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ABSTRACTIntroduction: Asthma is an airway disease characterized by airway inflammation. It is associated with significant morbidity, mortality, and costs to the healthcare system and society. Interleukin-5 (IL-5) was identified for its role in eosinophil development, maturation, and survival in tissues, which has been related to disease severity and airway eosinophilia.Areas covered: In this review, we will present the pharmacokinetics and dynamics of mepolizumab in addition to efficacy and safety data.Expert Opinion: Mepolizumab is novel, new, first-in-class therapy targeting IL-5. It has been found to be particularly effective in the management of patients with asthma whose peripheral blood eosinophil count is at a well-defined cut point within the normative range. This easily available biomarker, along with a history of asthma exacerbations, has translated into a clinically significant reduction in asthma exacerbations and the dose of oral corticosteroids in patients who previously have been prednisone-dependent. The pivotal studies indicate that mepolizumab was well tolerated, with the most frequently reported adverse events being headache, nasopharyngitis, worsening of asthma, and local injection reactions. These study investigators did not report any deaths or anaphylaxis related to mepolizumab.

Analysis of human tumour-derived cell lines has previously resulted in the identification of novel transformation-related elements and provided a useful tool for functional studies of different genes. To establish the utility of such cell lines as indicators of change relevant to urothelial cancer, we have characterised the expression of five genes (p53, MDM2, Rb, E-cadherin, APC) within a panel of human bladder carcinoma cell lines. Using single-strand conformation polymorphism (SSCP) and direct sequencing, p53 mutations were identified in 7/15 (47%) cell lines reflecting events reported in bladder tumours. Immunohistochemical analysis of p53 in cultured cells and in paraffin-embedded sections of xenografts from the cell line panel revealed discordant results. An absence of p53 nuclear staining was associated with an exon 5 mutation in EJ and with multiple p53 mutations found in J82. Two cell lines positive for p53 staining in the absence of detectable mutation displayed overexpression of MDM2 (PSI, HT1197) in Western blot analysis. Loss or aberrant Rb expression was recorded in 5/15 (TCCSUP, SCaBER, 5637, HT1376, J82) cell lines. Absence of E-cadherin was recorded in 5/15 cell lines (TCCSUP, EJ, KK47, UM-UC-3, J82) with loss of alpha-catenin in immunoprecipitated E-cadherin complexes of CUBIII. Western blot analysis of APC revealed a truncated protein in 1/15 (CUBIII) cell lines. The characterisation of oncogenic events within this panel of human bladder carcinoma cell lines establishes a representation of change observed in bladder tumours and better defines the genotypic background in these experimental human cell models of neoplastic progression.

BACKGROUND: Obstructive sleep apnea-hypopnea (OSAH) is a common disorder characterized by recurrent collapse of the upper airway during sleep. Patients experience a reduced quality of life and an increased risk of motor vehicle crashes (MVCs). Continuous positive airway pressure (CPAP), which is the first-line therapy for OSAH, improves sleepiness, vigilance and quality of life.OBJECTIVE: To assess the cost-effectiveness of CPAP therapy versus no treatment for OSAH patients who are drivers.METHODS: A Markov decision analytical model with a five-year time horizon was used. The study population consisted of male and female patients, between 30 and 59 years of age, who were newly diagnosed with moderate to severe OSAH. The model evaluated the cost-effectiveness of CPAP therapy in reducing rates of MVCs and improving quality of life. Utility values were obtained from previously published studies. Rates of MVCs under the CPAP and no CPAP scenarios were calculated from Insurance Corporation of British Columbia data and a systematic review of published studies. MVCs, equipment and physician costs were obtained from the British Columbia Medical Association, published cost-of-illness studies and the price lists of established vendors of CPAP equipment in British Columbia. Findings were examined from the perspectives of a third-party payer and society.RESULTS: From the third-party payer perspective, CPAP therapy was more effective but more costly than no CPAP (incremental cost-effectiveness ratio [ICER] of $3,626 per quality-adjusted life year). From the societal perspective, the ICER was similar ($2,979 per quality-adjusted life year). The ICER was most dependent on preference elicitation method used to obtain utility values, varying almost sixfold under alternative assumptions from the base-case analysis.CONCLUSION: After considering costs and impact on quality of life, as well as the risk of MVCs in individuals with OSAH, CPAP therapy for OSAH patients is a highly efficient use of health care resources. Provincial governments who do not provide funding for CPAP therapy should reconsider.

