Sublingual immunotherapy provides long-term relief in allergic rhinitis and reduces the risk of asthma: A retrospective, real-world database analysis.

BACKGROUND: Allergy immunotherapy (AIT) is the only treatment for allergic rhinitis (AR) and/or allergic asthma (AA) with long-term efficacy. However, there are few real-life data on the progression of AR and/or AA in patients receiving AIT. OBJECTIVES: To assess the real-world, long-term efficacy of grass pollen sublingual immunotherapy (SLIT) tablets in AR and their impact on asthma onset and progression. METHODS: In a retrospective analysis of a German longitudinal prescription database, AR patients treated with grass pollen SLIT tablets were compared with a control group not having received AIT. Multiple regression analysis was used to compare changes over time in rescue symptomatic AR medication use after treatment cessation, asthma medication use, and the time to asthma onset in the two groups. RESULTS: After applying all selection criteria, 2851 SLIT and 71 275 control patients were selected for the study. After treatment cessation, AR medication use was 18.8 percentage points lower (after adjustment for covariates, and relative to the pretreatment period) in SLIT tablet group than in the non-AIT group (P<.001). Asthma onset was less frequent in SLIT tablet group than in non-AIT group (odds ratio: 0.696, P=.002), and time to asthma was significantly longer (hazard ratio: 0.523; P=.003). After SLIT cessation, asthma medication use fell by an additional 16.7 percentage points (relative to the pretreatment period) in the SLIT tablet group vs the non-AIT group (P=.004). CONCLUSIONS: Real-world treatment of AR patients with grass pollen SLIT tablets was associated with slower AR progression, less frequent asthma onset, and slower asthma progression.

Treatment of allergic rhinitis using mobile technology with real-world data: The MASK observational pilot study.

BACKGROUND: Large observational implementation studies are needed to triangulate the findings from randomized control trials as they reflect "real-world" everyday practice. In a pilot study, we attempted to provide additional and complementary insights on the real-life treatment of allergic rhinitis (AR) using mobile technology. METHODS: A mobile phone app (Allergy Diary, freely available in Google Play and Apple App stores) collects the data of daily visual analog scales (VAS) for (i) overall allergic symptoms, (ii) nasal, ocular, and asthma symptoms, (iii) work, as well as (iv) medication use using a treatment scroll list including all medications (prescribed and over the counter (OTC)) for rhinitis customized for 15 countries. RESULTS: A total of 2871 users filled in 17 091 days of VAS in 2015 and 2016. Medications were reported for 9634 days. The assessment of days appeared to be more informative than the course of the treatment as, in real life, patients do not necessarily use treatment on a daily basis; rather, they appear to increase treatment use with the loss of symptom control. The Allergy Diary allowed differentiation between treatments within or between classes (intranasal corticosteroid use containing medications and oral H1-antihistamines). The control of days differed between no [best control], single, or multiple treatments (worst control). CONCLUSIONS: This study confirms the usefulness of the Allergy Diary in accessing and assessing everyday use and practice in AR. This pilot observational study uses a very simple assessment (VAS) on a mobile phone, shows novel findings, and generates new hypotheses.

Daily allergic multimorbidity in rhinitis using mobile technology: A novel concept of the MASK study.

