The evaluation of the correct use and ease-of use of the ELLIPTA DPI in children with asthma.

RATIONALE: Asthma studies show many children use inhalers incorrectly even after instruction. For two age groups of children with asthma, we determined the proportions who used the once-daily ELLIPTA dry-powder inhaler (DPI) correctly, and who found it easy to use. METHODS: This was a multicenter, single-arm, stratified, open-label, placebo study (NCT03478657). Children aged 5-7 and 8-11 years were trained in, and required to demonstrate, correct placebo ELLIPTA DPI use at their first clinic visit. The inhaler was used at home once daily for 28 ± 2 days. On returning to the clinic, children were randomized to an age-appropriate, ease-of-use questionnaire that had been developed and validated previously, and which rated the inhaler as "easy" or "hard" to use. Following questionnaire completion, children were then asked to demonstrate correct inhaler use. Correct use and ease-of use were assessed in each age group (co-primary endpoints) and overall (secondary endpoints). RESULTS: Of 222 enrolled children, 221 completed the study. Among children aged 5-7 years, 92% (n = 81/88) demonstrated correct ELLIPTA use on their first attempt, compared with 93% (n = 124/133) aged 8-11 years. Of these children, 98% (5-7 years: n = 79/81; 8-11 years: n = 121/124) rated the inhaler easy to use. Overall, 93% (n = 205/221) demonstrated correct inhaler use on their first attempt, and 98% (n = 200/205) rated it easy to use. CONCLUSION: ELLIPTA DPI was used correctly and easily by most children on their first attempt without additional training.

Elevated antigen-driven IL-9 responses are prominent in peanut allergic humans.

Food allergies, and peanut allergy in particular, are leading causes of anaphylactic fatalities worldwide. The immune mechanisms that underlie food allergy remain ill-defined and controversial, in part because studies in humans typically focus on analysis of a limited number of prototypical Th1/Th2 cytokines. Here we determine the kinetics and prevalence of a broad panel of peanut-driven cytokine and chemokine responses in humans with current peanut allergy vs those with stable, naturally occurring clinical tolerance to peanut. Our primary focus is identification of novel indicators of immune dysregulation. Antigen-specific cytokine mRNA and protein responses were elicited in primary culture via peanut or irrelevant antigen (Leishmania extract, milk antigens) mediated stimulation of fresh peripheral blood cells from 40 individuals. Peanut extract exposure in vitro induced a broad panel of responses associated with Th2/Th9-like, Th1-like and Th17-like immunity. Peanut-dependent Type 2 cytokine responses were frequently found in both peanut allergic individuals and those who exhibit clinical tolerance to peanut ingestion. Among Th2/Th9-associated cytokines, IL-9 responses discriminated between allergic and clinically tolerant populations better than did commonly used IL-4, IL-5 or IL-13 responses. Comparison with responses evoked by unrelated control antigen-mediated stimulation showed that these differences are antigen-dependent and allergen-specific. Conversely, the intensity of IL-12, IL-17, IL-23 and IFN-γ production was indistinguishable in peanut allergic and peanut tolerant populations. In summary, the ability to generate and maintain cytokine responses to peanut is not inherently distinct between allergic and peanut tolerant humans. Quantitative differences in the intensity of cytokine production better reflects clinical phenotype, with optimally useful indicators being IL-9, IL-5, IL-13 and IL-4. Equivalent, and minimal, Ag-dependent pro-inflammatory cytokine levels in both healthy and peanut allergic volunteers argues against a key role for such cytokines in maintenance of clinical tolerance to food antigens in humans.

Nutritional management of Eosinophilic Gastroenteropathies: Case series from the community.

Eosinophilic gastroenteropathies, such as eosinophilic esophagitis and eosinophilic colitis, have classically been treated with swallowed inhaled corticosteroids or oral corticosteroids. More recent studies have found elimination and elemental diets to be effective treatment alternatives to steroids. In this case series we describe the treatment of three children using nutritional management in a community setting. Elimination diets and elemental diets based on patch testing and skin prick tests reduced the eosinophil counts to normal levels in all three children. Food items which tested positive were then reintroduced while symptoms and eosinophil counts were monitored. Nutritional management of eosinophilic esophagitis and eosinophilic colitis was found to be effective in reducing symptoms. However, obstacles facing patients who choose this type of therapy include limitations due to the cost of repeated endoscopies, palatability of elimination/elemental diets and the availability of subspecialists trained in management (e.g. Allergy, Gastroenterology, and Pathology). It may be a worthwhile endeavour to overcome these obstacles as nutritional management minimizes the potential long-term effects of chronic steroid therapy.