OBJECTIVE: To evaluate the prevalence of gastroesophageal reflux disease (GERD) in patients presenting with asthma and chronic cough.PATIENTS AND METHODS: The charts of 358 consecutive patients who were referred for ambulatory gastroesophageal pH monitoring to the Lung Centre in Vancouver, British Columbia, were reviewed, and the data of 108 (30%) patients with asthma and 134 (37%) patients with chronic cough were analyzed. The maintenance treatment for GERD was discontinued before patients underwent the pH monitoring study. One hundred eighteen (33%) patients were excluded.RESULTS: Reflux episodes identified reflux events as the percentage of time where the pH was less than four. For asthma patients, 70 (64.8%) had distal total reflux, 50 (46.3%) had distal upright reflux, 41 (38.3%) had distal supine reflux and 73 (67.6%) had other distal refluxes. Proximal total reflux in asthmatic patients was present in 56 (52%), proximal upright reflux in 55 (51%) and proximal supine reflux in 56 (52%) patients. For chronic cough patients, 70 (52.6%) had distal total reflux, 59 (44.4%) had distal upright reflux, 45 (34.4%) had distal supine reflux and 75 (56%) patients had other distal refluxes. In chronic cough patients, proximal total reflux was present in 70 (52%), proximal upright reflux in 80 (60%) and proximal supine reflux in 59 (44%). Presenting respiratory and/or reflux symptoms were absent in approximately 25% of patients with asthma and reflux, and in approximately 50% of patients with chronic cough and reflux. During pH monitoring, symptoms did not differ significantly between those with and without distal reflux in both study groups, except for more significant heartburn in patients with chronic cough and reflux (RR 2.0).CONCLUSIONS: The data of the present study support the observation that there is a high prevalence of GERD in patients with asthma or chronic cough. The use of different pH parameters for detecting acid reflux during 24 h ambulatory pH monitoring, such as proximal esophageal acid measurement, should be considered as part of the routine interpretation of such testing. A low threshold for diagnosing GERD in patients with asthma or chronic cough is essential, because respiratory and/or reflux symptoms can be absent or atypical in some of these patients.

BACKGROUND: Asthma mortality and morbidity continue to be a serious global problem. Systematic reviews provide an opportunity to review risk factors in detail.OBJECTIVE: To review all of the literature for risk factors associated with near-fatal asthma (NFA) and fatal asthma (FA).METHODS: A literature search from 1960 to January 2004 in MEDLINE and EMBASE was conducted. Studies were included based on the following criteria: NFA was defined as an asthma exacerbation resulting in respiratory arrest requiring mechanical ventilation or a partial pressure of CO2 of at least 45 mmHg or asthma resulting in death (FA); the study reported the number of cases (NFA and/or FA) and asthmatic controls; there was explicit reporting of risk factors; cases that were adult and pediatric in nature; and all study types. Studies that included patients with chronic obstructive pulmonary disease were excluded.RESULTS: Four hundred and three articles were identified, of which 27 met the inclusion criteria. Increased use of medications such as beta-agonists via metered dose inhalers (OR=1.67, 95% CI 0.99 to 2.84, P=0.057) and nebulizers (OR=2.45, 95% CI 1.52 to 3.93, P=0.0002), oral steroids (OR=2.71, 95% CI 1.34 to 5.51, P=0.006) and oral theophylline (OR=2.02, 95% CI 1.03 to 3.98, P=0.04) and a history of hospital (OR=2.62, 95% CI 1.04 to 6.58, P=0.04) and/or intensive care unit (OR=5.14, 95% CI 1.91 to 13.86, P=0.001) admissions and mechanical ventilation (OR=6.69, 95% CI 2.80 to 15.97, P=0.0001) due to asthma were predictors of NFA and FA. Prior emergency department assessment did not confer a greater risk of NFA and FA (OR=1.13, 95% CI 0.43 to 2.92, P=0.810).The use of inhaled corticosteroids (ICS) measured in a dose-independent fashion (did the patient take ICS previously; yes or no) inferred equivocal risk of NFA and FA (OR=1.31, 95% CI 0.83 to 2.05, P=0.25). However, two studies measured the use of ICS in a dose-dependent fashion (ie, measured the number of prescriptions filled within the previous six to 12 months). Both studies showed a trend toward a protective effect against FA. One study showed that the premature cessation of ICS can hasten death.CONCLUSIONS: In the present study, risk factors of NFA and FA have been more accurately defined. Clinicians should identify patients with these characteristics to reduce their risk of NFA and FA. Further research should focus on quantifying the impact of risk factors on asthma deaths.

