American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Feb 2019
Randomized Controlled TrialAnti-IL5 in Mild Asthma Alters Rhinovirus-Induced Macrophage, B Cell and Neutrophil Responses (MATERIAL): A Placebo-Controlled, Double-Blind Study.
Eosinophils drive pathophysiology in stable and exacerbating eosinophilic asthma, and therefore treatment is focused on the reduction of eosinophil numbers. Mepolizumab, a humanized monoclonal antibody that neutralizes IL-5 and efficiently attenuates eosinophils, proved clinically effective in severe eosinophilic asthma but not in mild asthma. ⋯ Mepolizumab failed to prevent activation of remaining eosinophils and changed RV16-induced immune responses in mild asthma. Although these latter effects likely are caused by attenuated eosinophil numbers, we cannot exclude a role for basophils. Clinical trial registered with www.clinicaltrials.gov (NCT 01520051).
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Am. J. Respir. Crit. Care Med. · Feb 2019
ReviewChildhood Asthma: Advances Using Machine Learning and Mechanistic Studies.
A paradigm shift brought by the recognition that childhood asthma is an aggregated diagnosis that comprises several different endotypes underpinned by different pathophysiology, coupled with advances in understanding potentially important causal mechanisms, offers a real opportunity for a step change to reduce the burden of the disease on individual children, families, and society. Data-driven methodologies facilitate the discovery of "hidden" structures within "big healthcare data" to help generate new hypotheses. These findings can be translated into clinical practice by linking discovered "phenotypes" to specific mechanisms and clinical presentations. ⋯ The key question of which component of these exposures can be translated into interventions requires confirmation. Increasing mechanistic evidence is demonstrating that shaping the microbiome in early life may modulate immune function to confer protection. Iterative dialogue and continuous interaction between experts with different but complementary skill sets, including data scientists who generate information about the hidden structures within "big data" assets, and medical professionals, epidemiologists, basic scientists, and geneticists who provide critical clinical and mechanistic insights about the mechanisms underpinning the architecture of the heterogeneity, are keys to delivering mechanism-based stratified treatments and prevention.
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Patients with severe uncontrolled asthma have disproportionally high morbidity and healthcare utilization as compared with their peers with well-controlled disease. Although treatment options for these patients were previously limited, with unacceptable side effects, the emergence of biologic therapies for the treatment of asthma has provided promising targeted therapy for these patients. Biologic therapies target specific inflammatory pathways involved in the pathogenesis of asthma, particularly in patients with an endotype driven by type 2 (T2) inflammation. ⋯ These targeted therapies have been shown to reduce asthma exacerbations, improve lung function, reduce oral corticosteroid use, and improve quality of life in appropriately selected patients. In addition to the currently approved biologic agents, several biologics targeting upstream inflammatory mediators are in clinical trials, with possible approval on the horizon. This article reviews the mechanism of action, indications, expected benefits, and side effects of each of the currently approved biologics for severe uncontrolled asthma and discusses promising therapeutic targets for the future.