BACKGROUND: Multimorbidity in allergic airway diseases is well known, but no data exist about the daily dynamics of symptoms and their impact on work. To better understand this, we aimed to assess the presence and control of daily allergic multimorbidity (asthma, conjunctivitis, rhinitis) and its impact on work productivity using a mobile technology, the Allergy Diary. METHODS: We undertook a 1-year prospective observational study in which 4 210 users and 32 585 days were monitored in 19 countries. Five visual analogue scales (VAS) assessed the daily burden of the disease (i.e., global evaluation, nose, eyes, asthma and work). Visual analogue scale levels <20/100 were categorized as "Low" burden and VAS levels ≥50/100 as "High" burden. RESULTS: Visual analogue scales global measured levels assessing the global control of the allergic disease were significantly associated with allergic multimorbidity. Eight hypothesis-driven patterns were defined based on "Low" and "High" VAS levels. There were <0.2% days of Rhinitis Low and Asthma High or Conjunctivitis High patterns. There were 5.9% days with a Rhinitis High-Asthma Low pattern. There were 1.7% days with a Rhinitis High-Asthma High-Conjunctivitis Low pattern. A novel Rhinitis High-Asthma High-Conjunctivitis High pattern was identified in 2.9% days and had the greatest impact on uncontrolled VAS global measured and impaired work productivity. Work productivity was significantly correlated with VAS global measured levels. CONCLUSIONS: In a novel approach examining daily symptoms with mobile technology, we found considerable intra-individual variability of allergic multimorbidity including a previously unrecognized extreme pattern of uncontrolled multimorbidity.

The Allergic Rhinitis and its Impact on Asthma (ARIA) score of allergic rhinitis using mobile technology correlates with quality of life: The MASK study.

Mobile technology has been used to appraise allergic rhinitis control, but more data are needed. To better assess the importance of mobile technologies in rhinitis control, the ARIA (Allergic Rhinitis and its Impact on Asthma) score ranging from 0 to 4 of the Allergy Diary was compared with EQ-5D (EuroQuol) and WPAI-AS (Work Productivity and Activity Impairment in allergy) in 1288 users in 18 countries. This study showed that quality-of-life data (EQ-5D visual analogue scale and WPA-IS Question 9) are similar in users without rhinitis and in those with mild rhinitis (scores 0-2). Users with a score of 3 or 4 had a significant impairment in quality-of-life questionnaires.

Comparison of scores associating symptoms and rescue medication use for evaluating the efficacy of allergy immunotherapy in seasonal allergic rhinoconjunctivitis: results from five trials.

BACKGROUND: Over the past decade, regulatory bodies and scientific societies recommended, as primary efficacy outcome, a score that reflects both symptom severity and use of rescue medication for clinical trials in allergy immunotherapy (AIT). OBJECTIVE: We sought to compare the results obtained with two subject-specific scores, the Combined Score (CS) and the Adjusted Symptom Score (AdSS), for assessment of AIT in seasonal allergic rhinoconjunctivitis due to birch and grass pollen allergens. METHODS: CS and AdSS were evaluated in subjects receiving a 300IR dose of allergen extract daily, by sublingual route, in four clinical trials with the 5-grass pollen tablet (NCT00367640, NCT00409409, NCT00955825 and NCT00418379) and one with the birch pollen solution (NCT01731249). The CS is derived from the Rhinoconjunctivitis Total Symptom Score (RTSS) and the Rescue Medication Score (RMS) giving equal weight to symptoms and medication use. The AdSS is a symptom score adjusting for rescue medication use. Efficacy end-points were analysed using an analysis of covariance linear model. RESULTS: In all trials, despite the different constructs of the two scores, Combined Score or Adjusted Symptom Score were similarly reduced in the 300IR group compared to the placebo group. Treatment effect was consistently demonstrated with both scores, CS and AdSS, used as either daily scores or average of the daily scores over the pollen season. Minor differences with the same statistical conclusions were observed between the results, leading to the same interpretation. CONCLUSIONS AND CLINICAL RELEVANCE: The two scores, combined and adjusted scores, for evaluation of clinical efficacy of AIT have led to similar results, with similar statistical conclusions and similar interpretation.

Allergen exposure chambers: harmonizing current concepts and projecting the needs for the future - an EAACI Position Paper.

