Search

Background: Epidemiological studies suggest that hookworm infection protects against asthma, and therefore that hookworm infection may have a direct or an indirect therapeutic potential in this disease. We now report the first clinical trial of experimental hookworm infection in people with allergic asthma., Objectives: To determine the effects of experimental hookworm infection in asthma., Methods: Thirty-two individuals with asthma and measurable airway responsiveness to adenosine monophosphate (AMP) were randomized and double blinded to cutaneous administration of either ten Necator americanus larvae, or histamine solution (placebo), and followed for 16 weeks. The primary outcome was the change in provocation dose of inhaled AMP required to reduce forced expiratory volume in 1 s by 20% (PD(20)AMP) from baseline to week 16. Secondary outcomes included change in several measures of asthma control and allergen skin sensitivity and the occurrence of adverse effects., Results: Mean PD(20)AMP improved in both groups, more in the hookworm [1.49 doubling doses (DD)] than the placebo group (0.98 DD), but the difference between groups was not significant (0.51 DD; 95% confidence interval: -1.79 to 2.80; P=0.65). There were no significant differences between the two groups for other measures of asthma control or allergen skin sensitization. Infection was generally well tolerated., Conclusions: Experimental infection with ten hookworm larvae in asthma did not result in significant improvement in bronchial responsiveness or other measures of asthma control in this study. However, infection was well tolerated and resulted in a non-significant improvement in airway responsiveness, indicating that further studies that mimic more closely natural infection are feasible and should be undertaken.

Background: Epidemiological studies suggest that dietary intake of vitamins A, C and E may be associated with the occurrence of asthma. A systematic review and meta-analysis was conducted in accordance with MOOSE guidelines to determine whether vitamins A, C and E, measured as dietary intakes or serum levels, are associated with asthma., Methods: MEDLINE, EMBASE, CINAHL, CAB abstracts and AMED (up to November 2007), conference proceedings and bibliographies of papers were searched to identify studies of asthma, wheeze or airway responsiveness in relation to intakes and serum concentrations of vitamins A, C and E. Pooled odds ratios (OR) or mean differences (MD) with 95% confidence intervals (CI) were estimated using random effects models., Results: A total of 40 studies were included. Dietary vitamin A intake was significantly lower in people with asthma than in those without asthma (MD -82 microg/day, 95% CI -288 to -75; 3 studies) and in people with severe asthma than in those with mild asthma (MD -344 microg/day; 2 studies). Lower quantile dietary intakes (OR 1.12, 95% CI 1.04 to 1.21; 9 studies) and serum levels of vitamin C were also associated with an increased odds of asthma. Vitamin E intake was generally unrelated to asthma status but was significantly lower in severe asthma than in mild asthma (MD -1.20 microg/day, 95% CI -2.3 to -0.1; 2 studies)., Conclusions: Relatively low dietary intakes of vitamins A and C are associated with statistically significant increased odds of asthma and wheeze. Vitamin E intake does not appear to be related to asthma status.

A high fruit intake may reduce the risk of asthma. The English National School Fruit Scheme was introduced in the East Midlands region of the UK in June 2003 and in the Eastern region in September 2004. Questionnaires were distributed to children aged 4-6 yrs in schools in May 2003. This was repeated in May 2004 when those in the East Midlands had received free fruit for 1 yr and those in the Eastern region had not. Responses were obtained in 2004 for 4,971 (53%) and 5,770 (54%) children in the intervention and control regions, respectively. Despite an increase in fruit consumption in the intervention compared with the control region between 2003 and 2004, there was no difference between the two regions in the prevalence or severity of asthma symptoms after 1 yr of fruit supplementation (odds ratio for wheeze in the past 12 months in intervention compared with control region 1.00, 95% confidence interval 0.88-1.14). Providing free fruit at school for 1 yr does not have any immediate effect on prevalence or severity of asthma in young children, although these data do not refute the hypothesis that a higher increase in fruit intake improves measures of asthma control.

