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RATIONALE: There is no consensus on criteria to include in an asthma remission definition in real-life. Factors associated with achieving remission post-biologic-initiation remain poorly understood. OBJECTIVES: To quantify the proportion of adults with severe asthma achieving multi-domain-defined remission post-biologic-initiation and identify pre-biologic characteristics associated with achieving remission which may be used to predict it. METHODS: This was a longitudinal cohort study using data from 23 countries from the International Severe Asthma Registry. Four asthma outcome domains were assessed in the 1-year pre- and post-biologic-initiation. A priori-defined remission cut-offs were: 0 exacerbations/year, no long-term oral corticosteroid (LTOCS), partly/well-controlled asthma, and percent predicted forced expiratory volume in one second ≥80%. Remission was defined using 2 (exacerbations + LTOCS), 3 (+control or +lung function) and 4 of these domains. The association between pre-biologic characteristics and post-biologic remission was assessed by multivariable analysis. MEASUREMENTS AND MAIN RESULTS: 50.2%, 33.5%, 25.8% and 20.3% of patients met criteria for 2, 3 (+control), 3 (+lung function) and 4-domain-remission, respectively. The odds of achieving 4-domain remission decreased by 15% for every additional 10-years asthma duration (odds ratio: 0.85; 95% CI: 0.73, 1.00). The odds of remission increased in those with fewer exacerbations/year, lower LTOCS daily dose, better control and better lung function pre-biologic-initiation. CONCLUSIONS: One in 5 patients achieved 4-domain remission within 1-year of biologic-initiation. Patients with less severe impairment and shorter asthma duration at initiation had a greater chance of achieving remission post-biologic, indicating that biologic treatment should not be delayed if remission is the goal. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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BACKGROUND: House dust mite (HDM) is the most common allergen trigger globally for allergic rhinitis and atopic asthma. OBJECTIVES: To expedite accurate confirmation of allergen sensitization, we designed fluorescent allergen tetramers to directly stain specific IgE on basophils to detect specific allergen sensitization using the flow cytometric CytoBas assay. METHODS: Recombinant proteins of major HDM allergens (component), Der f 1, Der p 1, and Der p 2 were biotinylated and conjugated with fluorochrome streptavidins as tetramers. Blood samples from 64 patients who are HDM-allergic and 26 controls that are non-HDM-sensitized were incubated with allergen tetramers for evaluation of basophil binding (CytoBas) and activation (BAT) with flow cytometry. RESULTS: The tetramers effectively bound and activated basophils from patients who are allergic but not from controls who are nonsensitized. CytoBas with Der p 1 as a single allergen had comparable sensitivity and specificity (92% and 100%) to BAT (91% and 100%) in detecting allergen sensitization, as did CytoBas with Der p 2 (95% and 96%) to BAT (95% and 87%). A positive staining for Der p 1 and/or Der p 2 in CytoBas was 100% sensitive and 96% specific for HDM allergy. CONCLUSIONS: CytoBas has diagnostic accuracy for group 1 and group 2 HDM allergens that is comparable to BAT, but with additional advantages of multiple allergen components in a single tube and no requirement for in vitro basophil activation. These findings endorse a single, multiplex CytoBas assay for accurate and component-resolved diagnosis of aeroallergen sensitization in patients with allergic asthma and/or rhinitis.
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Antígenos de Dermatophagoides , Proteínas de Artrópodes , Asma , Basófilos , Cisteína Endopeptidases , Citometria de Fluxo , Pyroglyphidae , Rinite Alérgica , Humanos , Antígenos de Dermatophagoides/imunologia , Proteínas de Artrópodes/imunologia , Basófilos/imunologia , Cisteína Endopeptidases/imunologia , Animais , Rinite Alérgica/imunologia , Rinite Alérgica/diagnóstico , Asma/imunologia , Asma/diagnóstico , Feminino , Adulto , Citometria de Fluxo/métodos , Masculino , Pyroglyphidae/imunologia , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Imunoglobulina E/imunologia , Imunoglobulina E/sangue , Alérgenos/imunologia , Sensibilidade e Especificidade , CriançaRESUMO
BACKGROUND: Food allergy is a leading cause of anaphylaxis worldwide. Allergen-specific immunotherapy is the only treatment shown to modify the natural history of allergic disease, but application to food allergy has been hindered by risk of severe allergic reactions and short-lived efficacy. Allergen-derived peptides could provide a solution. PVX108 comprises seven short peptides representing immunodominant T-cell epitopes of major peanut allergens for treatment of peanut allergy. METHODS: Pre-clinical safety of PVX108 was assessed using ex vivo basophil activation tests (n = 185). Clinical safety and tolerability of single and repeat PVX108 doses were evaluated in a first-in-human, randomized, double-blind, placebo-controlled trial in peanut-allergic adults (46 active, 21 placebo). The repeat-dose cohort received six doses over 16 weeks with safety monitored to 21 weeks. Exploratory immunological analyses were performed at pre-dose, Week 21 and Month 18 after treatment. RESULTS: PVX108 induced negligible activation of peanut-sensitised basophils. PVX108 was safe and well tolerated in peanut-allergic adults. There were no treatment-related hypersensitivity events or AEs of clinical concern. The only events occurring more frequently in active than placebo were mild injection site reactions. Exploratory immunological analyses revealed a decrease in the ratio of ST2+ Th2A:CCR6+ Th17-like cells within the peanut-reactive Th pool which strengthened following treatment. CONCLUSION: This study supports the concept that PVX108 could provide a safe alternative to whole peanut immunotherapies and provides evidence of durable peanut-specific T-cell modulation. Translation of these findings to clinical efficacy in ongoing Phase 2 trials would provide important proof-of-concept for using peptides to treat food allergy.
