Once-daily fluticasone furoate 50 mcg in mild-to-moderate asthma: a 24-week placebo-controlled randomized trial.

BACKGROUND: Inhaled glucocorticosteroids (ICS) are the mainstay of treatment in asthma. Fluticasone furoate (FF) is a novel, once-daily ICS asthma therapy. This study investigated the efficacy and safety of FF 50 mcg in patients with mild-to-moderate persistent asthma. METHODS: A 24-week, multicenter, randomized, placebo-controlled and active-controlled, double-blind, double-dummy, parallel-group phase III study. Three hundred and fifty-one patients (aged ≥12 years; uncontrolled by non-ICS therapy) were randomized to treatment (1 : 1 : 1) with once-daily FF 50 mcg dosed in the evening, twice-daily fluticasone propionate (FP) 100 mcg or placebo. The primary endpoint was change from baseline in evening trough forced expiratory volume in 1 s (FEV1 ) at Week 24. Secondary endpoints were change from baseline in the percentage of rescue-free 24-h periods (powered endpoint), change from baseline in evening and morning peak expiratory flow, change from baseline in the percentage of symptom-free 24-h periods and number of withdrawals due to lack of efficacy. RESULTS: Evening trough FEV1 at Week 24 was not statistically significantly increased with FF 50 mcg once-daily (37 ml [95% CI: -55, 128]; P = 0.430), but was with FP 100 mcg twice daily (102 ml [10, 194]; P = 0.030), vs placebo. No consistent trends were observed across other endpoints, including the powered secondary endpoint. No safety concerns were raised for either active treatment. CONCLUSIONS: FP 100 mcg twice daily improved evening trough FEV1 in patients with mild-to-moderate persistent asthma, but FF 50 mcg once daily did not demonstrate a significant effect. Secondary endpoints showed variable results. No safety concerns were identified for FF or FP.

Differences in both prevalence and titre of specific immunoglobulin E among children with asthma in affluent and poor communities within a large town in Ghana.

BACKGROUND: Reports from several African countries have noted an increasing prevalence of asthma in areas of extensive urbanization. OBJECTIVE: To investigate the relevance of allergen-specific sensitization and body mass index (BMI) to asthma/wheezing and exercise-induced bronchospasm (EIB) among children from affluent and poorer communities within a large town in Ghana. METHODS: Children with physician-diagnosed asthma and/or current wheezing aged 9-16 years (n=99; cases) from three schools with differing socio-economic backgrounds [urban affluent (UA), urban poor (UP) or suburban/rural (SR)] were recruited from a cross-sectional study (n=1848) in Kumasi, Ghana, and matched according to age, sex and area of residence with non-asthmatic/non-wheezy controls. We assayed sera for IgE antibodies to mite, cat, dog, cockroach, Ascaris and galactose-α-1,3-galactose. RESULTS: Children from the UA school had the lowest total serum IgE. However, cases from the UA school had a higher prevalence and mean titre of sIgE to mite (71.4%, 21.2 IU/mL) when compared with controls (14.3%, 0.8 IU/mL) or cases from UP (30%, 0.8 IU/mL) and SR community (47.8%, 1.6 IU/mL). While similar findings were observed with EIB in the whole population, among cases there was no difference in IgE antibody prevalence or titre between children with or without EIB. BMI was higher among UA children with and without asthma; in UP and SR communities, children with EIB (n=14) had a significantly higher BMI compared with children with asthma/wheezing without EIB (n=38) (18.2 vs. 16.4, respectively, P<0.01). CONCLUSIONS AND CLINICAL RELEVANCE: In the relatively affluent school, asthma/wheezing and EIB were associated with high titre IgE antibodies to mite, decreased total IgE, and increased BMI. This contrasted with children in the urban poor school and suggests that changes relevant to a Western model of childhood asthma can occur within a short geographical distance within a large city in Africa.

Household characteristics and allergen and endotoxin levels in Aleppo, Syrian Arab Republic.

Few data are available from Eastern Mediterranean countries about levels of domestic allergens and endotoxins. Dust samples were collected from mattresses and floors of 457 homes in the Syrian city of Aleppo and analysed for antigens and endotoxins. The most important predictors for detectable levels of house-dust mite allergen Der p 1 were Arabic-style houses (OR 3.21) and newer houses (OR 1.56). In homes without cats, rubber mattresses were associated with detectable cat allergen Fel d 1 in mattress dust (OR 1.6). Cockroach allergen Bla g 2 was significantly more likely to be detected in houses over 20 years old than newer houses. Endotoxin levels were significantly higher in wool/cotton mattresses and older houses.