TLR4 Asp299Gly and Thr399Ile polymorphisms: no impact on human immune responsiveness to LPS or respiratory syncytial virus.

BACKGROUND: A broad variety of natural environmental stimuli, genotypic influences and timing all contribute to expression of protective versus maladaptive immune responses and the resulting clinical outcomes in humans. The role of commonly co-segregating Toll-like receptor 4 (TLR4) non-synonymous single nucleotide polymorphisms Asp299Gly and Thr399Ile in this process remains highly controversial. Moreover, what differential impact these polymorphisms might have in at risk populations with respiratory dysfunction, such as current asthma or a history of infantile bronchiolitis, has never been examined. Here we determine the importance of these polymorphisms in modulating LPS and respiratory syncytial virus (RSV)--driven cytokine responses. We focus on both healthy children and those with clinically relevant respiratory dysfunction. METHODOLOGY: To elucidate the impact of TLR4 Asp299Gly and Thr399Ile on cytokine production, we assessed multiple immune parameters in over 200 pediatric subjects aged 7-9. Genotyping was followed by quantification of pro- and anti-inflammatory cytokine responses by fresh peripheral blood mononuclear cells upon acute exposure to LPS or RSV. PRINCIPAL FINDINGS: In contrast to early reports, neither SNP influenced immune responses evoked by LPS exposure or RSV infection, as measured by the intermediate phenotype of pro- and anti-inflammatory cytokine responses to these ubiquitous agents. There is no evidence of altered sensitivity in populations with "at risk" clinical phenotypes. CONCLUSIONS/SIGNIFICANCE: Genomic medicine seeks to inform clinical practice. Determination of the TLR4 Asp299Gly/Thr399Ile haplotype is of no clinical benefit in predicting the nature or intensity of cytokine production in children whether currently healthy or among specific at-risk groups characterized by prior infantile broncholitis or current asthma.

Are plasma IL-10 levels a useful marker of human clinical tolerance in peanut allergy?

BACKGROUND: Food allergies are a major component of the burden of allergic disease. Accurate risk assessment for prediction of future clinical reactivity or clinical tolerance is limited by currently available techniques. Recent studies suggest that constitutively elevated global serum levels of IL-10, a cytokine that down-regulates both Th1 and Th2 cytokine production, may be useful in identifying human clinical tolerance to foods. OBJECTIVE: Determine the usefulness of constitutive IL-10 levels as a marker of clinical tolerance to peanut in children and adults. METHODOLOGY/PRINCIPAL FINDINGS: 107 subjects who were clinically tolerant to peanut and 94 subjects who were clinically allergic to peanut participated. Plasma was analyzed via ELISA to quantify the frequency of individuals with constitutive IL-10 levels and the intensity of those responses. The data were then stratified by age, gender and clinical status to assess the utility of this putative biomarker in specific at-risk groups. All 201 subjects had readily quantified plasma IL-10. Levels were no higher in subjects who were clinically tolerant to peanut than those in individuals clinically allergic to peanut. Stratification by age, gender or both did not improve the capacity of IL-10 levels to identify clinical tolerance to peanut. CONCLUSIONS/SIGNIFICANCE: Plasma IL-10 levels are neither a useful biomarker of clinical tolerance to peanut nor a potential tool for identification of clinical tolerance to peanut in humans.

Diagnosing asthma in children: what is the role for methacholine bronchoprovocation testing?