BACKGROUND: Allergen exposure chambers (AECs) are clinical facilities allowing for controlled exposure of subjects to allergens in an enclosed environment. AECs have contributed towards characterizing the pathophysiology of respiratory allergic diseases and the pharmacological properties of new therapies. In addition, they are complementary to and offer some advantages over traditional multicentre field trials for evaluation of novel therapeutics. To date, AEC studies conducted have been monocentric and have followed protocols unique to each centre. Because there are technical differences among AECs, it may be necessary to define parameters to standardize the AECs so that studies may be extrapolated for driving basic immunological research and for marketing authorization purposes by regulatory authorities. METHODS: For this task force initiative of the European Academy of Allergy and Clinical Immunology (EAACI), experts from academia and regulatory agencies met with chamber operators to list technical, clinical and regulatory unmet needs as well as the prerequisites for clinical validation. RESULTS: The latter covered the validation process, standardization of challenges and outcomes, intra- and interchamber variability and reproducibility, in addition to comparability with field trials and specifics of paediatric trials and regulatory issues. CONCLUSION: This EAACI Position Paper aims to harmonize current concepts in AECs and to project unmet needs with the intent to enhance progress towards use of these facilities in determining safety and efficacy of new therapeutics in the future.

Pilot study of mobile phone technology in allergic rhinitis in European countries: the MASK-rhinitis study.

BACKGROUND: The use of Apps running on smartphones and tablets profoundly affects medicine. The MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) App (Allergy Diary) assesses allergic rhinitis symptoms, disease control and impact on patients' lives. It is freely available in 20 countries (iOS and Android platforms). AIMS: To assess in a pilot study whether (i) Allergy Diary users were able to properly provide baseline characteristics (ii) simple phenotypic characteristics based upon data captured by the Allergy Diary could be identified and (iii) information gathered by this study could suggest novel research questions. METHODS: The Allergy Diary users were classified into six groups according to the baseline data that they entered into the App: (i) asymptomatic; (ii) nasal symptoms excluding rhinorrhea; (iii) rhinorrhea; (iv) rhinorrhea plus 1-2 nasal/ocular symptoms; (v) rhinorrhea plus ≥3 nasal/ocular symptoms; and (vi) rhinorrhea plus all nasal/ocular symptoms. RESULTS: By 1 June 2016, 3260 users had registered with the Allergy Diary and 2710 had completed the baseline questionnaire. Troublesome symptoms were found mainly in the users with the most symptoms. Around 50% of users with troublesome rhinitis and/or ocular symptoms suffered work impairment. Sleep was impaired by troublesome symptoms and nasal obstruction. CONCLUSIONS: This is the first App (iOS and Android) to have tested for allergic rhinitis and conjunctivitis. A simple questionnaire administered by cell phones enables the identification of phenotypic differences between a priori defined rhinitis groups. The results suggest novel concepts and research questions in allergic rhinitis that may not be identified using classical methods.

Work productivity in rhinitis using cell phones: The MASK pilot study.

Allergic rhinitis often impairs social life and performance. The aim of this cross-sectional study was to use cell phone data to assess the impact on work productivity of uncontrolled rhinitis assessed by visual analogue scale (VAS). A mobile phone app (Allergy Diary, Google Play Store and Apple App Store) collects data from daily visual analogue scales (VAS) for overall allergic symptoms (VAS-global measured), nasal (VAS-nasal), ocular (VAS-ocular) and asthma symptoms (VAS-asthma) as well as work (VAS-work). A combined nasal-ocular score is calculated. The Allergy Diary is available in 21 countries. The app includes the Work Productivity and Activity Impairment Allergic Specific Questionnaire (WPAI:AS) in six EU countries. All consecutive users who completed the VAS-work from 1 June to 31 October 2016 were included in the study. A total of 1136 users filled in 5818 days of VAS-work. Symptoms of allergic rhinitis were controlled (VAS-global <20) in approximately 60% of the days. In users with uncontrolled rhinitis, approximately 90% had some work impairment and over 50% had severe work impairment (VAS-work >50). There was a significant correlation between VAS-global calculated and VAS-work (Rho=0.83, P<0.00001, Spearman's rank test). In 144 users, there was a significant correlation between VAS-work and WPAI:AS (Rho=0.53, P<0.0001). This pilot study provides not only proof-of-concept data on the work impairment collected with the app but also data on the app itself, especially the distribution of responses for the VAS. This supports the interpretation that persons with rhinitis report both the presence and the absence of symptoms.