Dietary antioxidant intake, allergic sensitization and allergic diseases in young children.

BACKGROUND: Allergic diseases have risen in prevalence over recent decades. The aetiology remains unclear but is likely to be a result of changing lifestyle and/or environment. A reduction in antioxidant intake, consequent to reduced intake of fresh fruits and vegetables, has been suggested as a possible cause. OBJECTIVE: To investigate whether dietary antioxidant intake at age 5 was related to atopy at 5 and 8 years of age amongst children in an unselected birth cohort. METHODS: Children were followed from birth. Parents completed a validated respiratory questionnaire and children were skin prick tested at 5 and 8 years of age. Serum IgE levels were measured at age 5. At age 5, antioxidant intake was assessed using a semi-quantitative food frequency questionnaire (FFQ). A nutrient analysis program computed nutrient intake, and frequency counts of foods high in the antioxidant vitamins A, C and E were assessed. RESULTS: Eight hundred and sixty-one children completed both the respiratory and FFQ. Beta-carotene intake was associated with reduced risk of allergic sensitization at age 5 [0.80 (0.68-0.93)] and 8 [0.81 (0.70-0.94)]. In addition, beta-carotene intake was negatively associated with total IgE levels (P = 0.002). Vitamin E intake was associated with an increased risk of allergic sensitization [1.19 (1.02-1.39)], only at age 5. There was no association between antioxidant intakes and wheeze or eczema. CONCLUSION: Increased beta-carotene intake was associated with a reduced risk of allergic sensitization and lower IgE levels, in 5- and 8-year-old children. Dietary antioxidants may play a role in the development of allergic sensitization.

Airway abnormalities at flexible bronchoscopy in patients with chronic cough.

The algorithms utilised in the diagnosis of chronic cough advocate sequential investigations and treatment trials for asthma-like syndromes, post-nasal drip and gastro-oesophageal reflux disease; however, the role of bronchoscopy is unclear. In the present authors' specialist clinic (North West Lung Centre Cough Clinic, Manchester, UK), flexible bronchoscopy is included in the diagnostic work-up of patients with chronic unexplained cough. In a retrospective review, the authors report on their experiences. Over an 18-month period, patients followed a diagnostic algorithm that included: chest radiography; pulmonary function; methacholine challenge; ear, nose and throat examination; and empirical reflux treatment. Where diagnosis remained elusive, bronchoscopy was performed. A total of 82 bronchoscopies were carried out for the sole indication of chronic cough. Patient age (mean+/-SD) was 54.9+/-11.22 yrs, with a median (range) cough duration of 5 (0.5-30) yrs. In nine (11%) subjects, a diagnosis was made on inspection or biopsy. These included seven cases of tracheobronchopathia osteochondroplastica (TPO), one case of elongated uvula and one case of endobronchial amyloidosis. All TPO patients had early changes, with a typical nodular appearance to the tracheal cartilage, without significant airway obstruction. These subtle changes could not have been predicted from less invasive procedures and would have been missed without bronchoscopy. Flexible bronchoscopy is indicated in persistent unexplained cough and may reveal contributing pathology.

Objective measurement of cough during pulmonary exacerbations in adults with cystic fibrosis.

BACKGROUND: Little is known about cough frequency in adults with cystic fibrosis (CF). This study aimed to determine (1) daytime and overnight cough rates in patients with CF at the beginning and end of a course of antibiotics for treatment of an exacerbation; (2) the relationship between cough frequencies and standard clinical measures of disease; and (3) the relationship between objective cough rates and the subjective assessment of cough. METHODS: Nineteen adult patients admitted with a pulmonary exacerbation performed daytime and overnight sound recordings on admission; 13 had repeat recordings prior to discharge. Coughs were manually quantified in cough seconds (time spent coughing). Patients subjectively scored their cough using a visual analogue scale (VAS) and numerical score. Lung function, C-reactive protein (CRP) levels, and sputum weights were recorded. RESULTS: Cough rates fell substantially with treatment; median fall in cough rate was 51.3% (IQR 32.3-77.5) (p<0.001) for daytime and 72.2% (28.6-90.1) (p = 0.049) for overnight. Multivariate regression analyses showed that forced expiratory volume in 1 second and CRP levels predicted overnight cough rates on admission. On discharge, sputum volume predicted daytime cough rates. Only the change in overnight VAS correlated with the change in objective cough rates. CONCLUSIONS: The cough rate significantly decreases with treatment of a pulmonary exacerbation in adults with CF. Lung function, sputum volume, and CRP influences the cough rate, with the effects differing from day to night and between admission and discharge. Subjective reporting of a nocturnal cough may indicate a pulmonary exacerbation of CF in adults.

