R. Robert Schellenberg

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma. As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling. Anti-inflammatory therapy, however, does not “cure” asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM. In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

Canadian clinical practice guidelines for acute and chronic rhinosinusitis

This document provides healthcare practitioners with information regarding the management of acute rhinosinusitis (ARS) and chronic rhinosinusitis (CRS) to enable them to better meet the needs of this patient population. These guidelines describe controversies in the management of acute bacterial rhinosinusitis (ABRS) and include recommendations that take into account changes in the bacteriologic landscape. Recent guidelines in ABRS have been released by American and European groups as recently as 2007, but these are either limited in their coverage of the subject of CRS, do not follow an evidence-based strategy, or omit relevant stakeholders in guidelines development, and do not address the particulars of the Canadian healthcare environment.Advances in understanding the pathophysiology of CRS, along with the development of appropriate therapeutic strategies, have improved outcomes for patients with CRS. CRS now affects large numbers of patients globally and primary care practitioners are confronted by this disease on a daily basis. Although initially considered a chronic bacterial infection, CRS is now recognized as having multiple distinct components (eg, infection, inflammation), which have led to changes in therapeutic approaches (eg, increased use of corticosteroids). The role of bacteria in the persistence of chronic infections, and the roles of surgical and medical management are evolving. Although evidence is limited, guidance for managing patients with CRS would help practitioners less experienced in this area offer rational care. It is no longer reasonable to manage CRS as a prolonged version of ARS, but rather, specific therapeutic strategies adapted to pathogenesis must be developed and diffused.Guidelines must take into account all available evidence and incorporate these in an unbiased fashion into management recommendations based on the quality of evidence, therapeutic benefit, and risks incurred. This document is focused on readability rather than completeness, yet covers relevant information, offers summaries of areas where considerable evidence exists, and provides recommendations with an assessment of strength of the evidence base and degree of endorsement by the multidisciplinary expert group preparing the document.These guidelines have been copublished in both Allergy, Asthma & Clinical Immunology and the Journal of Otolaryngology-Head and Neck Surgery.

Hypothesis: excessive bronchoconstriction in asthma is due to decreased airway elastance

Based on the strikingly different mechanical properties of airway smooth muscle preparations of different species, we hypothesized that a decrease in the elastance of nonmuscle elements within airway walls of asthmatics reduces the load limiting smooth muscle shortening, thereby allowing excessive smooth muscle shortening and bronchoconstriction. Full thickness, circumferentially cut, lobar bronchial preparations were obtained from one asthmatic and six nonasthmatic lobectomy subjects. Passive tension of the asthmatic preparation was less than that for any nonasthmatic preparation at all lengths below that for optimal force generation (Lmax). Maximal isometric force generation was greater in the asthmatic specimen (2.32 g) than in the nonasthmatic specimens (0.90 +/- 0.15 g), with stress threefold higher for the asthmatic tissue. Isotonic shortening of the asthmatic preparation was strikingly greater at starting lengths less than or equal to Lmax, with maximal fractional shortening being 31% versus 11 +/- 2% for nonasthmatic preparations. Morphometric analysis revealed no differences in cross-sectional areas of smooth muscle for asthmatic versus nonasthmatic preparations. We conclude that the reduced tissue elastance may account for the greater muscle shortening by placing a lesser load upon the smooth muscle. Airway inflammation in asthma may alter connective tissue matrix elements within airway walls leading to this decreased elastance and excessive smooth muscle shortening.

A Randomized Phase IIb Trial of Pulmicort Turbuhaler (Budesonide) in People with Dysplasia of the Bronchial Epithelium

Purpose: Preclinical studies suggest that inhaled budesonide may be an effective chemopreventive agent for lung cancer. We conducted a phase IIb study to determine the effects of inhaled budesonide in smokers with bronchial dysplasia. Experimental Design: A total of 112 smokers with more than or equal to one site of bronchial dysplasia > 1.2 mm in size identified by autofluorescence bronchoscopy-directed biopsy was randomly assigned to receive placebo or budesonide (Pulmicort Turbuhaler) 800 μg twice daily inhalation for 6 months. The primary end point was change in the histopathologic grade on repeat biopsy of the same sites at the end of 6 months. Results: There were no significant differences in the regression or progression rates of bronchial dysplasia between the two groups. There was a statistically significant but modest decrease in p53 and BclII expression in the bronchial biopsies after 6 months of Pulmicort Turbuhaler versus placebo (P = 0.01 and P = 0.001, respectively). There was a small but statistically significant decrease in the proportion of computed tomography-detected lung nodules after Pulmicort Turbuhaler compared with placebo (P = 0.024). Conclusions: Our results suggest that in smokers, inhaled budesonide in the dose of 1600 μg daily for 6 months had no effect in regression of bronchial dysplastic lesions or prevention of new lesions. Budesonide treatment resulted in a modest decrease in p53 and BclII protein expression in bronchial biopsies and a slightly higher rate of resolution of computed tomography-detected lung nodules. Whether budesonide truly has an effect in preneoplastic lesions in the peripheral airways and alveoli requires additional investigation.

