Short-course subcutaneous treatment with PQ Grass strongly improves symptom and medication scores in grass allergy.

BACKGROUND: A modified grass allergen subcutaneous immunotherapy (SCIT) product with MicroCrystalline Tyrosine and monophosphoryl lipid-A as an adjuvant system (Grass MATA MPL [PQ Grass]) is being developed as short-course treatment of grass-pollen allergic rhinitis (SAR) and/or rhinoconjunctivitis. We sought to evaluate the combined symptom and medication score (CSMS) of the optimized cumulative dose of 27,600 standardized units (SU) PQ Grass in a field setting prior to embarking on a pivotal Phase III trial. METHODS: In this exploratory, randomized, double-blind, placebo-controlled trial subjects were enrolled across 14 sites (Germany and the United States of America). Six pre-seasonal subcutaneous injections of PQ Grass (using conventional or extended regimens) or placebo were administered to 119 subjects (aged 18-65 years) with moderate-to-severe SAR with or without asthma that was well-controlled. The primary efficacy endpoint was CSMS during peak grass pollen season (GPS). Secondary endpoints included Rhinoconjunctivitis Quality of Life Questionnaire standardized (RQLQ-S) and allergen-specific IgG4 response. RESULTS: The mean CSMS compared to placebo was 33.1% (p = .0325) and 39.5% (p = .0112) for the conventional and extended regimens, respectively. An increase in IgG4 was shown for both regimens (p < .01) as well as an improvement in total RQLQ-S for the extended regimen (mean change -0.72, p = .02). Both regimens were well-tolerated. CONCLUSIONS: This trial demonstrated a clinically relevant and statistically significant efficacy response to PQ Grass. Unprecedented effect sizes were reached for grass allergy of up to ≈40% compared to placebo for CSMS after only six PQ Grass injections. Both PQ Grass regimens were considered equally safe and well-tolerated. Based on enhanced efficacy profile extended regime will be progressed to the pivotal Phase III trial.

Asthma: an inflammatory mediator soup.

Reversible or partially reversible airway obstruction, inflammation, and bronchial hyperresponsiveness to various stimuli are the defining characteristics of asthma. Airway obstruction in asthma is a complex event that is due to bronchospasm, inflammation, and mucus formation. Inflammation has assumed a more central role in the pathogenesis of the disease, as it contributes not only to airflow obstruction, but also to bronchial hyperresponsiveness. The inciting trigger, or inhaled allergen, in asthma induces the activation of mast cells and macrophages with the subsequent release of several proinflammatory mediators, including leukotrienes, chemotactic factors, and cytokines. Antigen processed by macrophages is presented to undifferentiated T helper cells, inducing differentiation to the Th2 phenotype, with the subsequent release of IL-4 and IL-5, causing IgE synthesis and eosinophil infiltration, respectively. Macrophage-derived cytokines, such as IL-1, TNF-alpha, and IFN-gamma, activate endothelial cells, upregulating the expression of adhesion molecules such as ICAM-1 and VCAM-1, which permit egression of leukocytes from the vasculature to the airway mucosa. Several inflammatory cells, such as eosinophils, mast cells, and macrophages, not only cause airway damage, but also synthesize cytokines that perpetuate the inflammatory process. This complex interplay of inflammatory cells and mediators causes the classic histopathophysiologic features in the airways of both symptomatic and asymptomatic individuals with asthma, emphasizing the importance of early recognition and antiinflammatory treatment.

Rat eosinophils: isolation and characterization of superoxide production.

Studies with isolated cells are important to the understanding of mechanisms by which eosinophils participate in allergic inflammation. Due to species variability, isolation techniques and cell biology need to be defined for each source. We developed methods to obtain rat eosinophils with purity and viability exceeding 90%, characterized the superoxide anion production of these cells in response to standard activators, and compared these results with those previously obtained in our laboratories with the use of human eosinophils. Rat eosinophils responded vigorously to phorbol myristate acetate and poorly to platelet-activating factor and to N-formyl-methionyl-leucyl-phenylalanine, parallel to the responses of human eosinophils. In contrast, rat eosinophils responded unlike human eosinophils to other activators, having a larger response to calcium ionophore A23187, a smaller response to serum-treated or serum-opsonized zymosan, and a negative rather than positive modulatory effect of cytochalasin B. We conclude that rat eosinophils can be obtained in high purity and with intact responsiveness to a number of different activators.

Asthma and exercise.

There is evidence that the overall prevalence of asthma is increasing in the general population. Asthma is the leading cause of chronic illness and the most common chronic respiratory disorder in children. Given sufficient exercise intensity, exercise can trigger acute exacerbations in virtually all individuals with asthma. Heat loss, water loss, postexertional airway rewarming, and the role of several mediators have been proposed as possible mechanisms responsible for the airway obstruction induced by exercise. Exercise-induced asthma can be easily diagnosed and treated in the majority of patients. Physical training should be part of the asthmatic patient's overall plan of management. When properly treated, asthmatic individuals should be able to participate or compete in the majority of sports.

Steroid-resistant asthma.

The treatment of patients with asthma that is resistant to corticosteroids represents a therapeutic challenge, because corticosteroids are the most potent and potentially effective medications for severe asthma. Recent investigations have identified several functional defects in mononuclear cells and T lymphocytes isolated from patients with corticosteroid-resistant asthma, including abnormalities in proliferation, activation, and cytokine production. The development of medications with immunomodulatory effects on specific cellular functions represents an exciting step for more efficacious treatment for such patients.

The impact of respiratory infections on asthma.

It is apparent that the effects of viral respiratory infections on the development of airway hyperresponsiveness are multiple and interrelated and involved the production of viral specific IgE, upregulation of leukocyte inflammatory activity, enhancement of the factors involved in the generation of late phase allergic responses, altered beta-adrenergic and cholinergic nervous system activity, and damage to the airway epithelium. The summation of these effects is the development of airway inflammation rather than a direct effect on bronchial smooth muscle, per se. An understanding of this pathogenesis underscores the relative importance of anti-inflammatory rather than antimicrobial therapy in viral-induced exacerbations in asthma symptoms.