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Background: The anti-IgE monoclonal antibody omalizumab is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during 1 year of omalizumab treatment. Methods: One-year open-label Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 patients with severe (Global Initiative for Asthma step 4/5) uncontrolled atopic asthma (at least two severe exacerbations in the previous year) taking high-dose inhaled corticosteroids and long-acting ß-agonists with or without maintenance oral corticosteroids. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE); and 16-52 weeks, to assess late responses based on ⩾50% reduction in exacerbations or mOCS dose. All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. Measurements and Main Results: A total of 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ⩾50% and 57% (37 of 65) taking mOCSs had reduced their dose by ⩾50%. The primary outcomes 2,3-dinor-11-ß-PGF2α, GETE score, and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five volatile organic compounds and five plasma lipid biomarkers strongly predicted the ⩾50% reduction in exacerbations (receiver operating characteristic areas under the curve of 0.780 and 0.922, respectively) and early responses (areas under the curve of 0.835 and 0.949, respectively). In an independent cohort, gas chromatography/mass spectrometry biomarkers differentiated between severe and mild asthma. Conclusions: This is the first discovery of omics biomarkers that predict improvement in asthma with biologic agent treatment. Prospective validation and development for clinical use is justified.
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Antiasmáticos , Asma , Biomarcadores , Omalizumab , Humanos , Omalizumab/uso terapéutico , Asma/tratamiento farmacológico , Asma/sangre , Masculino , Femenino , Antiasmáticos/uso terapéutico , Adulto , Persona de Mediana Edad , Biomarcadores/sangre , Resultado del Tratamiento , Índice de Severidad de la Enfermedad , Inmunoglobulina E/sangre , Esputo/citología , Anticuerpos Antiidiotipos/uso terapéutico , Pruebas RespiratoriasRESUMEN
BACKGROUND: There are pre-existing inequities in asthma care. OBJECTIVE: To evaluate effect modification by race of the effect of insurance on biologic therapy use in patients with asthma and related diseases. METHODS: We conducted inverse probability weighted (IPW) analyses using electronic health records data from 2011-2020 from a large healthcare system in Boston, MA. We evaluated the odds of not initiating omalizumab or mepolizumab therapy within one year of prescription for an approved indication. RESULTS: We identified 1,132 individuals who met study criteria. Twenty-seven percent of these patients had public insurance and 12% belonged to a historically marginalized group (HMG). A quarter of patients did not initiate the prescribed biologic. Among patients with asthma, individuals belonging to HMG had higher exacerbation rates in the period before initiation compared to non-HMG individuals, regardless of insurance type. Among HMG patients with asthma, those with private insurance were less likely to not initiate therapy compared to those with public insurance, (Odds Ratio, (OR) 0.67, and 95% Confidence Interval, [CI] 0.56 - 0.79). Among non-HMG with asthma, privately insured and publicly insured individuals had similar rates of not initiating the prescribed biologic (OR: 1.02; 95% CI: 0.95 -1.09). Among those publicly insured with asthma, HMGs had higher odds of not initiating therapy compared to non-HMGs (OR 1.16; 95% CI 1.03 - 1.31), but privately-insured HMG and non-HMG did not differ significantly (OR: 0.99; 95% CI: 0.91 - 1.07). CONCLUSION: Publicly insured individuals belonging to HMG are less likely to initiate biologics when prescribed despite having more severe asthma, while there are no inequities by insurance in individuals belonging to other groups.
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BACKGROUND: Lung function is an independent predictor of mortality. We evaluated the lung function trajectories of a cohort of patients with asthma receiving biologic therapy. METHODS: We identified 229 monoclonal antibody-naïve adult patients with moderate-to-severe asthma who initiated omalizumab, mepolizumab, or dupilumab between 2010 and 2022 in a large healthcare system in Boston, MA. Generalized additive mixed models were used to estimate the lung function trajectories during the 156 weeks following biologic initiation. Response was defined as an improvement in FEV1 or a decrease of ≤0.5% per year. The Kaplan-Meier estimator was used to assess time to no additional improvement in FEV1 in responders. All models were adjusted for age, sex, body mass index, smoking status, baseline exacerbation rate, and baseline blood eosinophil count. RESULTS: Eighty-eight patients initiated mepolizumab, 76 omalizumab, and 65 dupilumab. Baseline eosinophil count was highest in the mepolizumab group (405 cells/mcL) and lowest for omalizumab (250 cells/mcL). Both FEV1 and FVC improved in the mepolizumab group (FEV1 + 20 mL/year; FVC +43 mL/year). For omalizumab, there was an initial improvement in the first year followed by decline with an overall FEV1 loss of -44 mL/year and FVC -32 mL/year. For dupilumab, both FEV1 (+61 mL/year) and FVC (+74 mL/year) improved over time. Fifty percent of the mepolizumab group, 58% omalizumab, and 72% of dupilumab were responders. The median time to no additional FEV1 improvement in responders was 24 weeks for omalizumab, 48 weeks for mepolizumab, and 57 weeks for dupilumab. CONCLUSION: In this clinical cohort, mepolizumab, omalizumab, and dupilumab had beneficial effects on FEV1 and FVC with distinct post-initiation trajectories.