In vitro responses of human asthmatic airway and pulmonary vascular smooth muscle.

Airway and pulmonary vascular smooth muscle was obtained from the surgically resected lobe of a human asthmatic allergic to grass pollen who presented with an endobronchial carcinoid tumor. Grass antigen induced sustained contractions of bronchial and pulmonary vein, but not pulmonary artery tissue. Capsaicin did not alter the bronchial response to grass antigen. Contractions to leukotrienes B4, C4, D4 and E4 and methacholine were equivalent to those seen in nonasthmatic human lung tissue, whereas those to histamine were strikingly greater and disproportionate to methacholine. The C3a octapeptide Ala-Ala-Ala-Leu-Gly-Leu-Ala-Arg produced contractions of pulmonary vein and pulmonary artery. These findings are compared with those obtained using human lung samples from nonasthmatic individuals.

The Use of Immunoglobulin Therapy for Patients With Primary Immune Deficiency: An Evidence-Based Practice Guideline

The standard treatment for patients with primary antibody deficiency is immunoglobulin (IG), but the care of these patients is complex. These guidelines, initiated by the Canadian Blood Services and the National Advisory Committee on Blood and Blood Products, have been developed to facilitate and standardize the care of these patients by the various physician specialties that are responsible for their care. A panel of national expert immunologists and methodologists developed salient clinical questions; and a systematic, expert, and bibliography literature search up to July 2008 was conducted. One thousand eighty-seven citations were retrieved, and 102 reports were used in the preparation of this guideline. The recommendations provide guidance (1) on the complexity of the treatment of these patients; (2) the established benefits of IG on morbidity and mortality; (3) dosage, routes of administration, and management of reactions; (4) the various IG formulations available; (5) vaccination of these patients; and (6) research priorities.

Interleukin-3, but not granulocyte–macrophage colony-stimulating factor and interleukin-5, inhibits apoptosis of human basophils through phosphatidylinositol 3-kinase: requirement of NF-κB-dependent and -independent pathways

Basophils are key effector cells of allergic reactions. Although proinflammatory cytokines, such as interleukin (IL)‐3, granulocyte–macrophage colony‐stimulating factor (GM–CSF) and IL‐5, inhibit eosinophil apoptosis in vitro, little is known about basophil apoptosis, and the signalling mechanisms required for basophil survival remain undefined. To address this issue, we used a novel negative‐selection system to isolate human basophils to a purity of > 95%, and evaluated apoptosis by morphology using light and transmission electron microscopy, and by annexin‐V binding and propidium iodide incorporation using flow cytometry. In this study, we demonstrated that the spontaneous rate of apoptotic basophils was higher than that of eosinophils as, at 24 hr, 57·6 ± 4·7% of basophils underwent apoptosis compared with 39·5 ± 3·8% of eosinophils. In addition, basophil cell death was significantly inhibited when cultured with IL‐3 for 48 hr (84·6 ± 4·9% vehicle‐treated cells versus 40·9 ± 3·9% IL‐3‐treated cells). IL‐3 also up‐regulated basophil CD69 surface expression. The effects of IL‐3 on apoptosis and CD69 surface expression of human basophils were completely blocked by LY294002 (LY), a potent inhibitor of phosphatidylinositol 3‐kinase (PI3‐K), but only partially inhibited by lactacystin, a proteasome inhibitor that prevents degradation of IκB and NF‐κB translocation. These observations reveal the novel finding that IL‐3 prevents basophil apoptosis through the activation of PI3‐K, which is only partially NF‐κB dependent. As basophils are active participants in allergic reactions and IL‐3 is one of the abundant proinflammatory cytokines in secretions from allergic tissue, we suggest that IL‐3‐mediated inhibition of basophil apoptosis may exacerbate the inflammation associated with allergic disorders.

