Joanne M. Duncan

The September epidemic of asthma exacerbations in children: A search for etiology

Background Predictable peaks of asthma exacerbation requiring hospital treatment, of greatest magnitude in children and of uncertain etiology, occur globally after school returns. Objective We wished to determine whether asthmatic children requiring emergency department treatment for exacerbations after school return in September were more likely to have respiratory viruses present and less likely to have prescriptions for control medications than children with equally severe asthma not requiring emergent treatment. Methods Rates of viral detection and characteristics of asthma management in 57 (of 60) children age 5 to 15 years presenting to emergency departments with asthma in 2 communities in Canada between September 10 and 30, 2001, (cases) were compared with those in 157 age-matched volunteer children with asthma of comparable severity studied simultaneously (controls). Results Human picornaviruses were detected in 52% of cases and 29% of controls (P =.002) and viruses of any type in 62% of cases and 41% of controls (P =.011). Cases were less likely to have been prescribed controller medication (inhaled corticosteroid, 49% vs 85%; P < .0001; leukotriene receptor antagonist, 9% vs 21%; P =.04). Conclusion Respiratory viruses were detected in the majority of children presenting to emergency departments with asthma during the September epidemic of the disease and in a significant minority of children with asthma in the community. The latter were more likely to have anti-inflammatory medication prescriptions than children requiring emergent treatment. Such medication may reduce the risk of emergency department treatment for asthma during the September epidemic.

Evidence that Herpes Simplex Virus VP16 Is Required for Viral Egress Downstream of the Initial Envelopment Event

ABSTRACT During infection with herpes simplex virus type 1 (HSV-1), VP16 serves multiple functions, including transcriptional activation of viral immediate early genes and downregulation of the virion host shutoff protein vhs. Furthermore, VP16 has been shown to be involved in some aspect of virus assembly and/or maturation. Experiments with a VP16 null virus, 8MA, suggested that VP16 plays a direct role in virion assembly, since removal of VP16 from the HSV-1 genome results in reduced levels of encapsidated DNA and a failure to produce extracellular enveloped particles. However, VP16 null mutants display a severe translational arrest due to unrestrained vhs activity, thus complicating interpretation of these data. We examine here the role of VP16 in virion assembly and egress in the context of a vhs null background, using the virus 8MA/ΔSma (VP16−vhs−). Comparison of 8MA and 8MA/ΔSma with respect to viral DNA accumulation and encapsidation and accumulation of the major capsid protein, VP5, revealed that the 8MA lethal phenotype is only partially due to uncontrolled vhs activity, indicating that VP16 is required in HSV-1 virion formation. Electron microscopy confirmed these results and further showed that VP16 is required for HSV-1 egress beyond the perinuclear space. In addition, we describe the isolation and characterization of an 8MA derivative capable of propagation on Vero cells, due to second site mutations in the vhs and UL53 (gK) genes. Taken together, these results show that VP16 is required for viral egress downstream of the initial envelopment step and further underscore the importance of VP16 in controlling vhs activity within an infected cell.

Attenuation of the September Epidemic of Asthma Exacerbations in Children: A Randomized, Controlled Trial of Montelukast Added to Usual Therapy

BACKGROUND. A recurring epidemic of asthma exacerbations in children occurs annually in September in North America when school resumes after summer vacation. OBJECTIVE. Our goal was to determine whether montelukast, added to usual asthma therapy, would reduce days with worse asthma symptoms and unscheduled physician visits of children during the September epidemic. PATIENTS AND METHODS. A total of 194 asthmatic children aged 2 to 14 years, stratified according to age group (2–5, 6–9, and 10–14 years) and gender, participated in a double-blind, randomized, placebo-controlled trial of the addition of montelukast to usual asthma therapy between September 1 and October 15, 2005. RESULTS. Children randomly assigned to receive montelukast experienced a 53% reduction in days with worse asthma symptoms compared with placebo (3.9% vs 8.3%) and a 78% reduction in unscheduled physician visits for asthma (4 [montelukast] vs 18 [placebo] visits). The benefit of montelukast was seen both in those using and not using regular inhaled corticosteroids and among those reporting and not reporting colds during the trial. There were differences in efficacy according to age and gender. Boys aged 2 to 5 years showed greater benefit from montelukast (0.4% vs 8.8% days with worse asthma symptoms) than did older boys, whereas among girls the treatment effect was most evident in 10- to 14-year-olds (4.6% [montelukast] vs 17.0% [placebo]), with nonsignificant effects in younger girls. CONCLUSIONS. Montelukast added to usual treatment reduced the risk of worsened asthma symptoms and unscheduled physician visits during the predictable annual September asthma epidemic. Treatment-effect differences observed between age and gender groups require additional investigation.

