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BACKGROUND: Asthma mortality rates in the United States have declined since 1999; however, asthma mortality by place of death has not been comprehensively evaluated. OBJECTIVE: To evaluate temporal trends in asthma mortality rates and place of death in the United States. METHODS: We conducted a population-based analysis using data from the Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research platform to evaluate deaths with asthma as the underlying cause (2000-2019) among US residents of all ages. Absolute numbers of asthma-related deaths were described by place of death. Counts were applied to US Census Bureau population counts to calculate mortality rates per 100,000 persons. RESULTS: In the 20-year period evaluated, 67,695 asthma deaths were registered in the United States. An overall 32% decline in the asthma mortality rate was observed, from 1.43 to 0.98 per 100,000 persons from 2000 to 2019, respectively. Although asthma mortality rates declined in all medical facility locations, the at-home asthma mortality rate remained stable (0.32 and 0.34 per 100,000 persons in 2000 and 2019, respectively). Consequently, the proportion of at-home asthma deaths increased from 23% in 2000 to 2001 to 36% in 2018 to 2019. The distribution of place of death varied by age, sex, race, ethnicity, and geographic region. CONCLUSION: Despite an overall decline in asthma mortality in the United States, at-home asthma mortality has remained unchanged. In recent years, more than one-third of asthma deaths have occurred at home. These findings warrant further study and underscore the importance of increased efforts to identify and treat uncontrolled asthma across demographic groups.
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Asma , Certificado de Defunción , Humanos , Estados Unidos/epidemiología , Etnicidad , Asma/epidemiología , Instituciones de Salud , MortalidadRESUMEN
BACKGROUND: In the United States, a few studies have evaluated geographic variation of severe asthma at the subnational level. OBJECTIVE: To assess state-level geographic variation in the prevalence and characteristics of severe persistent asthma in the United States. METHODS: Patients aged above or equal to 12 years with severe persistent asthma were identified using nationally representative data from IQVIA open-source Medical/Pharmacy Claims and PharMetrics Plus databases (January 2019-December 2020). The index date was defined as the patient's earliest qualifying date for a severe asthma diagnosis. Baseline characteristics were measured during the 12-month pre-index period. Outcomes including exacerbation occurrence, asthma control, and medication use were measured during the 12-month post-index period and compared across states using census-level projections. RESULTS: A total of 2,092,799 patients with asthma were identified; 496,750 (23.7%) met criteria for severe persistent asthma and all inclusion criteria. Mean age was 50.5 years; 68.4% were females. The prevalence of severe persistent asthma varied across states, ranging from 19.6% (New Mexico) to 31.9% (Alaska). Among patients with severe persistent asthma, 40.9% had more than or equal to 1 exacerbation, ranging from 34.2% (Vermont) to 45.6% (Louisiana); 21.1% had uncontrolled disease, ranging from 16.5% (Vermont) to 24.0% (Arizona). Among patients with exacerbations, 13.7% had exacerbation-related emergency department visits or hospitalizations, ranging from 7.0% (North Carolina) to 17.7% (Nevada). Among patients with severe uncontrolled asthma, 15.6% used biologics post-index, ranging from 2.2% (Hawaii) to 27.9% (Mississippi). CONCLUSION: There is significant variability in severe persistent asthma prevalence and disease burden across US states. Reasons for geographic variation may include differences in socioeconomic/environmental factors or asthma management.