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Anafilaxia , Hipersensibilidade a Amendoim , Adulto , Humanos , Dessensibilização Imunológica/efeitos adversos , Anafilaxia/etiologia , Basófilos , Arachis/efeitos adversos , Alérgenos , Administração OralRESUMO
BACKGROUND: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma. METHODS: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV1) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day. RESULTS: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria. CONCLUSIONS: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria.
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BACKGROUND: There is little agreement on clinically useful criteria for identifying real-world responders to biologic treatments for asthma. OBJECTIVE: To investigate the impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in adults with severe asthma. METHODS: This was a longitudinal, cohort study across 22 countries participating in the International Severe Asthma Registry (https://isaregistries.org/) between May 2017 and January 2023. Change in 4 asthma domains (exacerbation rate, asthma control, long-term oral corticosteroid [LTOCS] dose, and lung function) was assessed from biologic initiation to 1 year post-treatment (minimum 24 weeks). Pre- to post-biologic changes for responders and nonresponders were described along a categorical gradient for each domain derived from pre-biologic distributions (exacerbation rate: 0 to 6+/y; asthma control: well controlled to uncontrolled; LTOCS: 0 to >30 mg/d; percent-predicted forced expiratory volume in 1 second [ppFEV1]: <50% to ≥80%). RESULTS: Percentage of biologic responders (ie, those with a category improvement pre- to post-biologic) varied by domain and increased with greater pre-biologic impairment, increasing from 70.2% to 90.0% for exacerbation rate, 46.3% to 52.3% for asthma control, 31.1% to 58.5% for LTOCS daily dose, and 35.8% to 50.6% for ppFEV1. The proportion of patients having improvement post-biologic tended to be greater for anti-IL-5/5R compared with for anti-IgE for exacerbation, asthma control, and ppFEV1 domains, irrespective of pre-biologic impairment. CONCLUSION: Our results provide realistic outcome-specific post-biologic expectations for both physicians and patients, will be foundational to inform future work on a multidimensional approach to define and assess biologic responders and response, and may enhance appropriate patient selection for biologic therapies. TRIAL REGISTRATION: The ISAR database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization studies (ENCEPP/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EUPAS38288) and with all applicable local and international laws and regulation, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=38289). Governance was provided by ADEPT (registration number: ADEPT1220).
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Antiasmáticos , Asma , Humanos , Asma/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Antiasmáticos/uso terapêutico , Estudos Longitudinais , Resultado do Tratamento , Índice de Gravidade de Doença , Corticosteroides/uso terapêutico , Sistema de Registros , IdosoAssuntos
Antibacterianos , Hipersensibilidade a Drogas , Combinação Piperacilina e Tazobactam , beta-Lactamas , Humanos , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/imunologia , Hipersensibilidade a Drogas/etiologia , Combinação Piperacilina e Tazobactam/efeitos adversos , beta-Lactamas/efeitos adversos , beta-Lactamas/imunologia , Masculino , Feminino , Antibacterianos/efeitos adversos , Antibacterianos/imunologia , Pessoa de Meia-Idade , Idoso , Rotulagem de Medicamentos , Adulto , Piperacilina/efeitos adversos , Piperacilina/imunologiaRESUMO
AIM: Speech pathology is the first-line treatment for inducible laryngeal obstruction (ILO) and involves behavioral techniques to address symptoms and modify maladaptive laryngeal postures. Benefit from speech pathology is reliant on patients engaging in treatment sessions, regular home practice, and generalizing techniques to everyday activities. There is limited research exploring engagement in speech pathology treatment for ILO, particularly from the patient perspective. This study aimed to explore the experiences of living with ILO and how this experience may impact the way patients engage in speech pathology treatment. STUDY DESIGN: Qualitative study. METHODS: Semistructured interviews were completed with seven participants exploring their experiences living with ILO, their diagnostic process and their experiences with speech pathology treatment. Data were analyzed using reflexive thematic analysis to determine shared meanings across participants and themes were developed. FINDINGS: Three major themes were identified - Life with ILO, Challenges of Speech Pathology Treatment, and What Matters to Me. Patients' reports of living with ILO and interacting with speech pathology suggested that these experiences impacted their readiness to start treatment and persist through the challenges of the treatment. Engagement appeared to be positively associated with significant ILO symptom burden and life impact, confidence in the diagnostic process, recommendation for speech pathology treatment, a tailored intervention by a patient-perceived expert in the field and working in a partnership with the speech pathologist to develop a sense of agency. Patients indicated their engagement was negatively influenced by competing time demands, social embarrassment when using symptom relief techniques and laryngeal exercises, and a low ILO symptom burden and life impact. CONCLUSION: The reasons behind engagement in speech pathology treatment for ILO appear to be a complex interaction between previous experiences of living with ILO including the diagnostic process and the experience of speech pathology treatment. A patient-centered approach to therapy may help to maximize engagement by exploring readiness and expectations for treatment. The greater understanding of the patient experience provided through this study may allow speech pathologists to devise meaningful ways to maximize engagement in treatment for people with ILO.
