Clare S. Murray

Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children

Background: Asthma exacerbation is the most common cause of hospital admission in children. A study was undertaken to investigate the importance of allergen exposure in sensitised individuals in combination with viral infections and other potentially modifiable risk factors precipitating asthma hospital admission in children. Methods: Eighty four children aged 3–17 years admitted to hospital over a 1 year period with an acute asthma exacerbation (AA) were matched for age and sex with two control groups: stable asthmatics (SA) and children admitted to hospital with non-respiratory conditions (IC). Risk factors were assessed by questionnaires and determination of allergen sensitisation, home allergen exposure, pollen exposure, and respiratory virus infection. Results: Several non-modifiable factors (atopy, duration of asthma) were associated with increased risk. Among the modifiable factors, pet ownership, housing characteristics, and parental smoking did not differ between the groups. Regular inhaled corticosteroid treatment was significantly less common in the AA group than in the SA group (OR 0.2, 95% CI 0.1 to 0.6; p = 0.002). A significantly higher proportion of the AA group were virus infected (44%) and sensitised and highly exposed to sensitising allergen (76%) compared with the SA (18% and 48%) and IC groups (17% and 28%; both p<0.001). In a multiple conditional logistic regression (AA v SA), allergen sensitisation and exposure or virus detection alone were no longer independently associated with hospital admission. However, the combination of virus detection and sensitisation with high allergen exposure substantially increased the risk of admission to hospital (OR 19.4, 95% CI 3.7 to 101.5, p<0.001). Conclusions: Natural virus infection and real life allergen exposure in allergic asthmatic children increase the risk of hospital admission. Strategies for preventing exacerbations will need to address these factors.

Allergy or tolerance in children sensitized to peanut: Prevalence and differentiation using component-resolved diagnostics

BACKGROUND Not all peanut-sensitized children develop allergic reactions on exposure. OBJECTIVE To establish by oral food challenge the proportion of children with clinical peanut allergy among those considered peanut-sensitized by using skin prick tests and/or IgE measurement, and to investigate whether component-resolved diagnostics using microarray could differentiate peanut allergy from tolerance. METHODS Within a population-based birth cohort, we ascertained peanut sensitization by skin tests and IgE measurement at age 8 years. Among sensitized children, we determined peanut allergy versus tolerance by oral food challenges. We used open challenge among children consuming peanuts (n = 45); others underwent double-blind placebo-controlled challenge (n = 34). We compared sensitization profiles between children with peanut allergy and peanut-tolerant children by using a microarray with 12 pure components (major peanut and potentially cross-reactive components, including grass allergens). RESULTS Of 933 children, 110 (11.8%) were peanut-sensitized. Nineteen were not challenged (17 no consent). Twelve with a convincing history of reactions on exposure, IgE > or =15 kUa/L and/or skin test > or =8mm were considered allergic without challenge. Of the remaining 79 children who underwent challenge, 7 had > or =2 objective signs and were designated as having peanut allergy. We estimated the prevalence of clinical peanut allergy among sensitized subjects as 22.4% (95% CI, 14.8% to 32.3%). By using component-resolved diagnostics, we detected marked differences in the pattern of component recognition between children with peanut allergy (n = 29; group enriched with 12 children with allergy) and peanut-tolerant children (n = 52). The peanut component Ara h 2 was the most important predictor of clinical allergy. CONCLUSION The majority of children considered peanut-sensitized on the basis of standard tests do not have peanut allergy. Component-resolved diagnostics may facilitate the diagnosis of peanut allergy.

Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study.

BACKGROUND Wheezing and asthma often begins in early childhood, but it is difficult to predict whether or not a wheezy infant will develop asthma. Some researchers suggest that treatment with inhaled corticosteroids at the first signs of wheezing in childhood could prevent the development of asthma later in life. However, other investigators have reported that although such treatment could help control symptoms, the benefits can disappear within months of stopping treatment. We tested our hypothesis that to prevent loss of lung function and worsening asthma later in childhood, anti-inflammatory treatment needs to be started early in life. METHODS We did a randomised, double-blind, controlled study of inhaled fluticasone propionate 100 mug twice daily in young children who were followed prospectively and randomised after either one prolonged (>1 month) or two medically confirmed wheezy episodes. The dose of study drug was reduced every 3 months to the minimum needed. If the symptoms were not under control by 3 months, open-label fluticasone propionate 100 mug twice daily was added to the treatment. Children were followed-up to 5 years of age, at which point we gave their parents or guardians questionnaires, and measured the childrens lung function (specific airways resistance [sR(aw)], forced expiratory volume in 1s [FEV1]) and airway reactivity (eucapnic voluntary hyperventilation [EVH] challenge). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN86717853. FINDINGS We followed 1073 children prospectively, of whom 333 were eligible, and 200 of these began treatment (130 male, median age 1.2 years [range 0.5-4.9]; 101 placebo, 99 treatment); 173 (85 treatment, 88 placebo) completed the follow-up at age five years. The groups did not differ significantly in the proportion of children with current wheeze, physician-diagnosed asthma or use of asthma medication, lung function, or airway reactivity (percentage change in FEV1, adjusted mean for placebo 5.5% [95% CI -2.5 to 13.4]) vs for treatment 5.0% [-2.2 to 12.2], p=0.87). There were no differences in the results after adjustment for open-label fluticasone propionate, nor between the two groups in the time before the open-label drug was added (estimated hazard ratio 1.12 [95% CI 0.73-1.73], p=0.60), or the proportion needing the open-label drug (43 [42.57%] placebo, 41 [41.41%] treatment). INTERPRETATION The early use of inhaled fluticasone propionate for wheezing in preschool children had no effect on the natural history of asthma or wheeze later in childhood, and did not prevent lung function decline or reduce airway reactivity.