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Antiasmáticos , Anticuerpos Monoclonales Humanizados , Asma , Omalizumab , Pruebas de Función Respiratoria , Humanos , Asma/tratamiento farmacológico , Asma/fisiopatología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Masculino , Femenino , Omalizumab/uso terapéutico , Persona de Mediana Edad , Antiasmáticos/uso terapéutico , Adulto , Resultado del Tratamiento , Índice de Severidad de la Enfermedad , Pulmón/fisiopatología , Pulmón/efectos de los fármacos , Estudios de Cohortes , AncianoRESUMEN
BACKGROUND: It is unclear how the efficacy of tezepelumab, approved for the treatment of type 2 high and low asthma, compares to the efficacy of other biologics for type 2-high asthma. OBJECTIVES: We sought to conduct an indirect comparison of tezepelumab to dupilumab, benralizumab, and mepolizumab in the treatment of eosinophilic asthma. METHODS: The investigators conducted a systematic review and Bayesian network meta-analyses. They identified randomized controlled trials indexed in PubMed, Embase, or Cochrane Central Register of Controlled Trials (CENTRAL) between January 1, 2000, and August 12, 2022. Outcomes included exacerbation rates, prebronchodilator FEV1, and the Asthma Control Questionnaire. RESULTS: Ten randomized controlled trials (n = 9201) met eligibility. Tezepelumab (relative risk: 0.63; 95% credible interval [CI]: 0.46-0.86) was associated with significantly lower exacerbation rates than benralizumab and larger improvements in FEV1 compared to mepolizumab (mean difference [MD]: 66; 95% CI: -33 to 170) and benralizumab (MD: 62; 95% CI: -22 to 150), though the 95% CI crossed the null value of 0. Mepolizumab improved the Asthma Control Questionnaire score the most, but this improvement was not significantly different from that of tezepelumab (tezepelumab vs mepolizumab; MD: 0.14; 95% CI: -0.10 to 0.38). For efficacy by clinically important thresholds, tezepelumab, mepolizumab, and dupilumab achieved a >99% probability of reducing exacerbation rates by ≥50% compared to placebo, but benralizumab had only a 66% probability of doing so. Tezepelumab and dupilumab had a probability of 1.00 of improving prebronchodilator FEV1 by ≥100 mL above placebo. Compared to mepolizumab, dupilumab had >90% chance for improving FEV1 by ≥50 mL, but none of the differences between biologics exceeded 100 mL. CONCLUSIONS: In individuals with eosinophilic asthma, tezepelumab and dupilumab were associated with greater improvements (although below clinical thresholds) in exacerbation rates and lung function than benralizumab or mepolizumab.
