent dyspnea. METHODS: COPD patients with a persistent dyspnea (modified Medical Research Council scale (mMRC) ≥1) despite current stable treatment with at least one LAB were included. Spirometry, plethysmography and impulse oscillometry (IOS) were performed at peak effect of their LAB and repeat 45 min after the intake of two SAB (400 µg of salbutamol and 80 µg of ipratropium). Dyspnea improvement was assessed at 45 min after SAB through a comparative two-sided VAS (-100 mm for maximal improvement; +100 mm for maximal degradation). RESULTS: Twenty-two COPD patients were analyzed, mainly men (59.1 %) with a mean age of 60.6 years and a median FEV1 of 54 % of predicted values. Fifty percent of patients reported a severe basal dyspnea (mMRC ≥2). After SAB, spirometric and plethysmographic measurements were statistically improved. For IOS measurement, reactance at 5 Hz (X5) and area of reactance (AX) were also improved. Fifty percent of patients reported a clinically relevant improvement of their resting dyspnea. However, no correlation was found between dyspnea improvement and functional measures. CONCLUSIONS: Fifty percent of COPD patients regularly treated with one or two LAB still report a relevant improvement of resting dyspnea after the adjunctive intake of double short-acting bronchodilators. Physiological mechanisms associated with this improvement remain to be determined. CLINICAL TRIAL REGISTRATION: NCT02928744.

The IL-4/13-induced production of M2 chemokines by human lung macrophages is enhanced by adenosine and PGE2.

BACKGROUND AND PURPOSE: Lung macrophages (LMs) are critically involved in respiratory diseases. The primary objective of the present study was to determine whether or not an adenosine analog (NECA) and prostaglandin E2 (PGE2) affected the interleukin (IL)-4- and IL-13-induced release of M2a chemokines (CCL13, CCL17, CCL18, and CCL22) by human LMs. EXPERIMENTAL APPROACH: Primary macrophages isolated from resected human lungs were incubated with NECA, PGE2, roflumilast, or vehicle and stimulated with IL-4 or IL-13 for 24 h. The levels of chemokines and PGE2 in the culture supernatants were measured using ELISAs and enzyme immunoassays. KEY RESULTS: Exposure to IL-4 (10 ng/mL) and IL-13 (50 ng/mL) was associated with greater M2a chemokine production but not PGE2 production. PGE2 (10 ng/mL) and NECA (10-6 M) induced the production of M2a chemokines to a lesser extent but significantly enhanced the IL-4/IL-13-induced production of these chemokines. At either a clinically relevant concentration (10-9 M) or at a concentration (10-7 M) that fully inhibited phosphodiesterase 4 (PDE4) activity, roflumilast did not increase the production of M2a chemokines and did not modulate their IL-13-induced production, regardless of the presence or absence of PGE2. CONCLUSIONS: NECA and PGE2 enhanced the IL-4/IL-13-induced production of M2a chemokines. The inhibition of PDE4 by roflumilast did not alter the production of these chemokines. These results contrast totally with the previously reported inhibitory effects of NECA, PGE2, and PDE4 inhibitors on the lipopolysaccharide-induced release of tumor necrosis factor alpha and M1 chemokines in human LMs.

A successful linkage of a named patient products of sublingual immunotherapy-dispensing registry to French healthcare insurance database (SNDS): methodological constitution of the EfficAPSI cohort.

BACKGROUND: The only causal treatment for allergic rhinitis (AR) is allergen immunotherapy (AIT) including personalized liquid sublingual AIT (SLIT). We present the methodology for establishing the EfficAPSI cohort to further evaluate the real-life effectiveness and use of SLIT liquid. RESEARCH DESIGN AND METHODS: The EfficAPSI cohort was constituted by deterministic linkage of Stallergenes Greer dispensing and nationwide French healthcare insurance system (SNDS) databases. Data from 2006 to 2018 were extracted. All patients who initiated Stallergenes Greer SLIT liquid between 2010 and 2013 were considered as exposed and those dispensed with AR symptomatic treatment only as control. To limit the impact of confounding, the models will be weighted using the inverse probability of treatment weighting (IPTW). RESULTS: A total of 445,574 patients were included; median age was 38 years; 59.1% were female. Exposed patients (n = 112,492) were significantly younger, more frequently males, and less likely to have comorbidities than controls (n = 333,082). After IPTW, patients' characteristics from both groups were similar. CONCLUSIONS: To date, the EfficAPSI cohort has the largest number of person-years of follow-up in the field of AIT. The completeness of the data allows to evaluate SLIT liquid effectiveness with rigorous methodology, leading to important insights on personalized medicine in real-life.

Clinical relevance of pre- and coseasonal sublingual immunotherapy with a 300 index of reactivity 5-grass SLIT tablet in allergic rhinoconjunctivitis.