OBJECTIVE: To determine whether measurement of airways responsiveness to methacholine can help physicians diagnose asthma in children. METHODS: Children from the 1995 Manitoba birth cohort were assessed by asthma specialists, had skin testing and measurement of airways responsiveness to methacholine (PC20). We selected children with doctor-diagnosed asthma and healthy children as controls (no asthma, no allergic rhinitis, negative skin tests). Sensitivities and specificities for asthma were calculated. Receiver operating curves were calculated to determine the best fit of the methacholine challenge as a diagnostic test. RESULTS: 640 children were assessed. Two hundred fifteen children with doctor diagnosed asthma and 197 healthy controls successfully completed a methacholine challenge. Airways hyperresponsiveness was a moderately sensitive and specific measure for the diagnosis of asthma in girls, whether atopic (sensitivity of 71% and specificity of 69% at PC20 < or = 4.0 mg/ml) or not (sensitivity of 77% and specificity of 53% at PC20 < or =8.0 mg/ml). Airways hyperresponsiveness was also helpful for the diagnosis of asthma in atopic boys (sensitivity of 67% and specificity of 75% at PC20 < or =2.0 mg/ml), but of absolutely no help in the diagnosis of asthma in nonatopic boys. CONCLUSION: Measurement of airways hyperresponsiveness to methacholine can be useful in children who are atopic and of some value in nonatopic girls. The presence or absence of airways hyperresponsiveness to methacholine is of no help for the diagnosis of asthma in nonatopic boys. Laboratory tests must be placed in context of the clinical assessment of children for asthma.

Should Younger Siblings of Peanut-Allergic Children Be Assessed by an Allergist before Being Fed Peanut?

: The objective of this study was to determine the risk of peanut allergy in siblings of peanut-allergic children. In 2005-2006, 560 households of children born in 1995 in the province of Manitoba, Canada, were surveyed. The index children (8-to 10-year-olds) were assessed by a pediatric allergist and had skin-prick testing and/or capRAST for peanut allergy. Surveys were completed by parents for siblings to determine the presence of peanut allergy. Of 560 surveys, 514 (92%) were completed. Twenty-nine (5.6%) index children were peanut allergic. Fifteen of 900 (1.7%) siblings had peanut allergy. Four of 47 (8.5%) were siblings of peanut-allergic children and 11 of 853 (1.3%) were siblings of non-peanut-allergic children. The risk of peanut allergy was markedly increased in siblings of a peanut-allergic child (odds ratio 6.72, 95% confidence interval 2.04-22.12). Siblings of peanut-allergic children are much more likely to be allergic to peanut. An allergy assessment by a qualified allergist should be routinely recommended before feeding peanut to these children.

Asthma is not enough: continuation of smoking among parents with an asthmatic child.

BACKGROUND: Ideally, on diagnosis of asthma in a child, parents are counselled to decrease environmental tobacco smoke exposure to their children. OBJECTIVE: To determine whether a diagnosis of asthma in children altered parental smoking behaviour toward a reduction in environmental tobacco smoke exposure. METHODS: In 2002/2003, a survey was sent to 12,556 households with children born in 1995 in Manitoba. Parents were asked whether their seven-year-old child had asthma, and whether smokers were present in the home in 1995 and/or currently. The likelihood (OR) of a change in parental smoking behaviour was determined according to the presence of asthma in their child, a family history of asthma, the location of residence (rural or urban) and their socioeconomic status. RESULTS: A total of 3580 surveys (28.5%) were returned. The overall prevalence of parental smoking in 1995 and 2002/2003 was 32.2% and 23.4%, respectively (31.9%/23.2% and 32.3%/23.6% in rural and urban environments, respectively). In 2002/2003, the prevalence of parental smoking in homes with asthmatic children was 29.8%. Parents were not more likely to quit smoking (OR=1.01, 95% CI 0.66 to 1.54) or smoke outside (OR=1.02, 95% CI 0.56 to 1.83) if their child developed asthma. Parental smoking behaviour (quit smoking or smoked outside) did not change if there was a positive family history of asthma (OR=1.04, 95% CI 0.78 to 1.37), if they lived in a rural or urban location (OR=0.94, 95% CI 0.71 to 1.23), or if they were from a low- or high-income household (OR=1.12, 95% CI 0.85 to 1.47). CONCLUSIONS: The likelihood of altering parental smoking behaviour occurred independently of a diagnosis of asthma in their child, a family history of asthma, the location of residence and their socioeconomic status.

The relationship of breast-feeding, overweight, and asthma in preadolescents.