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Antiasmáticos , Asma , Productos Biológicos , Eosinofilia Pulmonar , Humanos , Antiasmáticos/uso terapéutico , Metaanálisis en Red , Teorema de Bayes , Asma/tratamiento farmacológico , Eosinofilia Pulmonar/tratamiento farmacológico , Productos Biológicos/uso terapéuticoRESUMEN
BACKGROUND: Multiple mAbs are currently approved for the treatment of asthma. However, there is limited evidence on their comparative effectiveness. OBJECTIVE: Our aim was to compare the effectiveness of omalizumab, mepolizumab, and dupilumab in individuals with moderate-to-severe asthma. METHODS: We emulated a hypothetical randomized trial using electronic health records from a large US-based academic health care system. Participants aged 18 years or older with baseline IgE levels between 30 and 700 IU/mL and peripheral eosinophil counts of at least 150 cells/µL were eligible for study inclusion. The study period extended from March 2016 to August 2021. Outcomes included the incidence of asthma-related exacerbations and change in baseline FEV1 value over 12 months of follow-up. RESULTS: In all, 68 individuals receiving dupilumab, 68 receiving omalizumab, and 65 receiving mepolizumab met the inclusion criteria. Over 12 months of follow-up, 31 exacerbations occurred over 68 person years (0.46 exacerbations per person year) in the dupilumab group, 63 over 68 person years (0.93 per person year) in the omalizumab group, and 86 over 65 person years (1.32 per person year) in the mepolizumab group (adjusted incidence rate ratios: dupilumab vs mepolizumab, 0.28 [95% CI = 0.09-0.84]; dupilumab vs omalizumab, 0.36 [95% CI = 0.12-1.09]; and omalizumab vs mepolizumab, 0.78 [95% CI = 0.32-1.91]). The differences in the change in FEV1 comparing patients who received the different biologics were as follows: 0.11 L (95% CI = -0.003 to 0.222 L) for dupilumab versus mepolizumab, 0.082 L (95% CI -0.040 to 0.204 L) for dupilumab versus omalizumab, and 0.026 L (95% CI -0.083 to 0.140 L) for omalizumab versus mepolizumab. CONCLUSIONS: Among patients with asthma and eosinophil counts of at least 150 cells/µL and IgE levels of 30 to 700 kU/L, dupilumab was associated with greater improvements in exacerbation and FEV1 value than omalizumab and mepolizumab.
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Antiasmáticos , Asma , Humanos , Antiasmáticos/uso terapéutico , Asma/etiología , Inmunoglobulina E/uso terapéutico , Omalizumab/uso terapéutico , Investigación sobre la Eficacia ComparativaRESUMEN
INTRODUCTION: Biomarkers are needed to inform the choice of biologic therapy in patients with asthma given the increasing number of biologics. We aimed to identify proteins associated with response to omalizumab and mepolizumab. METHODS: Aptamer-based proteomic profiling (SomaScan) was used to assess 1437 proteins from 51 patients with moderate to severe asthma who received omalizumab (n = 29) or mepolizumab (n = 22). Response was defined as the change in asthma-related exacerbations in the 12 months following therapy initiation. All models were adjusted for age, sex, and pre-treatment exacerbation rate. Additionally, body mass index was included in the omalizumab model and eosinophil count in the mepolizumab model. We evaluated the association between molecular signatures and response using negative binomial regression correcting for the false discovery rate (FDR) and gene set enrichment analyses (GSEA) to identify associated pathways. RESULTS: Over two-thirds of patients were female. The average age for omalizumab patients was 42 years and 57 years for mepolizumab. At baseline, the average exacerbation rate was 1.5/year for omalizumab and 2.4/year for mepolizumab. Lower levels of LOXL2 (unadjusted p: 1.93 × 10E-05, FDR-corrected: 0.028) and myostatin (unadjusted: 3.87 × 10E-05, FDR-corrected: 0.028) were associated with better response to mepolizumab. Higher levels of CD9 antigen (unadjusted: 5.30 × 10E-07, FDR-corrected: 0.0006) and MUC1 (unadjusted: 1.15 × 10E-06, FDR-corrected: 0.0006) were associated with better response to omalizumab, and LTB4R (unadjusted: 1.12 × 10E-06, FDR-corrected: 0.0006) with worse response. Protein-protein interaction network modeling showed an enrichment of the TNF- and NF-kB signaling pathways for patients treated with mepolizumab and multiple pathways involving MAPK, including the FcER1 pathway, for patients treated with omalizumab. CONCLUSIONS: This study provides novel fundamental data on proteins associated with response to mepolizumab or omalizumab in severe asthma and warrants further validation as potential biomarkers for therapy selection.