BACKGROUND: There is considerable interest in improving the scoring methods for evaluating the efficacy of allergen immunotherapy (AIT) and to show if this is associated with clinically meaningful results from the patient's perspective. We aimed to assess the efficacy and clinical relevance of a 300 index of reactivity (IR) 5-grass pollen sublingual immunotherapy (SLIT) tablet in children, adolescents and adults with moderate to severe grass-induced allergic rhinoconjunctivitis (ARC) with or without controlled asthma using the combined symptom and medication score CSMS0-36 . METHODS: The data of the European population that participated in 3 Phase III, international, randomized double-blind placebo-controlled clinical trials were analyzed post hoc. RESULTS: A total of 864 patients randomized to 300 IR 5-grass tablet or placebo were analyzed. Over the primary evaluation period, the difference in CSMS0-36 between the 300 IR and placebo groups was statistically significant (point estimates: -2.51, CI95% [-3.88; -1.14], p < 0.0001 in clinical trial1; -2.31, CI95% [-3.39; -1.23], p < 0.0001 in CT2; and -2.31, CI95% [-3.58; -1.03], p = 0.0004 in CT3). The relative differences between the 300 IR 5-grass tablet and placebo were -29.7%, -33.8%, and -26.3%, respectively. The results based on CSMS0-36 were consistent with those obtained with the primary endpoints of the trials and support the consideration of the 2-point threshold of the CSMS0-36 for clinical relevance of AIT. CONCLUSION: Post hoc analysis of 3 CTs with the 300 IR 5-grass SLIT tablet confirmed its significant and clinically relevant effect in the European population with grass pollen-induced ARC with or without controlled asthma.

Differential early response of monocyte/macrophage subsets to intra-operative corticosteroid administration in lung transplantation.

Introduction: Lung transplantation often results in primary and/or chronic dysfunctions that are related to early perioperative innate allo-responses where myeloid subsets play a major role. Corticosteroids are administered upon surgery as a standard-of-care but their action on the different myeloid cell subsets in that context is not known. Methods: To address this issue, we used a cross-circulatory platform perfusing an extracorporeal lung coupled to cell mapping in the pig model, that enabled us to study the recruited cells in the allogeneic lung over 10 hours. Results: Myeloid cells, i.e. granulocytes and monocytic cells including classical CD14pos and non-classical/intermediate CD16pos cells, were the dominantly recruited subsets, with the latter upregulating the membrane expression of MHC class II and CD80/86 molecules. Whereas corticosteroids did not reduce the different cell subset recruitment, they potently dampened the MHC class II and CD80/86 expression on monocytic cells and not on alveolar macrophages. Besides, corticosteroids induced a temporary and partial anti-inflammatory gene profile depending on cytokines and monocyte/macrophage subsets. Discussion: This work documents the baseline effects of the standard-of-care corticosteroid treatment for early innate allo-responses. These insights will enable further optimization and improvement of lung transplantation outcomes.

A benchmark study of data normalisation methods for PTR-TOF-MS exhaled breath metabolomics.

Volatilomics is the branch of metabolomics dedicated to the analysis of volatile organic compounds in exhaled breath for medical diagnostic or therapeutic monitoring purposes. Real-time mass spectrometry (MS) technologies such as proton transfer reaction (PTR) MS are commonly used, and data normalisation is an important step to discard unwanted variation from non-biological sources, as batch effects and loss of sensitivity over time may be observed. As normalisation methods for real-time breath analysis have been poorly investigated, we aimed to benchmark known metabolomic data normalisation methods and apply them to PTR-MS data analysis. We compared seven normalisation methods, five statistically based and two using multiple standard metabolites, on two datasets from clinical trials for COVID-19 diagnosis in patients from the emergency department or intensive care unit. We evaluated different means of feature selection to select the standard metabolites, as well as the use of multiple repeat measurements of ambient air to train the normalisation methods. We show that the normalisation tools can correct for time-dependent drift. The methods that provided the best corrections for both cohorts were probabilistic quotient normalisation and normalisation using optimal selection of multiple internal standards. Normalisation also improved the diagnostic performance of the machine learning models, significantly increasing sensitivity, specificity and area under the receiver operating characteristic (ROC) curve for the diagnosis of COVID-19. Our results highlight the importance of adding an appropriate normalisation step during the processing of PTR-MS data, which allows significant improvements in the predictive performance of statistical models.Clinical trials: VOC-COVID-Diag (EudraCT 2020-A02682-37); RECORDS trial (EudraCT 2020-000296-21).

Enhanced real-time mass spectrometry breath analysis for the diagnosis of COVID-19.