In allergic rhinitis, work, classroom and activity impairments are weakly related to other outcome measures.

BACKGROUND: The impact of grass pollen-induced allergic rhinitis (AR) on classroom/work productivity and activities can be assessed with a specific instrument: the Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questions: Allergy Specific (WPAI-AS). This study evaluated the relationships between the WPAI-AS and other outcome measures in AR. METHODS: Adolescents (aged 12-17) and adults (aged 18-65) consulting specialists for AR were enrolled in a four-week, multicentre, observational study. The management of AR was left to the physicians' discretion. Participants regularly rated the WPAI-AS, their symptoms (using the Rhinoconjunctivitis Total Symptom Score (RTSS) and a 0- to 100-mm visual analogue scale (VAS)) and quality of life (according to the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ)). RESULTS: A total of 247 adolescents and 292 adults showed similar baseline impairments in classroom/work productivity and activities other than work. In both age groups, the WPAI-AS scores were moderately correlated with the RQLQ score and, to a lesser extent, with the VAS score and the RTSS. A multiple regression analysis indicated that the RQLQ score was a weak but statistically significant predictor of both impaired work/classroom productivity and daily activities. A 50-mm VAS cut-off categorized patients in whom AR had the greatest impact on productivity. CONCLUSIONS: Grass pollen-induced AR impairs work/classroom and daily activity to a similar extent in adults and adolescents. The weak-to-moderate correlations with AR symptom scores and quality-of-life scores suggest that a specific tool (such as the WPAI-AS) should be used to assess AR's impact on word/classroom productivity and daily activities.

House dust mite sublingual immunotherapy is safe in patients with mild-to-moderate, persistent asthma: a clinical trial.

BACKGROUND: The safety of allergen immunotherapy (AIT) in asthma has not always been sufficiently documented; accordingly, fear of asthma exacerbations has made physicians somewhat reluctant to prescribe AIT in this context. In a double-blind, placebo-controlled, randomized clinical trial, house dust mite (HDM) sublingual AIT was found to be efficacious in moderate, persistent asthma. The trial's safety results are now reported in detail. METHODS: Asthmatic adults were randomized 2 : 1 to twelve months of daily treatment with a sublingual solution of Dermatophagoides pteronyssinus and Dermatophagoides farinae extracts or a placebo. Adverse events (AEs) at least possibly related to the investigational product were classified by the investigators as adverse drug reactions (ADRs). RESULTS: Overall, the patients in the safety analysis set (n = 484; active treatment: n = 322; placebo: n = 162) had mostly well-controlled, persistent asthma [mild in 290 patients (59.9%), moderate in 183 (37.8%) and severe in 11 (2.3%)]. No treatment-related serious AEs were reported. A total of 87.0% and 75.9% of the patients in the active and placebo groups, respectively, experienced at least one AE (mostly mild), and 78.9% and 48.1% experienced an ADR (mostly mild or moderate oral reactions). The incidence of asthma exacerbations (symptoms requiring a short course of oral corticosteroids) during the study was similar in the active treatment group (3.7%) and the placebo group (4.3%). There were no significant intergroup differences or intragroup changes over time in respiratory AEs, lung function or asthma-related quality of life. CONCLUSIONS: HDM sublingual AIT was safe and well tolerated in adult patients with mild-to-moderate, persistent asthma (ClinicalTrials.gov: NCT00660452).

Prevalence and reversibility of lung hyperinflation in adult asthmatics with poorly controlled disease or significant dyspnea.