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BACKGROUND: Lung ultrasound (LUS) is increasingly used as an extension of physical examination, informing clinical diagnosis, and decision making. There is particular interest in the assessment of patients with pulmonary congestion and extravascular lung water, although gaps remain in the evidence base underpinning this practice as a result of the limited evaluation of its inter-rater reliability and comparison with more established radiologic tests. METHODS: 30 patients undergoing haemodialysis were prospectively recruited to an observational cohort study (NCT01949402). Patients underwent standardised LUS assessment before, during and after haemodialysis; their total LUS B-line score was generated, alongside a binary label of whether appearances were consistent with an interstitial syndrome. LUS video clips were recorded and independently scored by two blinded expert clinician sonographers. Low-dose non-contrast thoracic CT, pre- and post dialysis, was used as a "gold standard" radiologic comparison. RESULTS: LUS detected a progressive reduction in B-line scores in almost all patients undergoing haemodialysis, correlating with the volume of fluid removed once individuals with no or minimal B-lines upon pre-dialysis examination were discounted. When comparing CT scans pre- and post dialysis, radiologic evidence of the change in fluid status was only identified in a single patient. CONCLUSIONS: This is the first study to demonstrate that LUS detects changes in extravascular lung water caused by changing fluid status during haemodialysis using a blinded outcome assessment and that LUS appears to be more sensitive than CT for this purpose. Further research is needed to better understand the role of LUS in this and similar patient populations, with the aim of improving clinical care and outcomes.
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Dupilumab has been associated with adverse reactions including symptomatic hypereosinophilia. This study reports the incidence of dupilumab-related eosinophilia and adverse reactions in severe asthma patients at an Australian tertiary centre. https://bit.ly/3JgZ5Ya.
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BACKGROUND: Exacerbation frequency strongly influences treatment choices in patients with severe asthma. RESEARCH QUESTION: What is the extent of the variability of exacerbation rate across countries and its implications in disease management? STUDY DESIGN AND METHODS: We retrieved data from the International Severe Asthma Registry, an international observational cohort of patients with a clinical diagnosis of severe asthma. We identified patients aged ≥ 18 years who did not initiate any biologics prior to baseline visit. A severe exacerbation was defined as the use of oral corticosteroids for ≥ 3 days or asthma-related hospitalization/ED visit. A series of negative binomial models were applied to estimate country-specific severe exacerbation rates during 365 days of follow-up, starting from a naive model with country as the only variable to an adjusted model with country as a random-effect term and patient and disease characteristics as independent variables. RESULTS: The final sample included 7,510 patients from 17 countries (56% from the United States), contributing to 1,939 severe exacerbations (0.27/person-year). There was large between-country variation in observed severe exacerbation rate (minimum, 0.04 [Argentina]; maximum, 0.88 [Saudi Arabia]; interquartile range, 0.13-0.54), which remained substantial after adjusting for patient characteristics and sampling variability (interquartile range, 0.16-0.39). INTERPRETATION: Individuals with similar patient characteristics but coming from different jurisdictions have varied severe exacerbation risks, even after controlling for patient and disease characteristics. This suggests unknown patient factors or system-level variations at play. Disease management guidelines should recognize such between-country variability. Risk prediction models that are calibrated for each jurisdiction will be needed to optimize treatment strategies.