Background: Although rapid screening for and diagnosis of coronavirus disease 2019 (COVID-19) are still urgently needed, most current testing methods are long, costly or poorly specific. The objective of the present study was to determine whether or not artificial-intelligence-enhanced real-time mass spectrometry breath analysis is a reliable, safe, rapid means of screening ambulatory patients for COVID-19. Methods: In two prospective, open, interventional studies in a single university hospital, we used real-time, proton transfer reaction time-of-flight mass spectrometry to perform a metabolomic analysis of exhaled breath from adults requiring screening for COVID-19. Artificial intelligence and machine learning techniques were used to build mathematical models based on breath analysis data either alone or combined with patient metadata. Results: We obtained breath samples from 173 participants, of whom 67 had proven COVID-19. After using machine learning algorithms to process breath analysis data and further enhancing the model using patient metadata, our method was able to differentiate between COVID-19-positive and -negative participants with a sensitivity of 98%, a specificity of 74%, a negative predictive value of 98%, a positive predictive value of 72% and an area under the receiver operating characteristic curve of 0.961. The predictive performance was similar for asymptomatic, weakly symptomatic and symptomatic participants and was not biased by COVID-19 vaccination status. Conclusions: Real-time, noninvasive, artificial-intelligence-enhanced mass spectrometry breath analysis might be a reliable, safe, rapid, cost-effective, high-throughput method for COVID-19 screening.

Development and validation of an electronic daily control score for asthma (e-DASTHMA): a real-world direct patient data study.

BACKGROUND: Validated questionnaires are used to assess asthma control over the past 1-4 weeks from reporting. However, they do not adequately capture asthma control in patients with fluctuating symptoms. Using the Mobile Airways Sentinel Network for airway diseases (MASK-air) app, we developed and validated an electronic daily asthma control score (e-DASTHMA). METHODS: We used MASK-air data (freely available to users in 27 countries) to develop and assess different daily control scores for asthma. Data-driven control scores were developed based on asthma symptoms reported by a visual analogue scale (VAS) and self-reported asthma medication use. We included the daily monitoring data from all MASK-air users aged 16-90 years (or older than 13 years to 90 years in countries with a lower age of digital consent) who had used the app in at least 3 different calendar months and had reported at least 1 day of asthma medication use. For each score, we assessed construct validity, test-retest reliability, responsiveness, and accuracy. We used VASs on dyspnoea and work disturbance, EQ-5D-VAS, Control of Allergic Rhinitis and Asthma Test (CARAT), CARAT asthma, and Work Productivity and Activity Impairment: Allergy Specific (WPAI:AS) questionnaires as comparators. We performed an internal validation using MASK-air data from Jan 1 to Oct 12, 2022, and an external validation using a cohort of patients with physician-diagnosed asthma (the INSPIRERS cohort) who had had their diagnosis and control (Global Initiative for Asthma [GINA] classification) of asthma ascertained by a physician. FINDINGS: We studied 135 635 days of MASK-air data from 1662 users from May 21, 2015, to Dec 31, 2021. The scores were strongly correlated with VAS dyspnoea (Spearman correlation coefficient range 0·68-0·82) and moderately correlated with work comparators and quality-of-life-related comparators (for WPAI:AS work, we observed Spearman correlation coefficients of 0·59-0·68). They also displayed high test-retest reliability (intraclass correlation coefficients range 0·79-0·95) and moderate-to-high responsiveness (correlation coefficient range 0·69-0·79; effect size measures range 0·57-0·99 in the comparison with VAS dyspnoea). The best-performing score displayed a strong correlation with the effect of asthma on work and school activities in the INSPIRERS cohort (Spearman correlation coefficients 0·70; 95% CI 0·61-0·78) and good accuracy for the identification of patients with uncontrolled or partly controlled asthma according to GINA (area under the receiver operating curve 0·73; 95% CI 0·68-0·78). INTERPRETATION: e-DASTHMA is a good tool for the daily assessment of asthma control. This tool can be used as an endpoint in clinical trials as well as in clinical practice to assess fluctuations in asthma control and guide treatment optimisation. FUNDING: None.

Adherence and persistence in allergen immunotherapy (APAIT): A reporting checklist for retrospective studies.