BACKGROUND: In asthma, inflammation affects both the proximal and distal airways and may induce significant hyperinflation (HI). This study sought to evaluate the prevalence of HI in asthmatic patients with poorly controlled disease and/or dyspnea. METHODS: Poor asthma control was defined by an Asthma Control Test (ACT) score <20 (n = 287), and dyspnea was defined as a modified Medical Research Council score ≥1 (n = 18). HI was defined as either a residual volume/total lung capacity (RV/TLC) above the upper limit of normal (RV-HI) or a functional residual capacity (FRC) >120% predicted (FRC-HI). HI reversibility after administration of salbutamol (400 µg) was defined as a decrease in RV >20% or a reduction in FRC >10%. Changes in dyspnea and chest tightness were evaluated on a visual analogue scale. RESULTS: Both RV-HI and FRC-HI were observed in 48% of the 305 patients (mean ± SD age: 49 ± 17; FEV1 : 75 ± 18% predicted) included in the study. The prevalence of HI was higher in patients with a FEV1 <60% predicted (93% for RV-HI and 71% for FRC-HI, vs 21% and 41% in patients with a FEV1 > 80%). In patients with HI, the ACT score was lower and chest tightness higher. HI reversibility was obtained in 38% of the asthmatics with FRC-HI and 29% of the asthmatics with RV-HI, whereas FEV1 reversibility was obtained in half of these patients. CONCLUSIONS: HI is highly prevalent in poorly controlled asthmatics suggesting small airway dysfunction and may represent an additional criteria for evaluating responsiveness to bronchodilators.

House dust mite sublingual immunotherapy is safe and appears to be effective in moderate, persistent asthma.

BACKGROUND: The efficacy and safety of sublingual immunotherapy in house dust mite-induced asthma have yet to be firmly established. We report the results of a double-blind, placebo-controlled, randomized clinical trial performed in mainland China. METHODS: After a three-month baseline period, 484 asthmatic adults were randomized 2 : 1 to 12 months of daily treatment with either an aqueous, standardized, 300 index of reactivity mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae extracts or a placebo. The primary efficacy criterion was well-controlled asthma for at least 16 of the last 20 weeks of treatment. RESULTS: In the active (n = 308) and placebo (n = 157) groups, well-controlled asthma was achieved by 85.4% and 81.5% of the patients, respectively (P = 0.244). A subsequent post hoc analysis by asthma severity revealed significant clinical benefits in actively treated subjects with moderate, persistent asthma at baseline [401-800 µg budesonide/day (n = 175)], with greater achievement of well-controlled asthma (80.5% and 66.1% for the active treatment and placebo groups, respectively; P = 0.021) and totally controlled asthma (54.0% and 33.9%, respectively, P = 0.008), a higher percentage of patients with an asthma control questionnaire score < 0.75 (56.6% and 40.0%, respectively; P = 0.039) and a greater mean reduction in inhaled corticosteroid use (218.5 µg and 126.2 µg, respectively; P = 0.004). The active vs placebo differences in disease control and corticosteroid use were not significant for mild, persistent asthma. No treatment-related serious adverse events were reported. CONCLUSIONS: Sublingual mite allergen immunotherapy was well tolerated in adult asthmatics and effectively controlled disease in patients with moderate (but not mild) persistent asthma (ClinicalTrials.gov: NCT00660452).

The minimally important difference in the Rhinoconjunctivitis Total Symptom Score in grass-pollen-induced allergic rhinoconjunctivitis.