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Asma , Índice de Severidad de la Enfermedad , Humanos , Asma/epidemiología , Estados Unidos/epidemiología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Prevalencia , Adolescente , Niño , Costo de Enfermedad , Anciano , Adulto JovenRESUMEN
OBJECTIVES: To estimate the preferences of patients with asthma and asthma-treating clinicians for attributes of biologic treatments, to compare patients' and clinicians' preferences, and to better understand the reasons for their preferences. METHODS: Adults with moderate-to-severe asthma and clinicians who treat asthma in the US completed a cross-sectional, online survey including a discrete choice experiment (DCE) that consisted of seven attributes spanning treatment efficacy, risk and convenience. Marginal utilities were estimated using a mixed logit model, and relative attribute importance scores calculated. Clinicians were also asked about the value of biomarker agnostic biologic treatments. The survey was followed by qualitative interviews targeting a sub-sample of survey participants, in which the rationale behind their survey responses was discussed. RESULTS: In the DCE, both patients and clinicians placed the most importance on exacerbation and hospitalization rate reduction, and risk of injection site reaction. Patients valued location of administration more than clinicians. Rationale for individual-level preferences varied, with patients and clinicians reporting their preference depended on event frequency and anticipated quality of life impacts. Clinicians mentioned compliance and financial impacts, while patients mentioned personal experience, particularly around site reactions. Most patients and clinicians would value a biomarker agnostic asthma treatment. CONCLUSIONS: Asthma treatment preferences are largely driven by treatment efficacy and minimizing the risk of site reactions, although preferences differ between patients and clinicians across other attributes, highlighting the need for shared decision-making and individualized care.
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BACKGROUND: Allergic asthma is the most common phenotype among patients with severe asthma. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab significantly reduced the annualized asthma exacerbation rate (AAER) versus placebo in patients with severe, uncontrolled asthma. This exploratory analysis evaluated the efficacy of tezepelumab in NAVIGATOR participants with evidence of severe allergic asthma. METHODS: Patients (12-80 years old) receiving medium- or high-dose inhaled corticosteroids and ≥ 1 additional controller medication, with or without oral corticosteroids, were randomized to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks in NAVIGATOR. In this analysis, the AAER, forced expiratory volume in 1 second (FEV1 ), patient-reported outcomes (PROs), and type 2 biomarker levels were evaluated in patients grouped by sensitivity to perennial aeroallergens, confirmed symptomatic allergy, and eligibility for omalizumab treatment according to the United States (OMA-US) and the European Union (OMA-EU) prescribing information, including subgroups according to baseline blood eosinophil counts and fractional exhaled nitric oxide (FeNO) levels. RESULTS: Of 1059 patients who received treatment in NAVIGATOR, 680 (64%) had perennial aeroallergen sensitivity and 318 (30%) had confirmed symptomatic allergy; 379 (36%) and 359 (34%) patients were OMA-US- and OMA-EU-eligible, respectively. Tezepelumab reduced the AAER over 52 weeks versus placebo by 58% (95% confidence interval [CI]: 47-67) to 68% (95% CI: 55-77) across these subgroups. Among omalizumab-eligible patients, AAERs were reduced in patients across baseline blood eosinophil counts and FeNO levels. Tezepelumab improved FEV1 and PROs, and reduced type 2 biomarkers, versus placebo in patients with and without perennial allergy. CONCLUSIONS: Tezepelumab was efficacious in patients with severe, uncontrolled asthma with evidence of allergic inflammation, defined by multiple clinically relevant definitions. These findings further support the benefits of tezepelumab in a broad population of patients with severe asthma, including those with severe allergic asthma.
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Antiasmáticos , Asma , Humanos , Omalizumab/uso terapéutico , Antiasmáticos/efectos adversos , Asma/diagnóstico , Asma/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Método Doble CiegoRESUMEN
BACKGROUND: Asthma exacerbation frequencies vary throughout the year owing to seasonal triggers. Tezepelumab is a human monoclonal antibody that targets thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab significantly reduced the annualized asthma exacerbation rate (AAER) vs placebo in patients with severe, uncontrolled asthma. OBJECTIVE: To evaluate the effect of tezepelumab on asthma exacerbations across all seasons in NAVIGATOR patients (post hoc). METHODS: NAVIGATOR was a multicenter, randomized, double-blind, placebo-controlled study. Patients (12-80 years old) were randomized 1:1 to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. AAER over 52 weeks was assessed by season. Data from patients in the Southern Hemisphere were transformed to align with Northern Hemisphere seasons. RESULTS: Tezepelumab reduced the AAER vs placebo by 63% (95% confidence interval [CI], 52-72) in winter, 46% (95% CI, 26-61) in spring, 62% (95% CI, 48-73) in summer, and 54% (95% CI, 41-64) in fall. In matched climates, during the spring allergy season (March 1 to June 15) and ragweed allergy season (September), tezepelumab reduced the AAER vs placebo in patients with seasonal allergy by 59% (95% CI, 29-77) and 70% (95% CI, 33-87), respectively. In patients with perennial allergy and in those with seasonal allergy, tezepelumab reduced the AAER vs placebo across all seasons. CONCLUSION: Tezepelumab reduced exacerbations across all seasons vs placebo in patients with severe, uncontrolled asthma, including patients with seasonal and perennial allergies. These data further support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03347279 (https://clinicaltrials.gov/ct2/show/NCT03347279).
