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.

Background African-Americans have a greater burden from asthma compared to Caucasians. Whether the pattern of airway inflammation differs between African-Americans and Caucasians is unclear. Objective To compare sputum airway inflammatory phenotypes of African-Americans and Caucasians treated or not treated with ICS (ICS+ and ICS-, respectively). Methods We performed a secondary analysis of self-identified African-Americans and Caucasians with asthma enrolled in clinical trials conducted by the National Heart, Lung, and Blood Institute-sponsored Asthma Clinical Research Network and AsthmaNet. Demographics, clinical characteristics, and sputum cytology following sputum induction were examined. We utilized a sputum eosinophil 2% cut point to define individuals with either an eosinophilic (≥2%) or non-eosinophilic (<2%) inflammatory phenotype. Results Among 1,018 participants, African-Americans (n=264) had a lower FEV1% predicted (80 vs. 85%, p<0.01), greater total IgE (197 vs. 120, p<0.01) and a greater proportion with uncontrolled asthma (43% vs. 28%, p<0.01) compared to Caucasians (n=754). There were 922 subjects in the ICS+ group (248 African-Americans, 674 Caucasians) and 298 subjects in the ICS− group (49 African-Americans, 249 Caucasians). Eosinophilic airway inflammation was not significantly different between African-Americans and Caucasians in either group (% with eosinophilic phenotype: ICS+ group: 19% vs. 16%, p=0.28; ICS− group: 39% vs. 35%, p=0.65; respectively). However, when adjusted for confounding factors, African-Americans were more likely to exhibit eosinophilic airway inflammation than Caucasians in the ICS+ group (OR:1.58; CI:1.01–2.48; p=0.046), but not in the ICS− group (p=0.984). Conclusion African-Americans exhibit greater eosinophilic airway inflammation, which may explain the greater asthma burden in this population.

13The National Heart Lung and Blood Institute's Severe Asthma Research Program-3 investigators are detailed in the supplemental acknowledgments. 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). 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. METHODS. ALX expression and levels of proresolving ligands (lipoxin

Exacerbations in 1,840 Asthma Subjects from 12 Clinical Trials (Median Observation Period=126-379 Days) Blacks (N=161) Genetic African Ancestry >82% is a Risk Factor for Exacerbations in Self-Reported Blacks. Whole-Genome Ancestry Estimated in Subgroup Factor for Exacerbations eported Blacks. Whites (N=489) p=0.03 Exacerbation-Prone Asthma in the Context of Race and Ancestry in Asthma Clinical Research Network Trials 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, selfreported race (black, non-Hispanic white, and other), and estimates of global genetic African ancestry in a subgroup (n 5 760).

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 ¼ 0.005] and 4.7 mmHg [P ¼ 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 ¼ 0.019] and 95.0 dyn·s/cm 5 [P ¼ 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.

There is an association between VKORC1-1639A variant and anticoagulant doses.

13The National Heart Lung and Blood Institute's Severe Asthma Research Program-3 investigators are detailed in the supplemental acknowledgments. 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). 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. METHODS. ALX expression and levels of proresolving ligands (lipoxin

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