BACKGROUND: The minimally important difference (MID) has been defined as the smallest improvement considered worthwhile by a patient. The MID has not been estimated for the Rhinoconjunctivitis Total Symptom Score (RTSS). METHODS: In a prospective multicentre study, patients consulting for grass-pollen-induced allergic rhinitis (AR) recorded a 15-point global rating of change scale (GRCS) score and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score on a weekly basis and the individual symptom scores comprising the RTSS on a daily basis over two consecutive weeks. The MID in the RTSS was determined with anchor-based methods (using the GRCS and the RQLQ) and a distribution-based method [based on the RTSS' standard deviation (SD)]. RESULTS: The study population comprised 806 patients (253 children, 250 adolescents and 303 adults). During the first week of the study, the mean ± SD RTSSs for these age groups were 6.5 ± 3.3, 6.8 ± 3.4 and 7.0 ± 3.4, respectively. For an improvement of 2 points in the GRCS or 0.5 points in the RQLQ score, the regression analysis yielded MIDs in the RTSS of 1.24 ± 0.17 and 1.12 ± 0.14 in children, 1.33 ± 0.14 and 1.20 ± 0.13 in adolescents and 1.13 ± 0.14 and 0.89 ± 0.12 in adults, respectively. When applying distribution-based methods, the MID ranged from 1.09 to 1.13 (based on 0.33 SDs of the first-week RTSS) and from 1.22 to 1.40 (based on 0.5 SDs of the difference in RTSSs between the first and second weeks). CONCLUSION: The MID in the RTSS was consistently estimated as 1.1-1.3 (and could conceivably be rounded to 1) in patients with grass-pollen-induced AR.

Visual analogue scale in patients treated for allergic rhinitis: an observational prospective study in primary care: asthma and rhinitis.

BACKGROUND: Allergic rhinitis (AR) severity is evaluated using scores such as Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ) and total symptom score (TSS). However, a simple assessment is needed to enable physicians to evaluate the severity of the AR and the efficacy of the treatment. OBJECTIVE: The main objective was to validate visual analogue scale (VAS) as a simple quantitative tool to assess the burden of AR in primary care. METHODS: The study was multi-centre prospective observational conducted in patients consulting general practitioners for symptomatic rhinitis. VAS, RQLQ and TSS6 were assessed at the consultation day and 14 days later, and changes were analysed using paired test. Correlations between VAS, RQLQ and TSS6 were assessed. Cut-off levels for VAS, which discriminate significant from insignificant changes, were established using Receiver Operating Characteristic curves. RESULTS: A total of 990 patients were included in the study. According to allergic rhinitis and its impact on asthma classification, mild intermittent rhinitis was diagnosed in 20% patients, mild persistent in 17%, moderate/severe intermittent in 15% and moderate/severe persistent in 48%, at the consultation day. At day-14, rhinitis symptoms and QoL improved significantly in almost all patients. Impairment incurred by AR and assessed with VAS improved also. The established cut-off variation of 23 mm for VAS was associated with a cut-off variation of 0.5 for RQLQ. Sensitivity analysis with RQLQ and TSS6 scales confirmed the aptitude of the cut-off value (23 mm) to discriminate changes in symptoms and QoL. CONCLUSION AND CLINICAL RELEVANCE: The VAS can detect with high sensitivity the variations of symptoms and QoL in patients with AR.

TNF-α-induced CXCL8 production by A549 cells: involvement of the non-neuronal cholinergic system.

It was recently suggested that the non-neuronal cholinergic system has a regulatory role in pulmonary inflammation. We investigated this system's involvement in the control of cytokine production by the A549 human alveolar epithelial cell line. CXCL8 and acetylcholine (ACh) concentrations were measured using ELISA and LC-MS/MS, respectively. The mRNA expression of muscarinic receptor (MR) subtypes was determined using RT-PCR. In A549 cells, TNF-α increased the release of CXCL8 and ACh and the expression of the subtype 3 MR (M3R). Furthermore, TNF-α-induced CXCL8 secretion was (i) inhibited by the MR antagonist tiotropium and the M3R antagonist 4-DAMP and (ii) enhanced by the M1/M3R agonist pilocarpine and the cholinesterase inhibitor physostigmine. Taken as a whole, these results suggest that ACh release by A549 cells enhances TNF-α-induced CXCL8 secretion through activation of the M3R. Western blot analysis revealed that pilocarpine and physostigmine enhanced the TNF-α-induced phosphorylation of ERK1/2 and p38 MAPK and the degradation of IκBα. Inhibition of these pathways with specific inhibitors abrogated the pilocarpine-induced CXCL8 release. Our results suggest that the TNF-α-induced secretion of CXCL8 in A549 cells is regulated by the release of ACh, the latter's binding to the M3R and the downstream activation of NF-κB and the ERK1/2 and p38 MAPK signaling pathways. Our findings suggest that MR antagonists may have anti-inflammatory effects by preventing pro-inflammatory events driven by endogenous, non-neuronal ACh.