BACKGROUND: Adherence is essential for the long-term efficacy of allergen immunotherapy (AIT) and has been evaluated in numerous retrospective studies. However, there are no published guidelines for best practice in measuring and reporting adherence or persistence to AIT, which has resulted in substantial heterogeneity among existing studies. The 'adherence and persistence in AIT (APAIT)' checklist has been developed to guide the reporting, design and interpretation of retrospective studies that evaluate adherence or persistence to AIT in clinical practice. METHODS: Five existing checklists, focussing on study protocol design, the use of retrospective databases/patient registries, and the appraisal and reporting of observational studies, were identified and merged. Relevant items were selected and tailored to be specific to AIT. The content of the checklist was discussed by 11 experts from Europe, the United States and Canada, representing allergy, healthcare and life sciences, and health technology appraisal. RESULTS: The APAIT checklist presents a set of items that should either be included or at least considered, when reporting retrospective studies that assess adherence or persistence to AIT. Items are organized into four categories comprising study objective, design and methods, data analysis, and results and discussion. The checklist highlights the need for clarity and transparency in reporting and emphasizes the importance of considering potential sources of bias in retrospective studies evaluating adherence or persistence to AIT. CONCLUSIONS: The APAIT checklist provides a pragmatic guide for reporting retrospective adherence and persistence studies in AIT. Importantly, it identifies potential sources of bias and discusses how these influence outcomes.

Assessment of an e-nose performance for the detection of COVID-19 specific biomarkers.

Early, rapid and non-invasive diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is needed for the prevention and control of coronavirus disease 2019 (COVID-19). COVID-19 mainly affects the respiratory tract and lungs. Therefore, analysis of exhaled breath could be an alternative scalable method for reliable SARS-CoV-2 screening. In the current study, an experimental protocol using an electronic-nose ('e-nose') for attempting to identify a specific respiratory imprint in COVID-19 patients was optimized. Thus the analytical performances of the Cyranose®, a commercial e-nose device, were characterized under various controlled conditions. In addition, the effect of various experimental conditions on its sensor array response was assessed, including relative humidity, sampling time and flow rate, aiming to select the optimal parameters. A statistical data analysis was applied to e-nose sensor response using common statistical analysis algorithms in an attempt to demonstrate the possibility to detect the presence of low concentrations of spiked acetone and nonanal in the breath samples of a healthy volunteer. Cyranose®reveals a possible detection of low concentrations of these two compounds, in particular of 25 ppm nonanal, a possible marker of SARS-CoV-2 in the breath.

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.

Therapeutic drug monitoring of corticosteroids/ß2-agonists in the hair of patients with asthma: an open-label feasibility study.

Background: Although adherence to inhaled medication is critically important for treatment efficiency, around half of patients taking these drugs are non-adherent or make critical errors when using their delivery device. Segmental hair analysis might be a valuable tool for therapeutic monitoring because hair concentrations reflect exposure from month to month. The objective of the present proof-of-concept study was to establish the feasibility of segmental hair analysis of inhaled budesonide and formoterol in asthma patients. Methods: We conducted a prospective, open-label, interventional study of adult patients being treated with budesonide/formoterol for controlled, moderate-to-severe asthma (CorticHair, NCT03691961). Asthma control, lung function, and medication adherence were recorded. Hair samples were taken 4 months after enrolment and cut into four 1 cm segments. Results: Samples were available from 21 patients (20 women; median age: 53; median budesonide dose: 600 µg/d). Budesonide and formoterol were detected in samples from 18 to 13 patients, respectively. The median hair concentrations were 6.25 pg/mg for budesonide and 0.9 pg/mg for formoterol. The intrapatient coefficient of variation between hair segments was 21% for budesonide and 40% for formoterol. Pearson's coefficients for the correlations between the hair concentration and the self-reported drug dose and the prescribed drug dose were respectively 0.42 (p = 0.08) and 0.29 (p = 0.25) for budesonide and 0.24 (p = 0.44) and 0.17 (p = 0.57) for formoterol. Conclusion: Segmental hair analysis of inhaled medications was feasible, with low intrapatient variability. This innovative, non-invasive means of assessing monthly drug exposure might help physicians to personalize drug regimens for patients with difficult-to-treat asthma.

Real-world data using mHealth apps in rhinitis, rhinosinusitis and their multimorbidities.

Digital health is an umbrella term which encompasses eHealth and benefits from areas such as advanced computer sciences. eHealth includes mHealth apps, which offer the potential to redesign aspects of healthcare delivery. The capacity of apps to collect large amounts of longitudinal, real-time, real-world data enables the progression of biomedical knowledge. Apps for rhinitis and rhinosinusitis were searched for in the Google Play and Apple App stores, via an automatic market research tool recently developed using JavaScript. Over 1500 apps for allergic rhinitis and rhinosinusitis were identified, some dealing with multimorbidity. However, only six apps for rhinitis (AirRater, AllergyMonitor, AllerSearch, Husteblume, MASK-air and Pollen App) and one for rhinosinusitis (Galenus Health) have so far published results in the scientific literature. These apps were reviewed for their validation, discovery of novel allergy phenotypes, optimisation of identifying the pollen season, novel approaches in diagnosis and management (pharmacotherapy and allergen immunotherapy) as well as adherence to treatment. Published evidence demonstrates the potential of mobile health apps to advance in the characterisation, diagnosis and management of rhinitis and rhinosinusitis patients.