Specific airway resistance in 3-year-old children: a prospective cohort study

BACKGROUND The development of a method to assess lung function in young children may provide new insight into asthma development. Plethysmographic measurement of specific airway resistance (sR(aw)) is feasible in this age group. We aimed to identify risk factors associated with low lung function in early childhood in a prospective birth cohort. METHODS Children were prenatally assigned to risk group according to parental atopic status (high risk, both parents atopic; medium risk, one parent atopic; low risk, neither parent atopic) and followed prospectively until age 3 years. We measured sR(aw) in 503 symptom-free children using whole-body plethysmography during tidal breathing. FINDINGS 803 of 868 children attended the clinic, of whom 503 obtained satisfactory sR(aw) readings. 200 who wheezed at least once during first 3 years of life had significantly higher sR(aw) than the 303 who had never wheezed (mean difference 5.8%, 95% CI 2.2-9.3, p=0.002). For children who had never wheezed there were significant differences in sR(aw) between risk groups (p<0.001). Children at high risk (n=87) had a higher sR(aw) (geometric mean 1.17 kPa/s, 1.12-1.22) than children at medium risk (n=162; 1.02 kPa/s, 1.00-1.05) and at low risk (54; 1.04 kPa/s, 0.99-1.11). Atopic children (n=62) had significantly higher sR(aw) (1.15 kPa/s, 1.09-1.21) than those who were not atopic (232; 1.05 kPa/s, 1.02-1.07, p=0.002). For non-atopic children, those at high risk (58) had higher sR(aw) (1.13kPa/s, 1.07-1.18) than those at medium risk (125, 1.01kPa/s, 0.98-1.05) or at low risk (49, 1.04 kPa/s, 0.97-1.10, p=0.003). We showed a significant interaction between history of maternal asthma and childs atopic status (p=0.006). INTERPRETATION Even in the absence of respiratory symptoms, children of atopic parents and those with personal atopy have impaired lung function in early life.

Bifidobacterial Species Differentially Affect Expression of Cell Surface Markers and Cytokines of Dendritic Cells Harvested from Cord Blood

ABSTRACT The gut microbiota may be important in the postnatal development of the immune system and hence may influence the prevalence of atopic diseases. Bifidobacteria are the most numerous bacteria in the guts of infants, and the presence or absence of certain species could be important in determining the geographic incidence of atopic diseases. We compared the fecal populations of bifidobacteria from children aged 25 to 35 days in Ghana (which has a low prevalence of atopy), New Zealand, and the United Kingdom (high-prevalence countries). Natal origin influenced the detection of bifidobacterial species in that fecal samples from Ghana almost all contained Bifidobacterium infantis whereas those of the other children did not. Choosing species on the basis of our bacteriological results, we tested bifidobacterial preparations for their effects on cell surface markers and cytokine production by dendritic cells harvested from cord blood. Species-specific effects on the expression of the dendritic-cell activation marker CD83 and the production of interleukin-10 (IL-10) were observed. Whereas CD83 expression was increased and IL-10 production was induced by Bifidobacterium bifidum, Bifidobacterium longum, and Bifidobacterium pseudocatenulatum, B. infantis failed to produce these effects. We concluded that B. infantis does not trigger the activation of dendritic cells to the degree necessary to initiate an immune response but that B. bifidum, B. longum, and B. pseudocatenulatum induce a Th2-driven immune response. A hypothesis is presented to link our observations to the prevalence of atopic diseases in different countries.