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Antiasmáticos , Asma , Humanos , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estaciones del Año , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Método Doble CiegoRESUMEN
Kabuki syndrome (KS) is a rare genetic disorder caused primarily by mutations in the histone modifier genes KMT2D and KDM6A. The genes have broad temporal and spatial expression in many organs, resulting in complex phenotypes observed in KS patients. Hypotonia is one of the clinical presentations associated with KS, yet detailed examination of skeletal muscle samples from KS patients has not been reported. We studied the consequences of loss of KMT2D function in both mouse and human muscles. In mice, heterozygous loss of Kmt2d resulted in reduced neuromuscular junction (NMJ) perimeter, decreased muscle cell differentiation in vitro and impaired myofiber regeneration in vivo. Muscle samples from KS patients of different ages showed presence of increased fibrotic tissue interspersed between myofiber fascicles, which was not seen in mouse muscles. Importantly, when Kmt2d-deficient muscle stem cells were transplanted in vivo in a physiologic non-Kabuki environment, their differentiation potential is restored to levels undistinguishable from control cells. Thus, the epigenetic changes due to loss of function of KMT2D appear reversible through a change in milieu, opening a potential therapeutic avenue.
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Anomalías Múltiples/metabolismo , Diferenciación Celular/genética , Proteínas de Unión al ADN/metabolismo , Cara/anomalías , Enfermedades Hematológicas/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Células Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteínas de Neoplasias/metabolismo , Transducción de Señal/genética , Enfermedades Vestibulares/metabolismo , Anomalías Múltiples/genética , Adolescente , Animales , Niño , Preescolar , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Femenino , Enfermedades Hematológicas/genética , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Lactante , Masculino , Ratones , Ratones Transgénicos , Células Musculares/patología , Mutación , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Neoplasias/genética , Unión Neuromuscular/genética , Unión Neuromuscular/metabolismo , Enfermedades Vestibulares/genéticaRESUMEN
Eosinophils are circulating and tissue-resident leukocytes that have potent proinflammatory effects in a number of diseases. Recently, eosinophils have been shown to have various other functions, including immunoregulation and antiviral activity. Eosinophil levels vary dramatically in a number of clinical settings, especially following eosinophil-targeted therapy, which is now available to selectively deplete these cells. There are key coronavirus disease 2019 (COVID-19)-related questions concerning eosinophils whose answers affect recommended prevention and care. First, do patients with eosinophilia-associated diseases have an altered course of COVID-19? Second, do patients with eosinopenia (now intentionally induced by biological drugs) have unique COVID-19 susceptibility and/or disease course? This is a particularly relevant question because eosinopenia is associated with acute respiratory deterioration during infection with the severe acute respiratory syndrome coronavirus 2, the causative agent of COVID-19. Third, do eosinophils contribute to the lung pathology induced during COVID-19 and will they contribute to immunopotentiation potentially associated with emerging COVID-19 vaccines? Herein, we address these timely questions and project considerations during the emerging COVID-19 pandemic.