Urticaria and angioedema

Urticaria (hives) is a common disorder that often presents with angioedema (swelling that occurs beneath the skin). It is generally classified as acute, chronic or physical. Second-generation, non-sedating H1-receptor antihistamines represent the mainstay of therapy for both acute and chronic urticaria. Angioedema can occur in the absence of urticaria, with angiotensin-converting enzyme (ACE) inhibitor-induced angioedema and idiopathic angioedema being the more common causes. Rarer causes are hereditary angioedema (HAE) or acquired angioedema (AAE). Although the angioedema associated with these disorders is often self-limited, laryngeal involvement can lead to fatal asphyxiation in some cases. The management of HAE and AAE involves both prophylactic strategies to prevent attacks of angioedema (i.e., trigger avoidance, attenuated androgens, tranexamic acid, and plasma-derived C1 inhibitor replacement therapy) as well as pharmacological interventions for the treatment of acute attacks (i.e., C1 inhibitor replacement therapy, ecallantide and icatibant). In this article, the authors review the causes, diagnosis and management of urticaria (with or without angioedema) as well as the work-up and management of isolated angioedema, which vary considerably from that of angioedema that occurs in the presence of urticaria.

Introduction of a Practice Guideline for Penicillin Skin Testing Improves the Appropriateness of Antibiotic Therapy

We hypothesized that the introduction of a practice guideline for penicillin skin testing would increase the appropriateness of skin testing and reduce antibiotic costs for patients with a history of penicillin allergy who have infections caused by penicillin-susceptible pathogens. We measured the appropriateness of skin testing and daily antibiotic costs before and after the introduction of a guideline for penicillin skin testing. For patients who had negative results of skin testing and were subsequently treated with a penicillin instead of an alternative antibiotic, we calculated the difference between the actual costs and the projected costs of continuing alternative antibiotics without skin testing. After the guideline was introduced, appropriateness of skin testing increased from 17% to 64%, but daily antibiotic costs did not change. For patients who had negative results of skin testing and who were subsequently treated with a penicillin, there was no difference between actual costs and the projected costs if they had not been skin tested. We conclude that introduction of a guideline for penicillin skin testing increases the percentage of eligible patients who have a skin test, and it does so without increasing costs.

Allergic sensitization increases airway reactivity in guinea pigs with respiratory syncytial virus bronchiolitis

BACKGROUND Respiratory syncytial virus (RSV) causes acute bronchiolitis in children and has been implicated in the pathogenesis of recurrent wheezing and asthma. However, few children exposed to RSV experience acute bronchiolitis or its sequelae, suggesting a subgroup of susceptible children. An allergic diathesis may predispose children to subsequent airway disease. OBJECTIVE This study was carried out to determine whether a preexisting allergic state, induced by repeated inhalational exposures to ovalbumin, potentiates nonspecific airway responsiveness to acetylcholine and increases airway inflammation during acute RSV bronchiolitis in guinea pigs. METHODS Forty guinea pigs were randomized into four groups: nonsensitized, noninfected (ovalbumin-, RSV-); sensitized, noninfected (ovalbumin+, RSV-); nonsensitized, infected (ovalbumin-, RSV+); sensitized, infected (ovalbumin+, RSV+). Depending on grouping, animals were exposed to either repeated aerosols of ovalbumin or saline solution and were subsequently inoculated with either human RSV or uninfected culture medium. Six days after inoculation, animals underwent acetylcholine challenge, and lung specimens were prepared for histologic scoring of airway inflammation. RESULTS Maximal increases in pulmonary resistance (centimeters of water per milliliter per second) to acetylcholine were greater for RSV alone (12.4 +/- 3.9) and ovalbumin alone (13.7 +/- 3.9) compared with controls (4.3 +/- 1.1), but significantly greater increases occurred in ovalbumin+, RSV+ animals (34.0 +/- 11.0). These ovalbumin+, RSV+ animals demonstrated the combined histologic changes noted with RSV alone and ovalbumin alone including airway epithelial necrosis, mononuclear and granulocyte infiltrates, airway wall edema, hyperplasia of bronchus-associated lymphoid tissue, and goblet cell metaplasia. CONCLUSION Prior allergic sensitization potentiates the physiologic and structural changes induced by acute RSV bronchiolitis. These results suggest that an allergic diathesis may increase the severity of RSV infections in children.