Background: To identify which environmental exposures underpin the emergence of asthma epidemics, we need to study epidemics as they appear, as is now happening in the Jimma region of Ethiopia. We have previously studied risk factors for asthma in adults in Jimma and have now completed a survey of young children., Aim: To establish the prevalence of asthma in urban and rural children in Jimma, and to identify locally important risk factors., Design: Cross-sectional survey., Methods: All children aged 1-5 years living in Jimma town and three surrounding rural regions were identified. Data were collected using an interviewer-led questionnaire, and consenting children had skin prick tests to house dust mite and cockroach., Results: We surveyed 7155 children, of whom 3623 (51%) were female and 4285 (60%) lived in the urban area. The prevalence of wheeze in the last year was 3.4%, and was lower in the rural area (OR 0.47; 95%CI 0.34-0.66). In the urban area, the main risk factors for wheeze were a longer duration of breastfeeding, use of kerosene, and environmental tobacco smoke, while living with animals was protective. In rural children, the main risk factors were a positive skin prick test and living with animals., Discussion: The prevalence of wheeze in children in the Jimma region is low, particularly in rural children. In addition to having an impact on disease prevalence, place of residence also appears to modify the impact of environmental risk factors for wheeze.

Asthma is one of the commonest chronic diseases of affluent societies. The striking increase in prevalence of asthma over recent decades and the rarity of this disease in less affluent populations confirms the importance of environmental factors in the cause of asthma--although which environmental factors are responsible is still not clear. Family studies show that genetic factors are also important in determining individual susceptibility to asthma, with results of genetic studies suggesting that there are many genes with moderate effects rather than a few major genes. Asthmatic airways show inflammation and remodelling, with CD4+ helper cells, mast cells, and eosinophils characterising the inflammatory response. Inhaled corticosteroids remain the cornerstone of treatment with the addition of long-acting beta agonists as the next step if symptoms continue. Leukotriene antagonists, the only new drugs to reach the market in the past decade, have modest effects. However, a better understanding of the mechanisms underlying asthma and the genetic and environmental factors that predispose individuals to asthma should lead to better preventative strategies and new therapeutic approaches.

Airway responsiveness and variability in peak expiratory flow (PEF) are widely used as objective diagnostic measures of asthma, but it is not clear how these variables should be calculated or adjusted to obtain the highest diagnostic validity for physician-diagnosed asthma in the community. Data from a community-based sample of 1,513 adults has been used. Airway responsiveness to methacholine and 7-day PEF data were obtained in 1991, asthma and respiratory symptoms were diagnosed by questionnaires in 1991 and 1999. Airway responsiveness was expressed as the provocative dose causing a 20% fall in forced expiratory volume in one second (PD20), two-point and least-squares regression slopes. PEF variability was expressed as daily amplitude, weekly standard deviation and mean of the two lowest readings. Continuous measures were adjusted for measures of baseline airway calibre by linear regression. Measures of airway responsiveness had greater sensitivity for specificity for self-reported diagnosed asthma than expressions of PEF variability, before and after adjustment for airway calibre. Diagnostic validity was substantially better in adults aged <50 yrs; PD20 provided the best sensitivity for specificity (61% for 95% at 8.3 micromol). In those aged > or =50 yrs, no measure was closely related to diagnosed asthma. In younger age groups, provocative dose causing a 20% fall in forced expiratory volume in one second provides a valuable objective measure of asthma for epidemiological studies, but is unable to distinguish between asthma and chronic obstructive pulmonary disease in older people.