The National Asthma Campaign Manchester Asthma and Allergy Study

The NACManchester Asthma and Allergy Study is a prospective study of the development of asthma and allergies in childhood. The subjects (995 children at age 3 years) were recruited in utero by screening parents in the antenatal clinic using skin prick testing and a questionnaire regarding allergic diseases. Children were assigned to risk groups according to parental atopic status (high risk, both parents atopic; medium risk, one parent atopic; low risk, neither parent atopic). A subgroup of those at high risk (with no pets in the home) was randomized to stringent environmental control (allergen impermeable covers for the parental and infant bed, hot washing of bedding weekly, HEPA vacuum cleaner, hard floor for the nursery), and the remainder followed a normal regime. The children have been followed prospectively. The environmental influences are very clearly defined. Measurements of environmental exposures include levels of house dust mite; cat and dog allergens during pregnancy and early life; pet ownership and exposure; childcare arrangements; number of siblings; vaccination uptake; thorough dietary questionnaire; and endotoxin exposure. Further unique objective outcome in the cohort is the assessment of lung function in preschool children using specific airways resistance, which at age 3 years clearly reflects both genetic and environmental influences.

Fecal microbiota in sensitized wheezy and non‐sensitized non‐wheezy children: a nested case–control study

Background It has been suggested that intestinal microbiota of allergic and non‐allergic children differs in composition, and that microbiota–immune system interactions may predispose children to develop sensitization. Previous studies have examined fecal microbiota of allergic children with atopic dermatitis, but little is known about that of atopic wheezy children.

Rhinoconjunctivitis in 5-year-old children: A population-based birth cohort study

Background:  There is a paucity of data on the prevalence, risk factors and natural history of rhinitis in early childhood.

Reported versus confirmed wheeze and lung function in early life

Aims: To investigate the relation between parentally reported wheeze (unconfirmed), physician confirmed wheeze, and subsequent lung function. Methods: Children at risk of allergic disease (one parent atopic) were recruited antenatally and followed prospectively from birth. During the first three years of life parents were asked to contact the study team if their child was wheezy. The presence of wheeze was confirmed or not by the primary care or study physician. Respiratory questionnaire and specific airway resistance measurement (sRaw, body plethysmograph) were completed at age 3 years. Results: A total of 454 children were followed from birth to 3 years of age. One hundred and eighty six (40.9%) of the parents reported their child wheezing in the first three years of life, and in 130 (28.6%) the wheeze was confirmed. A total of 428 children attended the three year clinic review, of whom 274 (64%) successfully carried out lung function tests. There was no significant difference in sRaw (kPa·s; geometric mean, 95% CI) between children who had never wheezed (n = 152; 1.03, 1.00 to 1.06) and those with a parentally reported but unconfirmed wheeze (n = 36; 1.02, 0.96 to 1.07, p = 1.00). sRaw was significantly higher in children with a physician confirmed wheeze (n = 86; 1.17, 1.11 to 1.22, p < 0.001) compared to those with no history of wheeze or with unconfirmed wheeze. Conclusions: Children with physician confirmed wheeze have significantly poorer lung function compared to those with parentally reported but unconfirmed and those who have never wheezed. A proportion of parents may have little understanding of what medical professionals mean by the term “wheeze”.

Lung function at one month of age as a risk factor for infant respiratory symptoms in a high risk population

Background: Abnormal premorbid lung function is a risk factor for subsequent wheezing in children with one or no atopic parent. This study was undertaken to establish whether early lung function in high risk infants (both parents atopic) was a risk factor for respiratory symptoms in infancy and to examine the influence of maternal asthma, smoking, and allergen exposure during pregnancy on any association. Methods: Infants were recruited from the NAC Manchester Asthma and Allergy Study cohort at birth. Partial forced expiratory flow volume technique under sedation was carried out to determine maximal flow at FRC (V′maxFRC). Children were followed prospectively and parents completed a standard respiratory questionnaire at one year of age. Results: Sixty nine term infants (34 boys; 88% mothers non-smokers; no household pets) underwent respiratory function testing. Size adjusted V′maxFRC was significantly lower in infants who had recurrent wheeze during the first year of life (mean 1.3 ml/s/cm, 95% CI 0.99 to 1.60) than in those who did not (mean 2.03 ml/s/cm, 95% CI 1.71 to 2.36; p=0.01). V′maxFRC was also significantly lower in infants who had recurrent cough symptoms. In multivariate regression analysis, when adjusted for age at test, sex, maternal asthma, smoking and maternal mattress Der 1 levels, a lower size adjusted V′maxFRC score remained strongly associated with wheezing (OR 0.37, 95% CI 0.18 to 0.77, p=0.007). Maternal smoking also remained an independent risk factor (OR 29.85, 95% CI 2.46 to 362.5, p=0.008). Conclusion: Significantly diminished lung function was present in high risk infants who subsequently wheezed and coughed. This was independent of maternal exposure to mite allergen, asthma, and smoking during pregnancy.