Population pharmacokinetics of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Interest in antifibrinolytic tranexamic acid (TA) has grown since the widespread removal of aprotinin, but its dosing during cardiac surgery is still debated. The objectives of this study were to investigate the population pharmacokinetics (PK) of TA given with either low- or high-dose continuous infusion schemes in adult cardiac surgery patients during cardiopulmonary bypass (CPB). METHODS: Patients were randomized to receive either low-dose (10 mg kg(-1) followed by an infusion of 1 mg kg(-1) h(-1) throughout the operation, and 1 mg kg(-1) into the CPB) or high-dose (30 mg kg(-1), then 16 mg kg(-1) h(-1), and 2 mg kg(-1) into the CPB) TA. Serum TA concentrations were measured in 61 patients and the data were modelled using Monolix. RESULTS: TA concentrations were 28-55 µg ml(-1) in the low-dose group and 114-209 µg ml(-1) in the high-dose group throughout surgery. TA PK was best described by a two-compartment open model. The main covariate effect was bodyweight, whereas the CPB did not influence the PK. Assuming a bodyweight of 70 kg, the population estimates were 4.8 litre h(-1) for clearance, 6.6 litre for the volume of the central compartment, 32.2 litre h(-1) for the diffusional clearance, and the peripheral volume of distribution was 10.8 litre. CONCLUSIONS: The PK of TA was satisfactorily described by an open two-compartmental model, which was used to propose a dosing scheme suitable for obtaining and maintaining the desired plasma concentration in a stable and narrow range in cardiac surgery patients.

Identification by cluster analysis of patients with asthma and nasal symptoms using the MASK-air® mHealth app.

BACKGROUND: The self-reporting of asthma frequently leads to patient misidentification in epidemiological studies. Strategies combining the triangulation of data sources may help to improve the identification of people with asthma. We aimed to combine information from the self-reporting of asthma, medication use and symptoms to identify asthma patterns in the users of an mHealth app. METHODS: We studied MASK-air® users who reported their daily asthma symptoms (assessed by a 0-100 visual analogue scale - "VAS Asthma") at least three times (either in three different months or in any period). K-means cluster analysis methods were applied to identify asthma patterns based on: (i) whether the user self-reported asthma; (ii) whether the user reported asthma medication use and (iii) VAS asthma. Clusters were compared by the number of medications used, VAS asthma levels and Control of Asthma and Allergic Rhinitis Test (CARAT) levels. FINDINGS: We assessed a total of 8,075 MASK-air® users. The main clustering approach resulted in the identification of seven groups. These groups were interpreted as probable: (i) severe/uncontrolled asthma despite treatment (11.9-16.1% of MASK-air® users); (ii) treated and partly-controlled asthma (6.3-9.7%); (iii) treated and controlled asthma (4.6-5.5%); (iv) untreated uncontrolled asthma (18.2-20.5%); (v) untreated partly-controlled asthma (10.1-10.7%); (vi) untreated controlled asthma (6.7-8.5%) and (vii) no evidence of asthma (33.0-40.2%). This classification was validated in a study of 192 patients enrolled by physicians. INTERPRETATION: We identified seven profiles based on the probability of having asthma and on its level of control. mHealth tools are hypothesis-generating and complement classical epidemiological approaches in identifying patients with asthma.

Analysis of allergen immunotherapy studies shows increased clinical efficacy in highly symptomatic patients.