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Antiasmáticos , Asma , Humanos , Femenino , Adulto , Masculino , Omalizumab/uso terapéutico , Omalizumab/efectos adversos , Miostatina/uso terapéutico , Proteómica , Asma/diagnóstico , Asma/tratamiento farmacológico , Asma/inducido químicamente , Biomarcadores , Mucina-1RESUMEN
BACKGROUND: The comparative safety and efficacy of the biologics currently approved for asthma are unclear. OBJECTIVE: We compared the safety and efficacy of mepolizumab, benralizumab, and dupilumab in individuals with severe eosinophilic asthma. METHODS: We performed a systematic review of peer-reviewed literature published 2000 to 2021. We studied Bayesian network meta-analyses of exacerbation rates, prebronchodilator FEV1, the Asthma Control Questionnaire, and serious adverse events in individuals with eosinophilic asthma. RESULTS: Eight randomized clinical trials (n = 6461) were identified. We found in individuals with eosinophils ≥300 cells/µL the following: in reducing exacerbation rates compared to placebo: dupilumab (risk ratio [RR], 0.32; 95% credible interval [CI], 0.23 to 0.45), mepolizumab (RR, 0.37; 95% CI, 0.30 to 0.45), and benralizumab (RR, 0.49; 95% CI, 0.43 to 0.55); in improving FEV1: dupilumab (mean difference in milliliters [MD] 230; 95% CI, 160 to 300), benralizumab (MD, 150; 95% CI, 100 to 200), and mepolizumab (MD, 150; 95% CI, 66 to 220); and in reducing Asthma Control Questionnaire scores: mepolizumab (MD, -0.63; 95% CI, -0.81 to -0.45), dupilumab (MD, -0.48; 95% CI, -0.83 to -0.14), and benralizumab (MD, -0.32; 95% CI, -0.43 to -0.21). In individuals with eosinophils 150-299 cells/µL, benralizumab (RR, 0.62; 95% CI, 0.52 to 0.73) and dupilumab (RR, 0.60; 95% CI, 0.38 to 0.95) were associated with lower exacerbation rates; and only benralizumab (MD, 81; 95% CI, 8 to 150) significantly improved FEV1. These differences were minimal compared to clinically important thresholds. For serious adverse events in the overall population, mepolizumab (odds ratio, 0.67; 95% CI, 0.48 to 0.92) and benralizumab (odds ratio, 0.74; 95% CI, 0.59 to 0.93) were associated with lower odds of a serious adverse event, while dupilumab was not different from placebo (odds ratio, 1.0; 95% CI, 0.74 to 1.4). CONCLUSION: There are minimal differences in the efficacy and safety of mepolizumab, benralizumab, and dupilumab in eosinophilic asthma.
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Antiasmáticos , Asma , Eosinofilia Pulmonar , Humanos , Metaanálisis en Red , Teorema de Bayes , Asma/tratamiento farmacológico , Asma/inducido químicamente , Eosinofilia Pulmonar/tratamiento farmacológico , Eosinófilos , Antiasmáticos/efectos adversosRESUMEN
BACKGROUND: Genetic ancestry plays a role in asthma health disparities. OBJECTIVE: Our aim was to evaluate the impact of ancestry on and identify genetic variants associated with asthma, total serum IgE level, and lung function. METHODS: A total of 436 Peruvian children (aged 9-19 years) with asthma and 291 without asthma were genotyped by using the Illumina Multi-Ethnic Global Array. Genome-wide proportions of indigenous ancestry populations from continental America (NAT) and European ancestry from the Iberian populations in Spain (IBS) were estimated by using ADMIXTURE. We assessed the relationship between ancestry and the phenotypes and performed a genome-wide association study. RESULTS: The mean ancestry proportions were 84.7% NAT (case patients, 84.2%; controls, 85.4%) and 15.3% IBS (15.8%; 14.6%). With adjustment for asthma, NAT was associated with higher total serum IgE levels (P < .001) and IBS was associated with lower total serum IgE levels (P < .001). NAT was associated with higher FEV1 percent predicted values (P < .001), whereas IBS was associated with lower FEV1 values in the controls but not in the case patients. The HLA-DR/DQ region on chromosome 6 (Chr6) was strongly associated with total serum IgE (rs3135348; P = 3.438 × 10-10) and was independent of an association with the haplotype HLA-DQA1â¼HLA-DQB1:04.01â¼04.02 (P = 1.55 × 10-05). For lung function, we identified a locus (rs4410198; P = 5.536 × 10-11) mapping to Chr19, near a cluster of zinc finger interacting genes that colocalizes to the long noncoding RNA CTD-2537I9.5. This novel locus was replicated in an independent sample of pediatric case patients with asthma with similar admixture from Brazil (P = .005). CONCLUSION: This study confirms the role of HLA in atopy, and identifies a novel locus mapping to a long noncoding RNA for lung function that may be specific to children with NAT.