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Asma , Progressão da Doença , Sistema de Registros , Índice de Gravidade de Doença , Humanos , Asma/tratamento farmacológico , Asma/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Hospitalização/estatística & dados numéricos , Corticosteroides/uso terapêuticoRESUMO
Background: To date, studies investigating the association between pre-biologic biomarker levels and post-biologic outcomes have been limited to single biomarkers and assessment of biologic efficacy from structured clinical trials. Aim: To elucidate the associations of pre-biologic individual biomarker levels or their combinations with pre-to-post biologic changes in asthma outcomes in real-life. Methods: This was a registry-based, cohort study using data from 23 countries, which shared data with the International Severe Asthma Registry (May 2017-February 2023). The investigated biomarkers (highest pre-biologic levels) were immunoglobulin E (IgE), blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO). Pre- to approximately 12-month post-biologic change for each of three asthma outcome domains (i.e. exacerbation rate, symptom control and lung function), and the association of this change with pre-biologic biomarkers was investigated for individual and combined biomarkers. Results: Overall, 3751 patients initiated biologics and were included in the analysis. No association was found between pre-biologic BEC and pre-to-post biologic change in exacerbation rate for any biologic class. However, higher pre-biologic BEC and FeNO were both associated with greater post-biologic improvement in FEV1 for both anti-IgE and anti-IL5/5R, with a trend for anti-IL4Rα. Mean FEV1 improved by 27-178 mL post-anti-IgE as pre-biologic BEC increased (250 to 1000 cells/µL), and by 43-216 mL and 129-250 mL post-anti-IL5/5R and -anti-IL4Rα, respectively along the same BEC gradient. Corresponding improvements along a FeNO gradient (25-100 ppb) were 41-274 mL, 69-207 mL and 148-224 mL for anti-IgE, anti-IL5/5R, and anti-IL4Rα, respectively. Higher baseline BEC was also associated with lower probability of uncontrolled asthma (OR 0.392; p=0.001) post-biologic for anti-IL5/5R. Pre-biologic IgE was a poor predictor of subsequent pre-to-post-biologic change for all outcomes assessed for all biologics. The combination of BEC + FeNO marginally improved the prediction of post-biologic FEV1 increase (adjusted R2: 0.751), compared to BEC (adjusted R2: 0.747) or FeNO alone (adjusted R2: 0.743) (p=0.005 and <0.001, respectively); however, this prediction was not improved by the addition of IgE. Conclusions: The ability of higher baseline BEC, FeNO and their combination to predict biologic-associated lung function improvement may encourage earlier intervention in patients with impaired lung function or at risk of accelerated lung function decline.
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Asma , Produtos Biológicos , Biomarcadores , Eosinófilos , Imunoglobulina E , Humanos , Asma/tratamento farmacológico , Asma/diagnóstico , Asma/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Adulto , Eosinófilos/imunologia , Produtos Biológicos/uso terapêutico , Antiasmáticos/uso terapêutico , Resultado do Tratamento , Sistema de Registros , Índice de Gravidade de Doença , Contagem de Leucócitos , Óxido Nítrico/metabolismo , Idoso , Estudos de CoortesRESUMO
BACKGROUND: Biologic effectiveness is often assessed as response, a term that eludes consistent definition. Identifying those most likely to respond in real-life has proven challenging. OBJECTIVE: To explore definitions of biologic responders in adults with severe asthma and investigate patient characteristics associated with biologic response. METHODS: This was a longitudinal cohort study using data from 21 countries, which shared data with the International Severe Asthma Registry. Changes in four asthma outcome domains were assessed in the 1-year period before and after biologic initiation in patients with a predefined level of prebiologic impairment. Responder cutoffs were 50% or greater reduction in exacerbation rate, 50% or greater reduction in long-term oral corticosteroid daily dose, improvement in one or more category in asthma control, and 100 mL or greater improvement in FEV1. Responders were defined using single and multiple domains. The association between prebiologic characteristics and postbiologic initiation response was examined by multivariable analysis. RESULTS: A total of 2,210 patients were included. Responder rate ranged from 80.7% (n = 566 of 701) for exacerbation response to 10.6% (n = 9 of 85) for a four-domain response. Many responders still exhibited significant impairment after biologic initiation: 46.7% (n = 206 of 441) of asthma control responders with uncontrolled asthma before the biologic still had incompletely controlled disease postbiologic initiation. Predictors of response were outcome-dependent. Lung function responders were more likely to have higher prebiologic FeNO (odds ratio = 1.20 for every 25-parts per billion increase), and shorter asthma duration (odds ratio = 0.81 for every 10-year increase in duration). Higher blood eosinophil count and the presence of type 2-related comorbidities were positively associated with higher odds of meeting long-term oral corticosteroid, control, and lung function responder criteria. CONCLUSIONS: Our findings underscore the multimodal nature of response, showing that many responders experience residual symptoms after biologic initiation and that predictors of response vary according to the outcome assessed.