BACKGROUND: The assessment of allergen immunotherapy (AIT) efficacy in the treatment for seasonal allergic rhinoconjunctivitis (SAR) symptoms is challenging. Allergen immunotherapy differs from symptomatic therapy in that while symptomatic therapy treats patients after symptoms appear and aims to reduce symptoms, AIT is administered before symptoms are present and aims to prevent them. Thus, clinical studies of AIT can neither establish baseline symptom levels nor limit the enrolment of patients to those with the most severe symptoms. Allergen immunotherapy treatment effects are therefore diluted by patients with low symptoms for a particular pollen season. The objective of this analysis was to assess the effect possible to achieve with AIT in the groups of patients presenting the most severe allergic symptoms. METHODS: Study centres were grouped into tertiles categorized according to symptom severity scores observed in the placebo patients in each centre (low, middle and high tertiles). The difference observed in the average score in each tertile in active vs placebo-treated patients was assessed. This allowed an estimation of the efficacy that could be achieved in patients from sites where symptoms were high during the pollen season. RESULTS: An increased treatment effect was observed in the most severe patients and was independent of the study analysed and symptom score used. CONCLUSIONS: The use of a tertile approach to analyse efficacy in AIT in SAR clinical studies can give a more accurate assessment of potential clinical benefit.

[Take-home messages from the COPD 2021 biennial of the French Society of Respiratory Diseases. Understanding to so as to better innovate]. / Principaux messages de la première Biennale BPCO 2021 de la SPLF. Mieux comprendre pour innover.

INTRODUCTION: The first COPD biennial organized by the French Society of Respiratory Diseases (SPLF) took place on 17 December 2021. STATE OF THE ART: The objective of the biennial was to discuss current knowledge regarding COPD pathophysiology, current treatments, research development, and future therapeutic approaches. PERSPECTIVES: The different lecturers laid emphasis on the complexity of pathophysiologic mechanisms including bronchial, bronchiolar and parenchymal alterations, and also dwelt on the role of microbiota composition in COPD pathenogenesis. They pointed out that addition to inhaled treatments, ventilatory support and endoscopic approaches have been increasingly optimized. The development of new therapeutic pathways such as biotherapy and cell therapy (stem cells…) call for further exploration. CONCLUSIONS: The dynamism of COPD research was repeatedly underlined, and needs to be further reinforced, the objective being to "understand so as to better innovate" so as to develop effective new strategies for treatment and management of COPD.

The average Adjusted Symptom Score, a new primary efficacy end-point for specific allergen immunotherapy trials.

BACKGROUND: In clinical trials, the efficacy of immunotherapy for allergic rhinoconjunctivitis symptoms is often evaluated with the average Rhinoconjunctivitis Total Symptom Score (ARTSS). Effective treatment is associated with a lower ARTSS vs. placebo but use of rescue medication to alleviate symptoms reduces the RTSS and decreases the mean difference between active treatment and placebo groups. OBJECTIVE: To develop and describe the average Adjusted Symptom Score (AdSS), a new end-point reflecting symptom severity and rescue medication use in allergic rhinoconjunctivitis trials. METHODS: To calculate the AdSS, the RTSS is adjusted as follows: if a patient takes rescue medication on day d, the day's AdSS (AdSS(d)) is defined as the value of RTSS(d) or AdSS(d-1), whichever is higher. The AdSS on the following day (AdSS(d+1)) is defined as the value of RTSS(d+1) or AdSS(d), whichever is higher. The average of the daily AdSSs (during the season) was calculated post hoc for two trials investigating the efficacy of five-grass pollen sublingual immunotherapy tablets in adult and paediatric patients and compared with the ARTSS and three other outcome measures (the average Rescue Medication Score (ARMS), the ARTSS and the average Combined Score). RESULTS: The average AdSS clearly discriminated between active and placebo treatments and confirmed the original ARTSS results. Adjustment for rescue medication use decreased the observed placebo effect. CONCLUSION AND CLINICAL RELEVANCE: The average AdSS can be a valuable alternative to the ARTSS as a primary efficacy end-point in grass pollen allergic rhinoconjunctivitis trials. By adjusting the RTSS for rescue medication use, the AdSS can estimate symptom severity and the treatment effect more accurately. The AdSS is now being tested prospectively in large clinical trials.