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Asma/genética , Genotipo , Inmunoglobulina E/metabolismo , Pueblos Indígenas , Pulmón/metabolismo , Adolescente , Américas , Asma/epidemiología , Niño , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Antígenos HLA-DQ/metabolismo , Humanos , Pulmón/inmunología , Masculino , Perú/epidemiología , Polimorfismo de Nucleótido Simple , ARN Largo no Codificante/genética , España , Adulto JovenAsunto(s)
Antiasmáticos , Anticuerpos Monoclonales Humanizados , Asma , Humanos , Asma/tratamiento farmacológico , Antiasmáticos/uso terapéutico , Antiasmáticos/farmacocinética , Niño , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Eosinofilia , Eosinófilos/inmunología , Índice de Severidad de la Enfermedad , Resultado del TratamientoAsunto(s)
Asma , Rinitis , Humanos , Adolescente , Asma/diagnóstico , Asma/prevención & control , Adulto Joven , MáscarasAsunto(s)
Asma , Ruidos Respiratorios , Preescolar , Humanos , Ruidos Respiratorios/etiología , Instituciones Académicas , Asma/diagnósticoRESUMEN
BACKGROUND: In asthmatics, making a diagnosis of anaphylaxis could be challenging as respiratory symptoms are a common feature of both conditions. Identifying anaphylaxis is important to providing appropriate care. A prior study showed that anaphylaxis is sometimes misdiagnosed as acute asthma in children. We sought to identify the percentage of adults admitted to the intensive care unit (ICU) with asthma exacerbations who met criteria for anaphylaxis. METHODS: Retrospective chart review of adults admitted with acute asthma to the ICU at Jacobi Medical Center, a Level 1 trauma centre in Bronx, New York. Study period was January 2012 to December 2014. Using the criteria outlined in the World Allergy Organization's Anaphylaxis Guidelines, we identified patients who met criteria for anaphylaxis. RESULTS: 105 patients were identified: 17 were excluded because their main reason(s) for admission was not asthma. 7 (8%) of the 88 cases eligible for the study met diagnostic criteria for anaphylaxis while 3 (3.4%) were highly likely to have had anaphylaxis. The baseline characteristics of the seven patients were similar to that of the overall population studied. They however had shorter onset of symptoms (median (IQR): 3.5 (2-6) vs 24 hours (12-72), p<0.001), were more likely to have been intubated (71%vs31%, p=0.04), received intramuscular epinephrine by the emergency medical services or in the emergency room (86%vs42%, p=0.04) and received antihistamines (28.6%vs1.2%, p=0.02). None of these seven patients died. Only one of the seven patients was prescribed an epinephrine pen injector and referred to an allergist at discharge. CONCLUSION: In this single-centre retrospective review, 3.4% of adults admitted to the ICU for acute severe asthma also met criteria for anaphylaxis.
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Anafilaxia/etiología , Asma/complicaciones , Unidades de Cuidados Intensivos/estadística & datos numéricos , Adulto , Anafilaxia/epidemiología , Asma/epidemiología , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Unidades de Cuidados Intensivos/organización & administración , Masculino , Persona de Mediana Edad , New York/epidemiología , Prevalencia , Estudios RetrospectivosAsunto(s)
Eficiencia , Becas , Medicina/organización & administración , Tutoría , Humanos , Modelos OrganizacionalesRESUMEN
INTRODUCTION: Care guidelines can improve the quality of care by making current evidence available in a concise format. Emergency departments (EDs) are an ideal site for guidelines given the wide variety of presenting conditions and treating providers, and the need for timely decision making. We designed a programme for guideline development and implementation and evaluated its impact in an ED. METHODS: The setting was an urban paediatric ED with an annual volume of 60â 000. Common and/or high-risk conditions were identified for guideline development. Following implementation of the guidelines, their impact on effectiveness of care, patient outcomes, efficiency and equitability of care was assessed using a web-based provider survey and performance on identified metrics. Variation in clinical care between providers was assessed using funnel plots. RESULTS: Eleven (11) guidelines were developed and implemented. 3 years after the initiation of the programme, self-reported adherence to recommendations was high (95% for physicians and 89% for nurses). 97% of physicians and 92% of nurses stated that the programme improved the quality of care in the ED. For some guidelines, provider-to-provider care practice variation was reduced significantly. We found reduced disparity in imaging when assessing one guideline. There were also reductions in utilisation of diagnostic tests or therapies. As a balancing measure, the percentage of patients with any of the guideline conditions who returned to the ED within 72â h of discharge did not change from before to after guideline initiation. Overall, 80% of physician and 56% of nurse respondents rated the guideline programme at the highest value. CONCLUSIONS: A programme for guideline development and implementation helped to improve efficiency, and standardise and eliminate disparities in emergency care without jeopardising patient outcomes.