Study Objectives: Eosinophils and neutrophils play major roles, respectively, in the pathogenesis of asthma and COPD, and it is well recognized that levels of these cells in peripheral blood are increased in relation to their pulmonary involvement. However, the relation between peripheral blood cell counts of the other major leukocyte groups and these lung diseases or markers of allergy or airflow obstruction is less clear. We have therefore investigated the association between peripheral blood levels of eosinophils, neutrophils, basophils, monocytes, and lymphocytes and the occurrence of chronic respiratory symptoms, atopy, lung function, and bronchial hyperresponsiveness, and the modifying effect of age, in adults., Design: A cross-sectional general population study., Setting: Data on > 2,000 British adults, who originally participated in a study of diet and lung health, were analyzed using multiple linear and logistic regression to adjust for potential confounders, including age, sex, and smoking history., Results: We found that, like eosinophils, the peripheral basophil count was increased in relation to asthma and associated symptoms, and to airway hyperreactivity and increased total IgE, but differed from eosinophils in that basophils were unrelated to atopy. Monocytes were predominantly associated with symptoms indicative of obstructive airway disease, in similar relation to neutrophils, but both of these leukocyte counts were also increased in asthma patients in older age groups. Lymphocyte counts were unrelated to any objective or subjective marker of disease., Conclusions: If peripheral blood cell counts reflect pulmonary involvement of these leukocyte groups, basophils and monocytes may play a distinct role in the pathogenesis of allergic and nonallergic respiratory disease.

To determine whether asthma mortality is influenced by geographical or social factors, a retrospective analysis of deaths from asthma in England and Wales between 1979-1987 was performed. Death rates in the 15 Regional Health Authority areas of England and Wales were stratified by sex, age group (0-4, 5-34, 35-64, and > 64 years), and occupational social class. Detailed analysis was restricted to subjects aged 5-64 years because adequate social class data was only available over this age range. Death rates were higher in manual occupational groups (social class IIIb-V) than in non-manual occupations (social class I-IIIa), but on further analysis this effect was confined to males aged 35-64 years. In younger subjects (5-34 years), mortality was higher in the south of the country, and this difference was significant in males (P < 0.05). In older subjects (35-64 years), mortality in both sexes was significantly higher in the north of the country. This study demonstrates that mortality is not evenly distributed between social classes or regions of the country.

Nedocromil sodium is a non-steroidal prophylactic agent developed for the management of asthma. We have assessed the steroid sparing potential of inhaled nedocromil sodium 4 mg four times daily in a randomized, double blind, placebo controlled study in 69 asthmatic subjects controlled on inhaled beclomethasone dipropionate in the dose range 1000-2000 micrograms daily. Following a 4 week run-in period subjects added nedocromil sodium or placebo by metered dose inhaler to their usual medication for a further 4 weeks. The dose of inhaled steroid was then reduced at fortnightly intervals according to a predetermined schedule, with monitoring of asthma severity, symptom scores, bronchodilator use and peak flow recordings. Sixty subjects entered the steroid reduction phase and achieved median (range) % decreases in steroid dose of 80 (17-100)% with nedocromil sodium compared to 65 (0-100)% with placebo (P = 0.34) with 14 patients in the nedocromil sodium group and 10 in the placebo group being withdrawn completely from inhaled steroids. Subjective global assessment scores were significantly better with nedocromil sodium (mean 2.14) than with placebo (2.93; P < 0.02) though there was no difference between individual daily symptom scores. In this study therefore in asthmatic patients controlled on high doses of inhaled steroids, nedocromil sodium was well tolerated but the small differences in steroid sparing effect between nedocromil and placebo were not statistically significant.

The airway response and cardiovascular and hypokalaemic effects of fenoterol, salbutamol, and terbutaline given in multiples of standard doses from metered-dose inhalers were studied in ten patients with mild asthma. In a double-blind, crossover, placebo-controlled study the subjects received 2, 6, and 18 puffs of each drug with intervals of 90 min, and forced expiratory volume in 1 s, heart rate, QTc interval, plasma potassium concentration, tremor, and bronchial reactivity to histamine were measured. All three drugs produced similar bronchodilatation. However, the rises in heart rate, QTc interval, and tremor and the fall in plasma potassium were greater after fenoterol than after salbutamol or terbutaline. The maximum mean (SD) increases in heart rate for fenoterol, salbutamol, and terbutaline were 29 (24) bpm, 8 (9) bpm, and 8 (14) bpm, respectively; falls in plasma potassium were 0.76 (0.62) mmol/l, 0.46 (0.32) mmol/l, and 0.52 (0.39) mmol/l, respectively. Fenoterol afforded no additional protection against histamine compared with salbutamol. These findings suggest that at doses based on those used in clinical practice fenoterol causes more adverse effects than salbutamol or terbutaline. The most likely explanation for these effects is that fenoterol has been marketed at a higher dose than the other beta 2-agonists; fenoterol may in addition be less selective for beta 2 receptors.