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Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Eosinófilos/inmunología , Pandemias/prevención & control , Neumonía Viral/inmunología , Neumonía Viral/prevención & control , Vacunas Virales/inmunología , Animales , COVID-19 , Vacunas contra la COVID-19 , Humanos , SARS-CoV-2RESUMEN
As the novel coronavirus severe acute respiratory syndrome coronavirus 2 caused coronavirus disease 2019 cases in the United States, the initial test was developed and performed at the Centers for Disease Control and Prevention. As the number of cases increased, the demand for tests multiplied, leading the Centers for Disease Control and Prevention to use the Emergency Utilization Authorization to allow clinical and commercial laboratories to develop tests to detect the presence of the virus. Many nucleic acid tests based on RT-PCR were developed, each with different techniques, specifications, and turnaround time. As the illnesses turned into a pandemic, testing became more crucial. The test supply became inadequate to meet the need and so it had to be prioritized according to guidance. For surveillance, the need for serologic tests emerged. Here, we review the timeline of test development, the turnaround times, and the various approved tests, and compare them as regards the genes they detect. We concentrate on the point-of-care tests and discuss the basis for new serologic tests. We discuss the testing guidance for prioritization and their application in a hospital setting.
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Técnicas de Laboratorio Clínico/métodos , Infecciones por Coronavirus/diagnóstico , Neumonía Viral/diagnóstico , Pruebas Serológicas/métodos , Proteínas Virales/análisis , Betacoronavirus , COVID-19 , Prueba de COVID-19 , Humanos , Pandemias , Pruebas en el Punto de Atención , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , SARS-CoV-2RESUMEN
BACKGROUND: Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. OBJECTIVE: We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). METHODS: We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/ßGeo) mouse model and validated select findings in a patient with KS. RESULTS: Compared with wild-type littermates, Kmt2d+/ßGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d+/ßGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d+/ßGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. CONCLUSIONS: Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.
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Anomalías Múltiples/inmunología , Anomalías Múltiples/patología , Linfocitos B/patología , Cara/anomalías , Enfermedades Hematológicas/inmunología , Enfermedades Hematológicas/patología , Ganglios Linfáticos Agregados/patología , Enfermedades Vestibulares/inmunología , Enfermedades Vestibulares/patología , Animales , Linfocitos B/inmunología , Diferenciación Celular/inmunología , Movimiento Celular/inmunología , Proteínas de Unión al ADN/genética , Cara/patología , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Deficiencia de IgA/genética , Deficiencia de IgA/inmunología , Cadenas beta de Integrinas/metabolismo , Intestinos/inmunología , Ratones , Mutación , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Neoplasias/genética , Ganglios Linfáticos Agregados/inmunologíaRESUMEN
Kabuki syndrome (KS) is a disorder of epigenetic dysregulation due to heterozygous mutations in KMT2D or KDM6A, genes encoding a lysine-specific methyltransferase or demethylase, respectively. The phenotype is highly variable, including congenital cardiac and renal anomalies, developmental delay, hypotonia, failure to thrive, short stature, and immune dysfunction. All affected individuals have characteristic facial features. As KS natural history has not been fully delineated, limited information exists on its prenatal and perinatal history. Two tertiary centers collected retrospective data from individuals with KS (N = 49) using a questionnaire followed by review of medical records. Data from 49 individuals (age range: 7 months-33 years; 37% male; 36 with KMT2D mutations, 2 with KDM6A mutations, and 11 diagnosed clinically) were examined. Polyhydramnios affected 16 of 39 (41%) pregnancies. Abnormal quad screens in four out of nine (44%) pregnancies and reduced placental weights also complicated KS pregnancies. These data comprise the first large dataset on prenatal and perinatal history in individuals with confirmed (genetically or clinically) KS. Over a third of pregnancies were complicated by polyhydramnios, possibly secondary to abnormal craniofacial structures and functional impairment of swallowing. The differential diagnosis for polyhydramnios in the absence of intrauterine growth retardation should include KS.
