Friday, June 5, 2015
Development and validation of a novel risk score for asthma exacerbations: The risk score for exacerbations
Asthma management involves achieving and maintaining current asthma control and preventing exacerbations. Reports have shown, however, that there can be a disassociation between these two goals, meaning control may be achieved but risk of exacerbations may remain, or the opposite. The identification of patients at risk of future severe exacerbations, whose asthma might be less treatment-responsive, or both could focus treatment selection. To this end, Bateman et al have developed a simple risk score for exacerbations (RSE) for clinical use (J Allergy Clin Immunol 2015; 135(6): 1457-64).
The authors analyzed a large data set of patients enrolled in studies comparing the efficacy of budesonide-formoterol (BUD/FORM) maintenance and reliever therapy with fixed-dose inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) therapy. They included patients whose symptoms were not controlled on Global Initiative for Asthma (GINA) treatment steps 3 and 4 and who had experienced 1 or more exacerbations in the previous year. Using multivariate analysis, they found 4 dominant (all P <.001) predictors for both the risk of uncontrolled asthma and severe exacerbations: GINA step, reliever use, postbronchodilator FEV1, and 5-item Asthma Control Questionnaire score. Smoking status and asthma symptom scores were additional predictors for uncontrolled asthma, and body mass index was a fifth predictor for severe exacerbation.
Bateman et al show risk of uncontrolled asthma at 3 months of treatment and a severe exacerbation within 12 months can be estimated from simple clinical assessments. The prediction of treatment outcome could be particularly useful for patients similar to those in the current analysis, all of whom were receiving moderate-to-high ICS doses and 52% of whom were receiving LABAs and who had experienced at least 1 recent exacerbation, as it could identify patients who might benefit from intensified or alternative therapeutic measures.
Platelet-activating factor (PAF) is a potent phospholipid-derived mediator thought to play a pivotal role in the etiology of numerous immune and inflammatory conditions. Our knowledge of its effects has broadened to include those as a vasodilator and broncho-constrictor, a contributor to host defenses, and a mediatory of the inflammatory response, and PAF has been well-demonstrated in experimental models to function as a central mediator of anaphylaxis. Gill et al review what we know (J Allergy Clin Immunol 2015; 135(6): 1424-32).
PAF is produced and secreted by several types of cells including mast cells, monocytes, tissue macrophages, eosinophils, endothelial cells, neutrophils, and platelets. It is implicated in platelet aggregation and activation through release of vasoactive amines in the inflammatory response, resulting in effects including increased vascular permeability, circulatory collapse, and decreased cardiac output. Studies have shown patients with acute allergic reactions had elevated PAF serum levels, and patients with severe anaphylaxis had higher levels still. The latter group had respiratory or cardiovascular compromise, where both organ systems were targets of PAF bioactivity.
PAF is rapidly hydrolyzed and degraded to an inactive metabolite, lysoPAF, by the enzyme PAF-acetylhydrolase (PAF-AH), whose activity correlates inversely with PAF levels and predisposition to severe anaphylaxis. Several studies have confirmed more rapid rates of inactivation of PAF result in milder allergic manifestations. There is much interest around the development of therapies that selectively block the actions of PAF as both long-term prophylaxis and emergency treatment. In animal models, treatment with platelet-activating factor receptor (PAF-R) antagonists significantly reduced the severity of peanut-induced anaphylaxis and accelerated recovery from anaphylactic reactions. We are, however, still in the early stages of understanding PAF signaling, and further investigation of its role in pathology and therapeutic modulation is anticipated.
Platelets are anucleated blood elements involved in hemostasis and thrombosis. It is now understood that they can also act as inflammatory cells and contribute to host defense against infection, performing many functions normally associated with leukocytes. Studies have shown that platelet depletion compromises ability to resist microorganism infection. Given that many inflammatory diseases are the result of inappropriate activation of defense pathways, it is likely inappropriate platelet activation contributes to the pathogenesis of these diseases. Idzko et al present the currently available data investigating the role of platelets in allergic airway inflammation and asthma (J Allergy Clin Immunol 2015; 135(6): 1416-23).
Of particular relevance to allergic inflammation, it has been shown that platelets express IgE receptors on their surfaces. They play an essential role in killing certain parasites, and platelet activation has been shown to accompany allergen exposure of sensitized patients. Platelet activation has also been observed in patients with asthma, measured as an increase in the levels of a number of platelet-derived mediators in peripheral blood or in bronchoalveolar lavage fluid (BAL). It is evident that platelets can release a number of spasmogens that can constrict human airway smooth muscle, including 5-HT, which has been demonstrated to induce bronchoconstriction in asthmatic patients. And platelet depletion has been reported to reduce allergen-induced bronchial hyperresponsiveness in sensitized rabbits, associated with a reduction in eosinophil infiltration in the lungs.
The increasing number of observations suggesting a dichotomy of platelet activation between the signaling involved in thrombosis and hemostasis and the activation during inflammatory responses has considerable implication. For example, using adenosine diphosphate (ADP), the authors have recently demonstrated that P2Y1 receptors are required for platelet activation by inflammatory stimuli, whereas PY12 receptors required for platelet aggregation have no such effect. The dichotomy of function opens the real possibility of developing anti-inflammatory and anti-allergic therapies that target the novel pathways of platelet activation. It also raises the possibility of finding novel biomarkers for assessing disease, given the clear role of platelets in leukocyte recruitment.
Aspirin-exacerbated respiratory disease (AERD) is an acquired syndrome that is irreversible and debilitating. A chronic inflammatory disease characterized by the triad of asthma, nasal polyposis, and pathognomonic respiratory reactions after the ingestion of aspirin, it presents with an onset in young adulthood. Estimations indicate there are approximately 1.2 million adults in the United States living with AERD. Its pathogenesis likely involves disturbances in the mechanisms that regulate tissue recruitment of immune effector cells and activity of the 5-LO/LTC4S pathway. There is substantial evidence that platelets contribute to these mechanisms. Laidlaw et al review the evidence regarding asthma in general and AERD in particular (J Allergy Clin Immunol 2015; 135(6): 1407-14).
Platelets lack a nucleus and have no DNA. They are derived from cytoplasmic fragments of megakaryocytes and have a life span in the circulation of approximately 8-10 days before being removed by the spleen. In addition to their role in hemostasis, activated platelets can activate other immune cells, and upon adhesion to granulocytes, they can facilitate granulocyte recruitment into body tissues. They also secrete mediators including chemokines and lipids, which are released upon platelet activation. All of these contribute to symptomatic asthma exacerbations. Specific to AERD, patients with the condition have high numbers of platelet-adherent granulocytes in their nasal polyp tissue, which contributes to the overproduction of cysteinyl leukotrienes.
Whether or not the circulating platelets implicated in AERD possess an intrinsic defect is still unknown. In vitro stimulation studies have shown platelets from AERD patients released nearly twice as much ATP when activated with platelet-activating factor than those from healthy controls did. The platelets also released significantly increased levels of TXB2, which was not seen in the controls. Differences in biochemistry seem possible, suggesting trials examining targeted anti-platelet therapeutics may be appropriate. Studies have also suggested therapies aimed at reducing numbers of platelet-leukocyte aggregates, T-prostanoid receptor blockade, and P2Y12 receptor antagonism all may be of use, and relevant clinical trials are in their early stages.