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BACKGROUND: Minority groups of African descent experience disproportionately greater asthma morbidity compared with other racial groups, suggesting that genetic variation from a common ancestry could influence exacerbation risk. OBJECTIVE: We evaluated clinical trial measures in the context of self-reported race and genetic ancestry to identify risk factors for asthma exacerbations. METHODS: One thousand eight hundred forty multiethnic subjects from 12 Asthma Clinical Research Network and AsthmaNet trials were analyzed for incident asthma exacerbations with Poisson regression models that included clinical measures, self-reported race (black, non-Hispanic white, and other), and estimates of global genetic African ancestry in a subgroup (n = 760). RESULTS: Twenty-four percent of 1840 subjects self-identified as black. Black and white subjects had common risk factors for exacerbations, including a history of 2 or more exacerbations in the previous year and FEV1 percent predicted values, whereas chronic sinusitis, allergic rhinitis, and gastroesophageal reflux disease were only associated with increased exacerbation risk in black subjects. In the combined multiethnic cohort, neither race (P = .30) nor percentage of genetic African ancestry as a continuous variable associated with exacerbation risk (adjusted rate ratio [RR], 1.26 [95% CI, 0.94-1.70; P = .13]; RR per 1-SD change [32% ancestry], 0.97 [95% CI, 0.78-1.19; P = .74]). However, in 161 black subjects with genetic data, those with African ancestry greater than the median (≥82%) had a significantly greater risk of exacerbation (RR, 3.06 [95% CI, 1.09-8.6; P = .03]). CONCLUSION: Black subjects have unique risk factors for asthma exacerbations, of which global African genetic ancestry had the strongest effect.
Asunto(s)
Asma/etnología , Asma/genética , Negro o Afroamericano , Sistema de Registros , Autoinforme , Población Blanca , Adulto , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
OBJECTIVE: Exacerbations account for much of the morbidity in asthma. In a large intervention study, we sought to test the hypothesis that a Black adult exacerbation-prone phenotype - a group of Black people with asthma who are at high risk of repeat exacerbation within one year - exists in asthma independent of clinical control. METHODS: We analyzed exacerbation risk factors in 536 self-identified Black Americans with asthma eligible for, or on, Step 3 National Asthma Education and Prevention Program (NAEPP) therapy who participated in a randomized 6-18 month trial of tiotropium versus long acting beta agonist as add-on therapy to inhaled corticosteroids. Exacerbations were defined as events treated by oral or systemic corticosteroids. Clinical control was assessed by a validated asthma control questionnaire (ACQ5). RESULTS: Exacerbations became more likely with loss of clinical control. The mean baseline ACQs for exacerbators and non-exacerbators were 2.41 and 1.91, respectively (p < 0.001). The strongest independent factor associated with exacerbations across all ACQ levels was an exacerbation in the preceding year (adjusted OR 3.26; p < 0.001). The severity of prior exacerbations did not correlate with the likelihood of a future exacerbation. Lower baseline FEV1/FVC was also associated with increased risk of exacerbations. CONCLUSIONS: Even though exacerbations increase with loss of clinical control, an exacerbation susceptibility phenotype exists in Black adults with asthma, independent of clinical control. This phenotype requires precision therapeutic targeting.
Asunto(s)
Corticoesteroides/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Asma/tratamiento farmacológico , Negro o Afroamericano , Progresión de la Enfermedad , Bromuro de Tiotropio/uso terapéutico , Adulto , Asma/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoAsunto(s)
Corticoesteroides/administración & dosificación , Asma/complicaciones , Asma/tratamiento farmacológico , Colecalciferol/administración & dosificación , Enfermedades de los Senos Paranasales/complicaciones , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia del Tratamiento , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/tratamiento farmacológicoRESUMEN
Severe asthma is typically characterized by chronic airway inflammation that is refractory to corticosteroids and associated with excess morbidity. Patients were recruited into the National Heart, Lung, and Blood Institute-sponsored Severe Asthma Research Program and comprehensively phenotyped by bronchoscopy. Bronchoalveolar lavage (BAL) cells were analyzed by flow cytometry. Compared with healthy individuals (n = 21), patients with asthma (n = 53) had fewer BAL natural killer (NK) cells. Patients with severe asthma (n = 29) had a marked increase in the ratios of CD4+ T cells to NK cells and neutrophils to NK cells. BAL NK cells in severe asthma were skewed toward the cytotoxic CD56dim subset, with significantly increased BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56dim NK cells and CCR6-CCR4- T helper 1-enriched CD4+ T cells correlated inversely with lung function [forced expiratory volume in 1 s (FEV1) % predicted] in asthma. Relative to cells from healthy controls, peripheral blood NK cells from asthmatic patients had impaired killing of K562 myeloid target cells despite releasing more cytotoxic mediators. Ex vivo exposure to dexamethasone markedly decreased blood NK cell lysis of target cells and cytotoxic mediator release. NK cells expressed airway lipoxin A4/formyl peptide receptor 2 receptors, and in contrast to dexamethasone, lipoxin A4-exposed NK cells had preserved functional responses. Together, our findings indicate that the immunology of the severe asthma airway is characterized by decreased NK cell cytotoxicity with increased numbers of target leukocytes, which is exacerbated by corticosteroids that further disable NK cell function. These failed resolution mechanisms likely contribute to persistent airway inflammation in severe asthma.