Breastfeeding and allergies : time for a change in paradigm?

Purpose of reviewThis review examines recent studies of the relationships between breastfeeding and the epidemiology of allergic diseases, especially atopic dermatitis in infants and asthma in early and later childhood. Recent findingsResults from observational birth cohort studies, case–control studies, and one cluster randomized intervention trial have generally failed to demonstrate a protective effect of breastfeeding on outcomes of atopic dermatitis, allergic sensitization, wheezing, or asthma. Difficulties in interpretation relate to the absence of nonbreastfed control or reference groups in some studies, meaning outcomes can only be compared between different durations of breastfeeding. Studies with a nonbreastfed control group suggest there is an increased risk for atopy and asthma associated with breastfeeding and that prolonged breastfeeding may eventually reduce this increased risk. The family history, sex of the child, and the presence of other risk factors for allergy and asthma also influence the outcome. SummaryAlthough breastfeeding is strongly recommended for its multiple benefits on child health, most recent studies do not confirm the ‘conventional wisdom’ that breastfeeding is protective against allergy and asthma. Early reduction in childhood wheezing may reflect protection from viral infections, but allergies and asthma at later ages may be increased.

Changes in Exhaled Nitric Oxide Related to Estrogen and Progesterone During the Menstrual Cycle

BACKGROUND Significant changes in asthma and atopy occur throughout the menstrual cycle. We hypothesized that the characteristics of asthma (eg, symptoms, exhaled nitric oxide [eNO] levels as a marker of airway inflammation, pulmonary function, and atopy) vary throughout the menstrual cycle in relation to changes in the levels of estrogen or progesterone and that this variation is attenuated in women using oral contraception (OC). METHODS Seventeen women with asthma were studied over the course of their menstrual cycle through daily measurements of symptoms, eNO, spirometry, 17beta-estradiol, and progesterone levels, and through the performance of alternate-day allergy skin-prick tests (SPTs). RESULTS Of 534 potential daily visits, 526 (98.5%) were completed. Women not using OC (n = 8) had higher mean eNO levels (48.2 parts per billion [ppb]; 95% CI, 43.1 ppb to 53.3 ppb) than women using OC (27.0 ppb; 95% CI, 24.2 ppb to 29.7 ppb; p <or= 0.005). Among women not using OC, a 10 pmol/L increase in 17beta-estradiol levels was associated with a 15.2-ppm decrease in eNO levels (95% CI, -23.4 ppb to -7.0 ppm; p < 0.005). In contrast, an increase in progesterone level of 0.5 nmol/L was significantly associated with a 10.0-ppb increase in eNO (95% CI, 1.2 ppb to 18.7 ppb; p <or= 0.05). Consistent and significant results were found for 17beta-estradiol and progesterone levels and SPT. There were no significant associations between sex hormones and markers of asthma among women using OC. CONCLUSION During natural menstrual cycles, increases in estrogen levels were associated with decreased eNO levels, whereas increases in progesterone levels were associated with increased eNO levels and SPT wheal size. These effects were not observed among women using OC.

The Canadian Healthy Infant Longitudinal Development (CHILD) Study: examining developmental origins of allergy and asthma

The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study recruited 3624 pregnant women, most partners and 3542 eligible offspring. We hypothesise that early life physical and psychosocial environments, immunological, physiological, nutritional, hormonal and metabolic influences interact with genetics influencing allergic diseases, including asthma. Environmental and biological sampling, innate and adaptive immune responses, gene expression, DNA methylation, gut microbiome and nutrition studies complement repeated environmental and clinical assessments to age 5. This rich data set, linking prenatal and postnatal environments, diverse biological samples and rigorous phenotyping, will inform early developmental pathways to allergy, asthma and other chronic inflammatory diseases.