1. We have recently shown that ouabain, an inhibitor of Na+/K(+)-adenosine triphosphatase, causes contraction of bovine and human airways in vitro, and that amiloride causes relaxation and inhibits receptor-operated contraction in bovine trachealis. 2. To determine whether such drugs alter bronchial reactivity in vivo, we have studied the effect of oral digoxin (an inhibitor of Na+/K(+)-adenosine triphosphatase) and oral and inhaled amiloride on bronchial reactivity to histamine in three double-blind, placebo-controlled studies. 3. Histamine reactivity was measured as the provocative dose causing a 20% reduction in the forced expiratory volume in 1 s (PD20FEV1) or, when normal subjects were included, the provocative dose causing a 35% reduction in the specific airways conductance (PD35sGaw); the results are given as geometric mean values. 4. In study 1, 13 atopic asthmatic subjects were given 20 mg of oral amiloride or placebo on separate days. Two hours after the drug, the geometric mean PD20FEV1 for histamine was 0.43 mumol after amiloride and 0.54 mumol after placebo (95% confidence intervals for the difference: 0.9 to -0.2 doubling doses of histamine; P = 0.2). 5. In study 2, six normal and 24 atopic asthmatic men inhaled 10 ml of 10(-2) mol/l amiloride or diluent control in a crossover study. The mean values of PD35sGaw for histamine immediately after inhalation of amiloride and placebo were 3.0 mumol and 4.3 mumol, respectively, in the normal subjects (95% confidence intervals for the difference: -0.53 to 1.52 doubling doses, P = 0.2), and 0.33 mumol and 0.29 mumol in the asthmatic subjects (95% confidence intervals for the difference: -0.95 to 0.57 doubling doses; P = 0.6).(ABSTRACT TRUNCATED AT 250 WORDS)

A questionnaire on asthma in schools was circulated to 291 Nottingham schools. The response rate was 91%. Three areas of concern were identified: are schools aware of all their asthmatic pupils; should children have more access to their medications in school; and do teachers need more guidance in supervising illnesses.

Airway reactivity is known to increase in relation to the severity of asthma, and, in the community, hyperreactivity has been shown to be associated with respiratory symptoms such as wheezing and shortness of breath. However, the relation between change in airway reactivity and change in the severity of respiratory symptoms and change in the use of asthma medications within subjects has not been studied. We have investigated this relationship in a community population. In September 1984 and March 1985, the provocative dose of histamine producing a 20% fall in FEV1 (PD20) was measured, and respiratory symptoms and medication use assessed by questionnaire in 78 subjects taking part in a study of seasonal changes in airway reactivity. On both occasions, PD20 was negatively correlated with current frequency of wheezing, with the amount of asthma medication in regular use, and with the current general assessment of breathing problems. In the 45 subjects who had a PD20 value of 8 mumol or less on at least one of the two occasions tested, PD20 increased between September and March by 0.46 (SEM, 0.32) doubling doses of histamine (p = 0.16). Within subjects, change in PD20 was negatively correlated with change in the frequency of wheezing in the past month (p less than 0.005) and with change in medication use (p less than 0.05). This study demonstrates that PD20 is related to the severity of respiratory symptoms and medication use, and that change in airway reactivity within subjects in a community population is associated with changes in the frequency of wheezing and in the use of asthma medication.