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BACKGROUND: In health, inflammation resolution is an active process governed by specialized proresolving mediators and receptors. ALX/FPR2 receptors (ALX) are targeted by both proresolving and proinflammatory ligands for opposing signaling events, suggesting pivotal roles for ALX in the fate of inflammatory responses. Here, we determined if ALX expression and ligands were linked to severe asthma (SA). METHODS: ALX expression and levels of proresolving ligands (lipoxin A4 [LXA4], 15-epi-LXA4, and annexin A1 [ANXA1]), and a proinflammatory ligand (serum amyloid A [SAA]) were measured in bronchoscopy samples collected in Severe Asthma Research Program-3 (SA [n = 69], non-SA [NSA, n = 51] or healthy donors [HDs, n = 47]). RESULTS: Bronchoalveolar lavage (BAL) fluid LXA4 and 15-epi-LXA4 were decreased and SAA was increased in SA relative to NSA. BAL macrophage ALX expression was increased in SA. Subjects with LXA4loSAAhi levels had increased BAL neutrophils, more asthma symptoms, lower lung function, increased relative risk for asthma exacerbation, sinusitis, and gastroesophageal reflux disease, and were assigned more frequently to SA clinical clusters. SAA and aliquots of LXA4loSAAhi BAL fluid induced IL-8 production by lung epithelial cells expressing ALX receptors, which was inhibited by coincubation with 15-epi-LXA4. CONCLUSIONS: Together, these findings have established an association between select ALX receptor ligands and asthma severity that define a potentially new biochemical endotype for asthma and support a pivotal functional role for ALX signaling in the fate of lung inflammation. TRIAL REGISTRATION: Severe Asthma Research Program-3 (SARP-3; ClinicalTrials.gov NCT01606826)FUNDING Sources. National Heart, Lung and Blood Institute, the NIH, and the German Society of Pediatric Pneumology.
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Iloprost, an inhaled synthetic prostacyclin analogue, improves hemodynamic and clinical status with minimal systemic adversity in patients with pulmonary arterial hypertension. Our single-site, prospective case series aimed to determine the effects of iloprost in subjects with group 2 pulmonary hypertension and heart failure with preserved ejection fraction. Patients referred to Boston Medical Center for initial evaluation of suspected pulmonary hypertension received a test dose of 2.5 µg inhaled iloprost, followed by two subsequent doses of 5 µg. Hemodynamic measurements were recorded for each inhalation after 15, 30, 60, and 90 minutes. Results were analyzed via paired t test and signed-rank test. Eight subjects fulfilled criteria and elected to enter the study. There was a reduction of pulmonary arterial pressure (by an average of 7.0 mmHg [P = 0.005] and 4.7 mmHg [P = 0.021] with the first and second 5-µg inhalations, respectively) and pulmonary vascular resistance (by an average of 161.9 dyn·s/cm(5) [P = 0.019] and 95.0 dyn·s/cm(5) [P = 0.014] with the first and second 5-µg inhalations, respectively). There were trends for increased cardiac output and decreased oxygen saturation. There were no changes in other vital or hemodynamic parameters, including pulmonary capillary wedge pressure. All patients completed each cycle of iloprost administration without preestablished termination criteria. In patients with pulmonary hypertension and heart failure with preserved ejection fraction, inhaled iloprost resulted in acute reduction of pulmonary arterial pressure and pulmonary vascular resistance. Further evaluation of iloprost in this subset of patients is warranted.