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.

Household characteristics and mite allergen levels in Manchester,UK.

BACKGROUND: Mite allergen levels vary enormously between different homes in the same geographical area. No large scale studies of mite levels in Manchester homes has been conducted to identify factors associated with higher levels. OBJECTIVES: To quantify exposure to mite allergens and to identify characteristics associated with higher Der p 1 levels in a large sample of homes in Manchester, UK. METHODS: Der p 1 was measured in dust from the living room floor, sofa, bedroom floor and mattress in 564 homes. Data on household characteristics were collected by administering a questionnaire. Univariate and multivariate analyses were performed to identify household characteristics associated with higher mite allergen levels. RESULTS: Der p 1 levels were highest in the mattress (GM 1.19 microg/g, 95% CI 0.98-1.45, P < 0.001). Two-thirds of homes contained Der p 1 levels > 2 microg/g in at least one dust reservoir, and 40.3% contained Der p 1 greater than 10 microg/g. There was a large range in Der p 1 levels between homes (> 10(3)-fold). Damp and condensation were common findings in homes. In the multivariate analyses, factors associated with higher Der p 1 levels in more than one dust reservoir were older homes, older living room carpets, damp, condensation and mixed glazing. Older mattresses were associated with higher mite allergen levels in the mattress where the age of the mattress was recorded. Twenty-four homes contained no detectable mite allergen, six of which reported damp. CONCLUSIONS: Mite allergen levels are high enough in two of every three homes to be associated with an increase in the risk of sensitization to mite. Factors such as older homes, carpets and mattresses, damp and condensation are associated with higher mite allergen. However, mite allergen levels are occasionally unpredictably very low in homes with risk factors for high levels.

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.

Decreased prevalence of sensitization to cats with high exposure to cat allergen.

We investigated the relationship between current exposure to cat allergen and sensitization to cats. A questionnaire was administered and skin prick testing and home visits for collection of dust samples (Fel d 1; ELISA) were performed in 2502 adults (mean age, 31.8 years; age range, 18-58 years; 1251 women). The results for Fel d 1 in relation to sensitization to cats were analyzed for 10 deciles of cat allergen exposure (cut points [microg/g]: 0.05, 0.34, 0.48, 0.72, 1.13, 1.92, 7.2, 44, 151). The prevalence of sensitization to cat was significantly decreased in the lowest and the highest exposure groups. In the multivariate regression analysis (age, sex, socioeconomic status, and current smoking being adjusted for), the risk of sensitization to cats was significantly increased with medium exposure to Fel d 1 (3rd centile, OR 2.3, 95% CI 1.2-4.4, P =.01; 4th centile, OR 2.1, 95% CI 1.1-4.0, P =.03; 5th centile, OR 2.2, 95% CI 1.2-4.3, P =.04, 6th centile, OR 2.5, 95% CI 1.3-4.9, P =.005). These results indicate that the prevalence of sensitization to cat is decreased in the lowest and highest cat allergen exposure groups.

Lymphoproliferative responses in cord blood and at one year: no evidence for the effect of in utero exposure to dust mite allergens.