BACKGROUND: The lack of a relationship between airway responsiveness and respiratory symptoms in epidemiological studies of children may, in part, reflect inaccuracies in symptom reporting or inadequate knowledge by the parent of the child's symptoms.OBJECTIVE: To relate airway responsiveness to methacholine in children with symptoms of respiratory illness in the child as reported by the parent and as reported by the child.POPULATION: Eight- to 10-year-old (n=290) randomly sampled schoolchildren.SETTING: Seven randomly selected schools in Ontario.METHODS: Parents completed a mailed questionnaire regarding the child's respiratory health. Children completed a similar interview-administered questionnaire at school and underwent methacholine challenge testing by the tidal breathing method.RESULTS: The cumulative prevalence of a history of physician-diagnosed asthma was 9.0%, and of any wheezing it was 25.5%. A further 9% of children reported wheezing not documented by their parent. Of 229 children consenting to methacholine challenge, 78 (34.1%) showed airway responsiveness in the range generally associated with asthma in adults (provocation concentration of methacholine causing a 20% fall [PC20] in forced expired volume in 1 s [FEV1] 8 mg/mL or less); half of these children had no history of respiratory symptoms reported by the parent. The sensitivity of airway hyperresponsiveness defined by a cut-point for PC20 8 mg/mL or less in relation to any history of recurrent wheezing reported by the parent was 48% and did not improve if only symptoms within the past year were considered (sensitivity 44%); the specificity of the test for parent-reported symptoms ever was 71%, and 68% in those with symptoms in the past year. None of these sensitivities or specificities was increased by using symptoms reported by the child or by combining parent and child reported symptoms. Receiver operating characteristic (ROC) curves for sensitivity and specificity of the methacholine test were constructed for parent and child reports of symptoms. For all symptom strata, the cut-point of PC20 producing optimal balance of sensitivity and specificity was between 4 and 8 mg/mL. A parental questionnaire positive for physician-diagnosed asthma was strongly related to methacholine response, producing an ROC curve with an area significantly different from 0.5 (P=0.006), as did all parent-reported wheezing (P=0.009). If the child reported asthma, there was an equally strong relationship, with a positive ROC curve (P=0.001), as there was for all child-reported wheezing (P=0.048).CONCLUSIONS: Airway hyperresponsiveness to methacholine in children relates closely with asthma and wheezing reported by either the parent or the child. In addition, the results confirm that respiratory symptoms and airway hyperresponsiveness are common in Canadian children, and that airway hyperresponsiveness may be found in children with no history of respiratory illness either at present or in the past.

OBJECTIVES: To characterize two cluster outbreaks of tuberculosis by DNA fingerprinting and to evaluate the possibility of their association with human immunodeficiency virus (HIV) infection and multiple drug-resistant Mycobacterium tuberculosis.SETTING: Two clusters of tuberculosis cases in adjoining aboriginal Canadian reserves and a control population.METHODS: All cases of tuberculosis diagnosed in the two communities and a number of control isolates were fingerprinted using a novel simplified DNA-based technique. Demographic data, purified protein derivative (PPD) skin test response to 5TU PPD, type of disease and HIV serology were also evaluated. Positive cultures were assessed for susceptibility to antituberculous drugs.RESULTS: Two distinct clusters with five cases in one community and 21 cases in the second were identified. Isolates from both communities differed in their DNA pattern but were identical within communities. Thirteen cases had bacteriologically proven disease and grew susceptible organisms. Serological analysis for HIV infection was carried out in 15 of 18 adults, and all were negative.CONCLUSIONS: The study shows the potential for the rapid transmission of tuberculosis infection in HIV-negative subjects with susceptible organisms. It further highlights the usefulness of DNA fingerprinting for molecular epidemiology in evaluating particular outbreaks.