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Anomalías Múltiples/diagnóstico , Proteínas de Unión al ADN/genética , Cara/anomalías , Retardo del Crecimiento Fetal/diagnóstico , Enfermedades Hematológicas/diagnóstico , Histona Demetilasas/genética , Proteínas de Neoplasias/genética , Polihidramnios/diagnóstico , Enfermedades Vestibulares/diagnóstico , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Adolescente , Adulto , Niño , Preescolar , Diagnóstico Diferencial , Cara/patología , Femenino , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/patología , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/patología , Humanos , Lactante , Masculino , Mutación , Fenotipo , Polihidramnios/genética , Polihidramnios/patología , Embarazo , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/patología , Adulto JovenRESUMEN
BACKGROUND: Kabuki syndrome (KS) is a clinically recognisable syndrome in which 70% of patients have a pathogenic variant in KMT2D or KDM6A. Understanding the function of these genes opens the door to targeted therapies. The purpose of this report is to propose diagnostic criteria for KS, particularly when molecular genetic testing is equivocal. METHODS: An international group of experts created consensus diagnostic criteria for KS. Systematic PubMed searches returned 70 peer-reviewed publications in which at least one individual with molecularly confirmed KS was reported. The clinical features of individuals with known mutations were reviewed. RESULTS: The authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined below) at some point of life. Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. Further criteria for a probable and possible diagnosis, including a table of suggestive clinical features, are presented. CONCLUSION: As targeted therapies for KS are being developed, it is important to be able to make the correct diagnosis, either with or without molecular genetic confirmation.
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Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Cara/anomalías , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/genética , Enfermedades Vestibulares/diagnóstico , Enfermedades Vestibulares/genética , Anomalías Múltiples/etiología , Consenso , Proteínas de Unión al ADN/genética , Femenino , Enfermedades Hematológicas/etiología , Histona Demetilasas/genética , Humanos , Discapacidad Intelectual/etiología , Masculino , Hipotonía Muscular/etiología , Mutación , Proteínas de Neoplasias/genética , Enfermedades Vestibulares/etiologíaAsunto(s)
Contaminación del Aire , Asma , Contaminación del Aire/efectos adversos , Niño , Células Epiteliales , Humanos , Interleucina-17 , NeutrófilosRESUMEN
BACKGROUND: Kabuki syndrome (KS) is a complex multisystem developmental disorder associated with mutation of genes encoding histone-modifying proteins. In addition to craniofacial, intellectual, and cardiac defects, KS is also characterized by humoral immune deficiency and autoimmune disease, yet no detailed molecular characterization of the KS-associated immune phenotype has been reported. OBJECTIVE: We sought to characterize the humoral immune defects found in patients with KS with lysine methyltransferase 2D (KMT2D) mutations. METHODS: We comprehensively characterized B-cell function in a cohort (n = 13) of patients with KS (age, 4 months to 27 years). RESULTS: Three quarters (77%) of the cohort had a detectable heterozygous KMT2D mutation (50% nonsense, 20% splice site, and 30% missense mutations), and 70% of the reported mutations are novel. Among the patients with KMT2D mutations (KMT2D(Mut/+)), hypogammaglobulinemia was detected in all but 1 patient, with IgA deficiency affecting 90% of patients and a deficiency in at least 1 other isoform seen in 40% of patients. Numbers of total memory (CD27(+)) and class-switched memory B cells (IgM(-)) were significantly reduced in patients with KMT2D(Mut/+) mutations compared with numbers in control subjects (P < .001). Patients with KMT2D(Mut/+) mutations also had significantly reduced rates of somatic hypermutation in IgG (P = .003) but not IgA or IgM heavy chain sequences. Impaired terminal differentiation was noted in primary B cells from patients with KMT2D(Mut/+) mutations. Autoimmune pathology was observed in patients with missense mutations affecting the SET domain and its adjacent domains. CONCLUSIONS: In patients with KS, autosomal dominant KMT2D mutations are associated with dysregulation of terminal B-cell differentiation, leading to humoral immune deficiency and, in some cases, autoimmunity. All patients with KS should undergo serial clinical immune evaluations.