BACKGROUND: Breast-feeding is suggested to be associated with overweight or asthma in children. Overweight and asthma may share common environmental influences of which breast-feeding may be one. OBJECTIVE: We evaluated whether short duration of exclusive breast-feeding and subsequent overweight were associated with asthma. METHODS: A nested case-control study included 246 children with pediatric allergist-diagnosed asthma and 477 controls without asthma at age 8 to 10 years. Information on exclusive breast-feeding was obtained from questionnaire data. Overweight at 8 to 10 years of age was defined as body mass index >/=85th percentile of age and sex-specific growth charts. The association between asthma and exclusive breast-feeding <12 weeks plus overweight, adjusted for sex, parental asthma, aboriginal origin, passive smoking at birth, residence location, and family income, was determined in logistic regression analyses. RESULTS: Exclusive breast-feeding <12 weeks was closely associated with overweight at age 8 to 10 years (P < .001). Exclusive breast-feeding <12 weeks plus overweight was significantly associated with asthma (adjusted OR, 1.81; 95% CI, 1.11-2.95; P = .018). This association appeared to be strong in children whose mothers had asthma (adjusted OR, 3.93; 95% CI, 1.17-13.2) and also in boys (adjusted OR, 2.22; 95% CI, 1.14-4.34). Asthma was not associated with either exclusive breast-feeding <12 weeks or overweight in the absence of the other. CONCLUSION: Short duration of exclusive breast-feeding and subsequent overweight are associated with asthma in susceptible children, suggesting a common pathway. CLINICAL IMPLICATIONS: This finding adds to the importance of promoting prolonged breast-feeding for the prevention of overweight and asthma.

Transient tachypnea of the newborn may be an early clinical manifestation of wheezing symptoms.

OBJECTIVE: To determine risk factors associated with transient tachypnea of the newborn (TTN) and whether TTN is associated with development of wheezing syndromes in early life. STUDY DESIGN: The Population Health Research Data Repository at the Manitoba Centre for Health Policy is a healthcare administrative and prescription database. Data for children diagnosed with a wheezing syndrome (defined as bronchiolitis, acute bronchitis, chronic bronchitis, asthma, or prescription for asthma medication) were obtained. Term children diagnosed with TTN at birth were selected. Cox proportional hazards regression analysis for time to first event of hospitalizations, physician visits, or prescription for an asthma medication up to 7 years of age were calculated. The hazard ratios for wheezing in a child with TTN were compared with healthy newborns. RESULTS: Twelve thousand seven hundred sixty-three children were born at term in 1995 and currently live in the province of Manitoba. Of these children, 308 (2.4%) developed TTN. Maternal asthma, birth weight > or = 4500 g, male sex, and urban location were risk factors for development of TTN. Infants with TTN at birth were at significantly increased risk of a wheezing disorder in childhood (adjusted hazard ratio [HR] = 1.17, 95% CI 1.02-1.34). CONCLUSION: TTN is associated with development of wheezing syndromes in childhood.

The risk of developing food allergy in premature or low-birth-weight children.

BACKGROUND: Premature or low-birth-weight children have increased gut permeability compared with term or normal-birth-weight children. OBJECTIVE: To determine whether premature or low-birth-weight children have an increased risk of developing food allergy compared with term or normal-birth-weight children. METHODS: The 1995 Manitoba Birth Cohort was studied using the Manitoba Health Services Insurance Plan (MHSIP) database. This database is a population-based, health care administrative and prescription database. It has records of every child born and subsequent utilization of the provincial health care system. The diagnosis of food allergy (ICD-9-CM code of 693 in hospital/medical claims or a prescription of injectable epinephrine excluding a sole diagnosis of venom allergy) was obtained up until the year 2002. The relative risks of food allergy in premature or low-birth-weight children compared with term or normal-birth-weight children were determined. RESULTS: A total of 13,980 children were born in 1995 and continue to live in the province of Manitoba. Of these, 592 children (4.23%) were found to have food allergy and epinephrine was prescribed in 316 (2.26%) children. No gestational age or birth weight group had a statistically significant increased risk for food allergy. CONCLUSION: Prematurity and low birth weight are not associated with a change in risk for development of food allergy in childhood. CLINICAL IMPLICATIONS: Immaturity of the gastrointestinal tract or immune response does not seem to change the risk for development of food allergies. We ask whether early exposure to food antigens may protect premature children by increasing immune tolerance to those antigens.