Eosinophils Target Therapy for Severe Asthma: Critical Points

Asthma is a chronic and heterogeneous disease, which is defined as severe disease whenever it requires treatment with a high dose of inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming ‘‘uncontrolled’’ or if it remains ‘‘uncontrolled’’ despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma, which is characterized by sputum eosinophilia, associated with mild to moderate increase in blood eosinophil count, frequently adult-onset, and associated with chronic rhinosinusitis with nasal polyps in half of the cases. Eosinophilic asthma is driven by T2 inflammation, characterized, among the others, by interleukin-5 production. IL-5 plays a key role in the differentiation, survival, migration, and activation of eosinophils, and it has become an appealing therapeutic target for eosinophilic asthma. In recent years two monoclonal antibodies (mepolizumab and reslizumab) directed against IL-5 and one monoclonal antibody directed against the alpha-subunit of the IL-5 receptor (benralizumab) have been developed. All these IL-5 target drugs have been shown to reduce the number of exacerbation in patients with severe asthma selected on the basis of peripheral blood eosinophil count. There are still a number of unresolved issues related to the anti-IL5 strategy in eosinophilic asthma, which are here reviewed. These issues include the effects of such therapy on airway obstruction and asthmatic symptoms, the level of baseline eosinophils that predicts a response to treatment, the relationship between blood and airway eosinophilia, and, perhaps most importantly, how to elucidate the pathogenetic role played by eosinophils in the individual patient with severe eosinophilic asthma

Il‐17 promotes nitric oxide production in non‐small‐cell lung cancer

Introduction: Lung cancer is the second most frequent malignancy worldwide, but its aetiology is still unclear. Inflammatory cytokines and Th cells, including Th17, are now emerging as being involved in NSCLC pathways, thus postulating a role of IL‐17 in tumour angiogenesis by stimulating the vascular endothelial growth factor and the release of nitric oxide. Despite the fact that many biomarkers are used for chest malignancy diagnosis, data on FeNO levels and inflammatory cytokines in NSCLC are still few. Our study aimed to evaluate the relationship between pulmonary nitric oxide production and VEGF and Th17‐related cytokines in the EBC of patients affected by early‐stage NSCLC. Methods: FeNO measurement and lung function tests were performed in both patients affected by NCSLC and controls; EBC samples were also taken, and Th1 (IL‐1, IL‐6, IL‐12, IFN‐g, TNF‐a), Th17 (IL‐17, IL‐23) and Th2 (IL‐4, IL‐5, IL‐13) related cytokines were measured. Results: Th1 and Th17‐related cytokines in EBC, except for IFN‐gamma and TNF-alpha, were significantly higher in patients than in healthy controls, whereas no differences were seen for Th2‐related cytokines. FeNO at the flow rate of 50 mL/s, JawNO and CalvNO levels were significantly higher in patients affected by NSCLC compared to controls. Significant correlations were found between FeNO 50 mL/s and IL‐17, IL‐1 and VEGF. JawNO levels positively correlated with IL‐6, IL‐17 and VEGF. No correlations were found between FeNO and Th2‐related cytokines. Conclusion: This is the first report assessing a relationship between FeNO levels and Th17‐related cytokines in the EBC of patients affected by early‐stage NSCLC. IL‐17, which could promote angiogenesis through the VEGF pathway, might be indirectly responsible for the increased lung production of NO in patients with NSCLC

Association of Checklist Use in Endotracheal Intubation With Clinically Important Outcomes: A Systematic Review and Meta-analysis

Importance: The ε4 allele of the apolipoprotein E (APOE) gene and lower apolipoprotein E (apoE) protein levels in plasma are risk factors for Alzheimer disease, but the underlying biological mechanisms are not fully understood. Half of plasma apoE circulates on high-density lipoproteins (HDLs). Higher apoE levels in plasma HDL were previously found to be associated with lower coronary heart disease risk, but the coexistence of another apolipoprotein, apoC3, modified this lower risk. Objective: To investigate associations between the presence of apoE in different lipoproteins with cognitive function, particularly the risk of dementia. Design, Setting, and Participants: This prospective case-cohort study embedded in the Ginkgo Evaluation of Memory Study (2000-2008) analyzed data from 1351 community-dwelling participants 74 years and older. Of this group, 995 participants were free of dementia at baseline (recruited from September 2000 to June 2002) and 521 participants were diagnosed with incident dementia during follow-up until 2008. Data analysis was performed from January 2018 to December 2019. Exposures: Enzyme-linked immunosorbent assay–measured concentration of apoE in whole plasma, HDL-depleted plasma (non-HDL), HDL, and HDL subspecies that contain or lack apoC3 or apoJ. Main Outcomes and Measures: Adjusted hazard ratios for risk of dementia and Alzheimer disease during follow-up and adjusted differences (β coefficients) in Alzheimer Disease Assessment–Cognitive Subscale (ADAS-cog) and Modified Mini-Mental State Examination scores at baseline. Results: Among 1351 participants, the median (interquartile range) age was 78 (76-81) years; 639 (47.3%) were women. The median (interquartile range) follow-up time was 5.9 (3.7-6.5) years. Higher whole plasma apoE levels and higher apoE levels in HDL were associated with better cognitive function assessed by ADAS-cog (whole plasma, β coefficient, −0.15; 95% CI, −0.24 to −0.06; HDL, β coefficient, −0.20; 95% CI, −0.30 to −0.10) but were unassociated with dementia or Alzheimer disease risk. When separated by apoC3, a higher apoE level in HDL that lacks apoC3 was associated with better cognitive function (ADAS-cog per SD: β coefficient, 0.17; 95% CI, −0.27 to −0.07; Modified Mini-Mental State Examination score per SD: β coefficient, 0.25; 95% CI, 0.07 to 0.42) and lower risk of dementia (hazard ratio per SD, 0.86; 95% CI, 0.76 to 0.99). In contrast, apoE levels in HDL that contains apoC3 were unassociated with any of these outcomes. Conclusions and Relevance: In a prospective cohort of older adults with rigorous follow-up of dementia, the apoE level in HDL that lacked apoC3 was associated with better cognitive function and lower dementia risk. This finding suggests that the cardioprotective associations of this novel lipoprotein extend to dementia

Treatment plan comparison in acute and chronic respiratory tract diseases : an observational study of doxophylline vs. theophylline

BACKGROUND: The main objective of this article is to estimate the global cost related to the use of the two drugs (associated drugs, specialist visits, hospital admissions, plasma drug monitoring). METHODS: The drug prescriptions were extracted from the Information System of the Pharmaceutical Prescriptions of the Marche Region for each ATC code in the years 2008-2012 and the number of patients per year and other outcomes measure were obtained. RESULTS: 13,574 patients were treated with theophylline and 19,426 patients with doxophylline. The number of patients treated was approximately 5,000 per year. Co-prescription with other drugs, use of corticosteroids, mean number of visits and hospital admissions (per 100 patients) were lower for doxophylline vs theophylline (1.55vs5.50, 0.3vs0.7, 2.05vs3.73 and 1.57vs3.3 respectively). The annual mean cost per patient was €187.4 for those treated with doxophylline and €513.5 for theophylline. CONCLUSIONS: In our study, doxophylline resulted to be associated with a reduction of the overall cost