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Anomalías Múltiples/genética , Anomalías Múltiples/inmunología , Linfocitos B/citología , Proteínas de Unión al ADN/genética , Cara/anomalías , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/inmunología , Proteínas de Neoplasias/genética , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/inmunología , Adolescente , Adulto , Agammaglobulinemia/genética , Agammaglobulinemia/inmunología , Linfocitos B/inmunología , Diferenciación Celular , Niño , Preescolar , Humanos , Lactante , Mutación , Adulto JovenRESUMEN
Bioactive lipids are critical regulators of inflammation. Over the last 75 years, these diverse compounds have emerged as clinically-relevant mediators of allergic disease pathophysiology. Animal and human studies have demonstrated the importance of lipid mediators in the development of asthma, allergic rhinitis, urticaria, anaphylaxis, atopic dermatitis, and food allergy. Lipids are critical participants in cell signaling events which influence key physiologic (bronchoconstriction) and immune phenomena (degranulation, chemotaxis, sensitization). Lipid-mediated cellular mechanisms including: (1) formation of structural support platforms (lipid rafts) for receptor signaling complexes, (2) activation of a diverse family of G-protein coupled receptors, and (3) mediating intracellular signaling cascades by acting as second messengers. Here, we review four classes of bioactive lipids (platelet activating factor, the leukotrienes, the prostanoids, and the sphingolipids) with special emphasis on lipid synthesis pathways and signaling, atopic disease pathology, and the ongoing development of atopy treatments targeting lipid mediator pathways.
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Hipersensibilidad/metabolismo , Animales , Eicosanoides/fisiología , Humanos , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/inmunología , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Leucotrienos/fisiología , Metabolismo de los Lípidos , Terapia Molecular Dirigida , Factor de Activación Plaquetaria/fisiología , Transducción de Señal , Esfingolípidos/fisiologíaAsunto(s)
Anomalías Múltiples , Enfermedades Hematológicas , Enfermedades Vestibulares , Cara/anomalías , Humanos , MutaciónRESUMEN
NFKB2 encodes the p100/p52 protein, a critical mediator of the canonical and noncanonical NFkB signaling pathways. Here we report the comprehensive immune evaluation of a child with a novel NFKB2 mutation and provide evidence that aberrant NFKB2 signaling not only causes humoral immune deficiency, but also interferes with the TCR-mediated proliferation of T cells. These observations expand the known phenotype associated with NFKB2 mutations.
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Síndromes de Inmunodeficiencia/genética , Subunidad p52 de NF-kappa B/genética , Preescolar , Humanos , Masculino , Mutación , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Understanding the implementation of key guideline recommendations is critical for managing severe asthma (SA) in the treatment of uncontrolled disease. OBJECTIVE: To assess specialist visits and medication escalation in US patients with SA after events indicating uncontrolled disease (EUD) and associations with health outcomes and social disparity indicators. METHODS: Patients with SA appearing in administrative claims data spanning 2015 to 2020 were indexed hierarchically on asthma-related EUD, including hospitalizations, emergency department visits with systemic corticosteroid treatment, or outpatient visits with systemic corticosteroid treatment. Patients with SA without EUD served as controls. Eligibility included age 12 or greater, 12 months enrollment before and after index, no biologic use, and no other major respiratory disease during the pre-period. Escalation of care in the form of specialist visits and medication escalation, health care resource use, costs, and disease exacerbations were assessed during follow-up. RESULTS: We identified 180,736 patients with SA (90,368 uncontrolled and 90,368 controls). Between 35% and 51% of patients with SA with an EUD had no specialist visit or medication escalation. Follow-up exacerbations ranged from 51% to 4% across EUD cohorts, compared with 13% in controls. Among uncontrolled patients with SA who were Black or Hispanic/Latino, 41% and 38%, respectively, had no specialist visit or medication escalation after EUD, compared with 33% of non-Hispanic White patients. CONCLUSIONS: A substantial proportion of uncontrolled patients with SA had no evidence of specialist visits or medication escalation after uncontrolled disease, and there was a clear relationship between uncontrolled disease and subsequent health care resource use and exacerbations. Findings highlight the need for improved guideline-based care delivery to patients with SA, particularly for those facing social disparities.