A questionnaire developed by the International Union against Tuberculosis and Lung Disease (IUATLD) to assess bronchial symptoms has been tested for its ability to predict the bronchial response to histamine in adults aged 18-64 years living in two areas of southern England. A number of questions were found to be independently associated with increased reactivity in the first randomly selected half of the subjects. These symptoms included wheeze, waking at night with shortness of breath, tightness in the chest or shortness of breath when exposed to animals, dust or feathers and the non-specific symptom of persistent problems with breathing. A predictive score based on these symptoms was more sensitive and only slightly less specific than the question on wheeze alone in predicting the response to histamine in the second half of the subjects. Questions about asthma though more specific were considerably less sensitive than either. Symptoms did not differentiate between reactivity associated with positive skin tests and that associated with smoking.

The bronchial response to inhaled histamine has been suggested as an epidemiological tool for assessing the prevalence of asthma, though the exact relationship between reactivity and asthma is unknown. Tests of bronchial reactivity to histamine were carried out in 511 subjects aged 18-64 years, randomly selected from the population in two areas of the South of England, who had returned questionnaires on respiratory symptoms. Bronchial reactivity to less than or equal to 8 mumol histamine was present in 14% and was associated with positive skin test responses to common allergens and with smoking history. Both of these relationships were in turn dependent on age, skin sensitivity being the more important determinant of reactivity in the young and smoking the more important in older subjects. Bronchial reactivity was least prevalent in the 35-44 year age group. No independent effect on reactivity of sex, social class, or area of residence was detected, and no significant effect from recent respiratory tract infections. Interpretation of the bronchial response to histamine in selected groups of subjects must take account of age, atopic state, and smoking history.

A relation between the prevalence of asthma and economic development has been suggested by studies in migrants and other surveys in developing countries. That this correlation might be partially explained by an increased intake of salt in the diet is supported by the observation that sales of table salt in the different regions of England and Wales are independently correlated with mortality from asthma for men and for children. As part of a wider survey of asthma 138 men living in two Hampshire villages and aged 18-64 were given a bronchial histamine challenge test and had their 24 hour urinary excretion of sodium measured. Bronchial reactivity was strongly related to 24 hour excretion of sodium after allowing for the effects of age, atopy, and cigarette smoking, there being on average a 10-fold difference in reactivity over the 95% range of sodium excretion recorded in the study. The data suggest that a high sodium diet may potentiate bronchial reactivity.

We have compared the effects of the leukotriene (LT) D4 antagonist L-649,923 and placebo on the airway response to antigen challenge in eight men with mild asthma known to have both an early and late response to inhaled antigen. Subjects ingested 1000 mg of L-649,923 or placebo in a randomized, double-blind protocol and, two hours later, inhaled the dose of antigen known to induce a 20% fall in FEV1. Pulmonary function (specific conductance, FEV1, peak expiratory flow rate, and maximal flow at 25% of vital capacity) was measured at intervals before and up to 9 hours after antigen. FEV1 fell in one subject after L-649,923 ingestion. L-649,923 in the other seven subjects caused no change in baseline pulmonary function, a small reduction in the early response to antigen for FEV1, peak expiratory flow rate, and maximal flow at 25% of vital capacity but not for specific airway conductance (six subjects only) and no effect on the late response. The mean maximum fall in FEV1 in the early response was 1.35 L after L-649,923 ingestion and 1.78 after placebo ingestion. This relatively small degree of protection by L-649,923 suggests either that L-649,923 is not a sufficiently potent antagonist to diminish the effect of endogenous LTD4 in vivo or that LTD4 does not play a major role in the airway response to antigen challenge.

Epidemiological problems arising from the absence of an agreed definition of asthma have led to the use of bronchial reactivity tests in community surveys of asthma prevalence. Since only a minority of the general population will develop bronchoconstriction in response to the dose of histamine considered acceptable for use in the community it is important to make maximum use of the data available. Several methods for summarising the information in the dose-response curve obtained from a histamine challenge test have been compared. A standardised histamine challenge test was administered to 797 subjects selected from two communities, and a repeat test to 106 subjects. The test was well accepted. For most subjects FEV1 rose initially after administration of histamine (median rise 100 ml), so maximum FEV1 was used as the baseline from which the 20% fall to achieve a PD20 was calculated. In order to use all the data rather than just two points on the FEV1-log dose graph, PD20 was estimated by means of curve fitting, and the values were compared with PD20 from linear interpolation. An exponential curve was found to fit the data well. Extrapolation from the maximum dose of 4 mumol up to 8 mumol was allowed in the estimation of PD20 by both methods. The curve fitting method gave slightly more reproducible PD20 values than did linear interpolation, and also gave more estimates in the range 0.03-8 mumol. The repeatability of PD20 compared well with that of asthmatic subjects tested in a clinical environment. Curve fitting has an advantage over linear interpolation in large community studies, for which analysis of data by computer is essential.