BACKGROUND: Maternal allergen exposure beyond the 22nd week of pregnancy may be important in foetal T cell priming. Allergen-specific cord blood mononuclear cell (CBMC) immunoproliferative responses without corresponding bacterial antigen responses (tetanus toxoid), have been suggested as evidence of in utero sensitization. OBJECTIVES: To investigate the relationship between lymphoproliferative responses at birth and at 1 year with maternal and 1-year infants house dust mite allergen exposure. METHODS: Home visits and dust sampling were performed by the 20th week of pregnancy, immediately after birth, and then at 1 years of age. Der p 1 was assayed using a two-site immunometric ELISA. CBMC immunoproliferative responses (AIM V serum-free medium; 1 x 105 cells/well) were measured for 225 neonates (171 had a high risk of atopy (HR)--both parents skin test positive; 59 had a low risk of atopy (LR) - both parents skin test negative, no history of atopy) by 3H-Thymidine (1microCi/well) incorporation after stimulation in primary culture with phytohaemagglutinin (PHA) (1 microg/mL), house dust mite [HDM] extract (30 microg/mL), immunopurified Der p 1 (30 microg/mL), Tetanus toxoid (TT) (aluma free, 30 Lf/mL) or vehicle. Blood was collected from 144 infants at the age of 1 years and stimulated proliferative responses were assessed using the same procedure. RESULTS: PHA-stimulated lymphoproliferative response was significantly lower in HR compared to LR neonates (mean difference 38%, 95% CI 15%-54%; P = 0.003); significantly lower proportion of positive CBMC responses to HDM occurred in LR than in HR neonates (30.4% vs. 46.6%; P = 0.034). There was no relationship between Der p 1 levels in maternal bed and CBMC immunoproliferative responses, despite the 21 000-fold range of maternal Der p 1 exposure. No significant differences in magnitude, or in proportion of positive responses to any stimulant were observed between the neonates at low, medium or high tertile of allergen exposure. Immunoproliferative responses at birth were not predictive of 1-year PBMC responses. There was no relationship between maternal allergen exposure in pregnancy and 1-year PBMC proliferative responses. However, the proportion of positive proliferative responses at 1 years significantly increased with increasing infant Der p 1 exposure at 1 years. CONCLUSION: These results indicate that the magnitude of immunoproliferative responses are unrelated to maternal mite allergen exposure and cannot be used as evidence for in utero sensitization to inhalant allergens. The immunoproliferative responses at 1 year seem to shift away from the genetically influenced responses at birth towards responses to specific stimulants which correlate with environmental exposure to those specific stimulants. These data support the concept of sensitization to inhalant allergens occurring in early life, but not in utero.

NAC Manchester Asthma and Allergy Study (NACMAAS): risk factors for asthma and allergic disorders in adults.

Asthma and atopic disorders are the most common chronic diseases in the developed countries. Knowledge of the risk factors for these disorders may facilitate the development of preventive strategies aimed at reducing prevalence rates. To investigate the risk factors for asthma and allergic diseases in a large number of adults who are the parents of children in the National Asthma Campaign Manchester Asthma and Allergy Study. All pregnant women and their partners attending "Booking" antenatal clinics were invited to take part in the study. Questionnaire data were collected including the history of asthma and other atopic diseases, pet ownership and smoking habits, and skin prick tests were performed. The prevalence of atopy and the risk factors for asthma and allergic disorders were investigated in all subjects who completed the questionnaire and underwent skin testing. Statistical analysis was carried out using logistic regression. Initially, risk factors were assessed by univariate analysis to see how each potential explanatory variable affected the probability of having allergic disease. Variables were then tested in a forward stepwise multivariate analysis. In 5687 adult subjects there was a very high (48.2%) prevalence of atopy, and 9.7% of subjects had a diagnosis of asthma. In a multivariate regression analysis sensitization to dust mite, cat, dog and mixed grasses were all independently associated with asthma. The odds ratios for current asthma increased with the increasing number of positive skin tests (any two allergens - OR 4.3, 95% CI 3.3-5.5; any three allergens - OR 7.0 95% CI 5.3-9.3; all four allergens - OR 10.4, 95% CI 7.7-14; P < 0.00001). Dog ownership (OR 1.31, 95% CI 1.10-1.57; P = 0.003) and current smoking (OR 1.36, 95% CI 1.15-1.62; P = 0.0004) were significantly and directly associated with "asthma ever". Thirteen per cent of participants reported a history of eczema. In the multivariate analysis the strongest independent associate of eczema was sensitization to dog (OR 1.37, 95% CI 1.14-1.63, P < 0.0001). Apart from dog, the strength of the association between sensitization to common allergens and eczema appeared to be much lower than in the case of asthma. The prevalence of hay fever was high (20.6%), and in the multivariate analysis the association between sensitization to pollen and hay fever was extremely strong (OR 13.6, 95% CI 11.3-16.3; P < 0.0001). The results of the current study emphasize the importance of sensitization to indoor allergens in asthma. However, evidence of a possible direct role of allergen exposure in asthma causation remains unclear.