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Asma , Humanos , Asma/tratamiento farmacológico , Asma/epidemiología , Asma/terapia , Estados Unidos/epidemiología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Adolescente , Adulto Joven , Hospitalización/estadística & datos numéricos , Antiasmáticos/uso terapéutico , Niño , Índice de Severidad de la Enfermedad , Disparidades en Atención de Salud , Corticoesteroides/uso terapéutico , AncianoRESUMEN
INTRODUCTION: Many patients with severe asthma continue to experience symptoms and exacerbations despite treatment with standard-of-care therapy. In the phase 3 NAVIGATOR study, tezepelumab significantly reduced exacerbations over 52 weeks compared with placebo in patients with severe, uncontrolled asthma. This analysis assessed the efficacy of tezepelumab in reducing asthma exacerbations in various clinically relevant subgroups of patients in NAVIGATOR. METHODS: NAVIGATOR was a phase 3, multicentre, randomized, double-blind, placebo-controlled study. Participants (12-80 years old) with severe, uncontrolled asthma were randomized 1:1 to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Pre-specified and post hoc analyses were performed to evaluate the annualized asthma exacerbation rate (AAER) over 52 weeks in clinically relevant subgroups of patients defined by baseline patient characteristics, medical history, exacerbation triggers, medication eligibility and medication use before and during the study. RESULTS: Tezepelumab reduced the AAER over 52 weeks compared with placebo across a wide range of patient subgroups assessed. Reductions in exacerbations were similar across subgroups defined by baseline patient characteristics, ranging from 48% (95% confidence interval [CI]: 21, 65) to 60% (95% CI: 44, 71) in subgroups analysed by sex, smoking history and body mass index. Among the asthma-related comorbidity subgroups investigated, patients with aspirin or NSAID sensitivity had the greatest reductions in AAER with tezepelumab compared with placebo (83%; 95% CI: 66, 91). In patients eligible to receive dupilumab, tezepelumab reduced exacerbations compared with placebo by 64% (95% CI: 54, 71). Reductions in the AAER with tezepelumab compared with placebo were also observed irrespective of exacerbation trigger category and the number of asthma controller medications patients were receiving at baseline. CONCLUSION: These findings further support the benefits of tezepelumab in patients with severe, uncontrolled asthma and can help to inform healthcare providers' treatment decisions. CLINICAL TRIAL REGISTRATION: NAVIGATOR (NCT03347279).
Asunto(s)
Antiasmáticos , Anticuerpos Monoclonales Humanizados , Asma , Humanos , Asma/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Femenino , Método Doble Ciego , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anciano , Antiasmáticos/uso terapéutico , Adolescente , Adulto Joven , Resultado del Tratamiento , Anciano de 80 o más Años , Niño , Índice de Severidad de la EnfermedadRESUMEN
Individuals with Kabuki syndrome present with immunodeficiency; however, how pathogenic variants in the gene encoding the histone-modifying enzyme lysine methyltransferase 2D (KMT2D) lead to immune alterations remain poorly understood. Following up on our prior report of KMT2D-altered integrin expression in B-cells, we performed targeted analyses of KMT2D's influence on integrin expression in T-cells throughout development (thymocytes through peripheral T-cells) in murine cells with constitutive- and conditional-targeted Kmt2d deletion. Using high-throughput RNA-sequencing and flow cytometry, we reveal decreased expression (both at the transcriptional and translational levels) of a cluster of leukocyte-specific integrins, which perturb aspects of T-cell activation, maturation, adhesion/localization, and effector function. H3K4me3 ChIP-PCR suggests that these evolutionary similar integrins are under direct control of KMT2D. KMT2D loss also alters multiple downstream programming/signaling pathways, including integrin-based localization, which can influence T-cell populations. We further demonstrated that KMT2D deficiency is associated with the accumulation of murine CD8+ single-positive (SP) thymocytes and shifts in both human and murine peripheral T-cell populations, including the reduction of the CD4+ recent thymic emigrant (RTE) population. Together, these data show that the targeted loss of Kmt2d in the T-cell lineage recapitulates several distinct features of Kabuki syndrome-associated immune deficiency and implicates epigenetic mechanisms in the regulation of integrin signaling.