The International Union against Tuberculosis and Lung Disease (IUATLD) Bronchial Symptoms Questionnaire (1984) was developed for use in studies of asthma and its reliability measured in an earlier survey in England. The association of the symptoms elicited by this questionnaire to bronchial response to histamine has also been described. This paper presents the results of studies of the questionnaire in four clinical centres in Europe. The reliability of the questionnaire and its ability to predict the bronchial response to histamine were compared for English, Finnish, French and German translations of the questionnaire in samples of diagnosed asthmatics and controls in Nottingham, Berlin, Helsinki and Paris. The answers to questions showed good repeatability, especially in Finland and Germany, particularly those questions on asthma and wheeze. The most sensitive symptom for predicting hyperresponsiveness was the question on wheeze, the most specific questions were those on waking at night with shortness of breath (Paris and Nottingham) and morning tightness (Helsinki and Berlin). This study shows that the IUATLD (1984) questionnaire may provide useful, valid and comparable data even in translation but these studies will need to be repeated in representative samples before such a possibility is accepted as fully demonstrated.

To determine the role of Na/K ATPase in determining bronchial reactivity in man, we studied the effect of 1 mg inhaled ouabain on histamine reactivity in six normal and 10 asthmatic subjects in a placebo controlled, crossover study. sGaw was measured before and up to 2 h after drug, followed by a histamine challenge test to estimate the dose of histamine causing a 35% reduction in sGAW (PD35). sGAW values after ouabain and placebo did not differ significantly. Ouabain did not affect bronchial reactivity, geometric mean (95% CI) PD35 histamine values following ouabain and placebo were 8.98 (3.8-21.2) and 7.75 (3.2-18.7) mumol respectively in normal subjects and 0.46 (0.18-1.21) and 0.69 (0.22-2.13) in asthmatic subjects. We were thus unable to demonstrate a role for Na/K ATPase in determining bronchial reactivity to histamine in man.

In studies of asthma prevalence bronchial responsiveness has usually been measured as the provocative dose of bronchoconstrictor causing a 20% fall in FEV1 (PD20FEV1). This is relatively insensitive and only 10-20% of subjects in a general population sample will show such a response. Attempts to increase sensitivity, such as the use of the provocative dose causing a 10% fall in FEV1 (PD10FEV1), have not demonstrated any overall advantage, due to poorer repeatability. It has been suggested that measurement of bronchial reactivity using flow at low lung volumes measured from a partial flow volume curve is a more sensitive index of bronchoconstriction than PD20FEV1. If equally repeatable, it would have advantages in epidemiological practice. In 20 subjects with asthma, we compared the sensitivity and repeatability of PD10FEV1, PD20FEV1, and the provocative dose causing a 40% fall in flow at 30% of vital capacity (PD40V30P) following methacholine challenge. PD40V30P was more sensitive than both PD20FEV1 and PD10FEV1 by 1.48 and 0.35 doubling doses (DD) of methacholine, respectively. PD20FEV1 and PD40V30P showed equal repeatability, the 95% range for a single estimate of both being 2.02 DD. PD10FEV1 was less repeatable, with a 95% range of 2.35 DD. Values for the intraclass correlation co-efficient, which measures the ability of a test to discriminate between subjects, were 0.63, 0.79 and 0.69 for PD10FEV1, PD20FEV1, and PD40V30P, respectively. The increased sensitivity and comparable repeatability of measurement of bronchial reactivity for PD40V30P suggest that this method may be useful for studies of asthma prevalence.