Apoptosis signals in atopy and asthma measured with cDNA arrays.

A variety of studies have stressed the importance of the control of inflammatory cell longevity and the balance of pro-survival and pro-apoptotic signalling. Recently, asthma was found to be associated with reduced apoptosis of inflammatory cells in lung tissue. The aim of the study was to investigate the systemic activation of apoptosis pathways using cDNA array technology in atopy and asthma. Eighteen atopic asthmatics (AA), eight atopic non-asthmatic (AN) and 14 healthy control subjects (C) were included in the study. Peripheral blood mononuclear cells were separated with gradient centrifugation, mRNA purified and the reverse-transcribed probes hybridized to cDNA arrays. The signals were compared by standardizing to the 100 most expressed genes and group differences assessed with the Mann-Whitney U-test. We found a concerted up-regulation of several pro-survival cytokines and growth factors in AN and AA. FAS and FASL were not differentially expressed, but FAST kinase was over-expressed in AN and AA. The tumour necrosis factor pathway was activated in AN and AA with increased cytokine and receptor levels and increased TRAF2, an intracellular signalling product. There were indications of a down-regulated p53 system. In contrast, the Bcl-2 family of genes showed a net pro-apoptotic profile in AN and AA. The group of caspases showed a constant gene expression pattern in all groups. In conclusion, significant differences in the expression of apoptosis-related genes were found in peripheral blood of atopic individuals with and without asthma. cDNA array technology proved to be useful and may be complementary to DNA-based studies in order to analyse interactive and multidimensional pathways as shown here for apoptosis.

Pneumothorax in adults with cystic fibrosis dependent on nasal intermittent positive pressure ventilation (NIPPV): a management dilemma.

The management of pneumothorax in three adult patients with cystic fibrosis dependent on nasal intermittent positive pressure ventilation is described.

Allergen avoidance: does it work?

The first recorded example of allergen avoidance in the treatment of allergic disorders dates from the 16th century. The Italian physician Gerolamo Cardano (1501-1576) was invited to Scotland by John Hamilton, Archbishop of St Andrews (and brother of the Regent), to give advice on the treatment of his asthma. Cardano recommended that the Archbishop should get rid of his feather bedding, which was followed by a 'miraculous' remission of otherwise troublesome symptoms. The first controlled attempts to treat asthma by environmental manipulation date to the beginning of 20th century. In 1925, the Leopold brothers treated patients with asthma and other allergic disorders by moving them into a dust free room. Storm van Leeuwen created a 'climate' chamber in The Netherlands in 1927 and demonstrated that asthmatic patients improved when moved from their homes into the chamber. One year later, Dekker observed that measures aimed at reducing the amount of dust in bedrooms had a beneficial effect on asthma symptoms in patients allergic to house dust. Van Leeuwen wrote: 'In our endeavours to find the cause of the attack ... we utilised the known fact that the environment of the asthmatic patient is, as a rule, of primary importance in determining the intensity and frequency of his attacks'. Nowadays, more than ever, it is essential to address the environmental influences on the increasing prevalence of asthma and allergic disorders.

The development of a quantitative PCR ELISA to determine HCMV DNAaemia levels in heart, heart/lung and lung transplant recipients.

The adaptation of the polymerase chain reaction (PCR) enzyme-linked immunosorbent assay (ELISA) using a co-amplified DNA standard to quantitate the human cytomegalovirus (HCMV) glycoprotein B (gB) gene in clinical samples is described. The PCR ELISA is a solution hybridisation system with colorimetric end stage detection of amplicons. A DNA internal standard (IS) was designed by replacing a probe sequence used currently within the gB region with a heterogeneous sequence, allowing co-amplification with the same oligonucleotide primer sets and differentiation by probe hybridisation. Two DNA fragments homologous to the gB and IS sequences were generated and used for co-amplification studies to construct a standard curve. From this the copy number of the gB gene present in clinical samples could be interpolated. Co-amplification with 1000 IS copies allowed quantitation of 10-1000000 gB DNA copies in a single PCR. This assay was validated subsequently using blood samples tested by the HCMV antigenaemia assay and showed a trend of increasing HCMV DNAaemia with increasing antigenaemia levels. This rapid assay avoids using gel electrophoresis and cumbersome quantitative systems. It has the potential for early identification of patients at high risk of developing HCMV disease, and for therapeutic monitoring.