Disparate geographic prevalences of asthma, allergic rhinoconjunctivitis and atopic eczema among adolescents in five Canadian cities.

Wang H‐Y, Pizzichini MMM, Becker AB, Duncan JM, Ferguson AC, Greene JM, Rennie DC, Senthilselvan A, Taylor BW, Sears MR. Disparate geographic prevalences of asthma, allergic rhinoconjunctivitis and atopic eczema among adolescents in five Canadian cities.
Pediatr Allergy Immunol 2010: 21: 867–877.
© 2010 John Wiley & Sons A/S

The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study: Assessment of environmental exposures

The Canadian Healthy Infant Longitudinal Development birth cohort was designed to elucidate interactions between environment and genetics underlying development of asthma and allergy. Over 3600 pregnant mothers were recruited from the general population in four provinces with diverse environments. The child is followed to age 5 years, with prospective characterization of diverse exposures during this critical period. Key exposure domains include indoor and outdoor air pollutants, inhalation, ingestion and dermal uptake of chemicals, mold, dampness, biological allergens, pets and pests, housing structure, and living behavior, together with infections, nutrition, psychosocial environment, and medications. Assessments of early life exposures are focused on those linked to inflammatory responses driven by the acquired and innate immune systems. Mothers complete extensive environmental questionnaires including time-activity behavior at recruitment and when the child is 3, 6, 12, 24, 30, 36, 48, and 60 months old. House dust collected during a thorough home assessment at 3–4 months, and biological specimens obtained for multiple exposure-related measurements, are archived for analyses. Geo-locations of homes and daycares and land-use regression for estimating traffic-related air pollution complement time-activity-behavior data to provide comprehensive individual exposure profiles. Several analytical frameworks are proposed to address the many interacting exposure variables and potential issues of co-linearity in this complex data set.

The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study for Patients on a Direct Oral Anticoagulant Who Need an Elective Surgery or Procedure: Design and Rationale

Background The perioperative management of patients who take a direct oral anticoagulant (DOAC) for atrial fibrillation and require treatment interruption for an elective surgery/procedure is a common clinical scenario for which best practices are uncertain. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study is designed to address this unmet clinical need. We discuss the rationale for the PAUSE design and analysis plan as well as the rationale supporting the perioperative DOAC protocol. Methods PAUSE is a prospective study with three parallel cohorts, one for each DOAC, to assess a standardized but patient-specific perioperative management protocol for DOAC-treated patients with atrial fibrillation. The perioperative protocol accounts for DOAC type, patients renal function and surgery/procedure-related bleeding risk. The primary study aim is to demonstrate the safety of the PAUSE protocol for the perioperative management of each DOAC. The secondary aim is to determine the effect of the pre-procedure interruption on residual anticoagulation when measured by the dilute thrombin time for dabigatran and anti-factor Xa levels for rivaroxaban and apixaban. The study hypothesis is that the perioperative management protocol for each DOAC is safe for patient care, defined by expected risks for major bleeding of 1% (80% power to exclude 2%), and for arterial thromboembolism of 0.5% (80% power to exclude 1.5%) in each DOAC group. Conclusion The PAUSE study has the potential to establish a standard-of-care approach for the perioperative management of DOAC-treated patients. The PAUSE management protocol is designed to be easily applied in clinical practice, as it is standardized and also patient specific.

The herpes simplex virus type 1 immediate-early polypeptide ICP4 is required for expression of globin genes located in the viral genome

We infected Vero cells with ICP4-deficient herpes simplex virus recombinants bearing the rabbit beta-globin and human alpha 2-globin genes under the control of their own promoters and found that globin gene expression occurred only when ICP4 was provided in trans. These results demonstrate that ICP4 is required for the activity of globin promoters located in the viral genome and support the hypothesis that these cellular promoters are functionally equivalent to HSV early regulatory regions.