Indoor mold levels and current asthma among school-aged children in Saskatchewan, Canada.

Current knowledge regarding the association between indoor mold exposures and asthma is still limited. The objective of this case-control study was to investigate the relationship between objectively measured indoor mold levels and current asthma among school-aged children. Parents completed a questionnaire survey of health history and home environmental conditions. Asthma cases had a history of doctor-diagnosed asthma or current wheeze without a cold in the past 12 months. Controls were age- and sex-matched to cases. Vacuumed dust samples were collected from the child's indoor play area and mattress. Samples were assessed for mold levels and quantified in colony-forming units (CFU). Sensitization to mold allergens was also determined by skin testing. Being a case was associated with family history of asthma, pet ownership, and mold allergy. Mold levels (CFU/m2 ) in the dust samples of children's mattress and play area floors were moderately correlated (r = 0.56; P < 0.05). High mold levels (≥30 000 CFU/m2 ) in dust samples from play [adjusted odds ratio (aOR) = 2.6; 95% CI: 1.03-6.43] and mattress (aOR) = 3.0; 95% CI: 1.11-8.00) areas were significantly associated with current asthma. In this study high levels of mold are a risk factor for asthma in children.

A dual CysLT1/2 antagonist attenuates allergen-induced airway responses in subjects with mild allergic asthma.

BACKGROUND: The cysteinyl leukotrienes (cysLTs) play a key role in the pathophysiology of asthma. In addition to functioning as potent bronchoconstrictors, cysLTs contribute to airway inflammation through eosinophil and neutrophil chemotaxis, plasma exudation, and mucus secretion. We tested the activity of the dual cysLT1/2 antagonist, ONO-6950, against allergen-induced airway responses. METHODS: Subjects with documented allergen-induced early (EAR) and late asthmatic response (LAR) were randomized in a three-way crossover study to receive ONO-6950 (200 mg) or montelukast (10 mg) or placebo q.d. on days 1-8 of the three treatment periods. Allergen was inhaled on day 7 two hours postdose, and forced expiratory volume in 1 s (FEV1 ) was measured for 7 h following challenge. Sputum eosinophils and airway hyperresponsiveness were measured before and after allergen challenge. The primary outcome was the effect of ONO-6950 vs placebo on the EAR and LAR. RESULTS: Twenty-five nonsmoking subjects with mild allergic asthma were enrolled and 20 subjects completed all three treatment periods per protocol. ONO-6950 was well tolerated. Compared to placebo, ONO-6950 significantly attenuated the maximum % fall in FEV1 and area under the %FEV1 /time curve during the EAR and LAR asthmatic responses (P < 0.05) and allergen-induced sputum eosinophils. There were no significant differences between ONO-6950 and montelukast. CONCLUSIONS: Attenuation of EAR, LAR, and airway inflammation is consistent with cysLT1 blockade. Whether dual cysLT1/2 antagonism offers additional benefit for treatment of asthma requires further study.

Allergen-induced early and late asthmatic responses to inhaled seasonal and perennial allergens.

BACKGROUND: The allergen bronchoprovocation (ABP) test is a validated model to study asthma pathophysiology and response to treatments. The inhibitory effect of agents on the allergen-induced late asthmatic response (LAR) is a predictor of their efficacy in asthma treatment. However, it is difficult to predict the magnitude of a LAR, which may vary according to immune responsiveness and the type of allergen used for ABP. AIM: To determine the relationship between the magnitudes of early asthmatic response (EAR) and LAR in mild asthmatic subjects according to the type of allergen inhaled and its determinants. METHODS: This is a retrospective analysis of a large database of ABPs, all performed with a common standardized methodology. Patients were either challenged with house dust mites (HDMs), animals or pollens allergens. EAR was defined as a ≥ 20% fall in forced expiratory volume in 1 s (FEV1 ) < 3 h following ABP and LAR as a ≥ 15% fall in FEV1 between 3 and 7 h post-ABP. The ratio of EAR % fall in FEV1 /LAR % fall in FEV1 was compared between the groups of subjects according to the allergen used for ABP. RESULTS: Data from 290 subjects were analysed: 87 had an isolated EAR and 203 had a dual response (EAR + LAR). Dual responders had a significantly lower baseline PC20 , a more marked fall in FEV1 at EAR, and a trend towards higher baseline sputum eosinophil percentages. The ratio of EAR over LAR was significantly lower in HDM compared with pollen ABP, indicating a larger LAR for a similar EAR. No correlations were observed between the ratio of EAR over LAR and the various parameters recorded in the different groups analysed. CONCLUSION: Different mechanisms may be involved in modulating the magnitude of the LAR, according to the type of allergen. HDM seems to induce a stronger LAR than pollens, animal allergens being intermediary in this regard.

Airway responsiveness to mannitol 24 h after allergen challenge in atopic asthmatics.

BACKGROUND: Airway responsiveness to indirect stimuli correlates positively with airway inflammation. In atopic asthmatics, allergen inhalation is associated with an influx of inflammatory cells and increased responsiveness to the direct-acting stimuli methacholine at 3 and 24 h after exposure. We have shown mannitol responsiveness decreases 3 h after allergen inhalation. The current investigation assessed mannitol responsiveness 24 h after allergen challenge. METHODS: Eleven mild atopic asthmatics completed allergen challenges on two separate occasions. In random order, methacholine or mannitol challenges were performed 24 h pre- and post-allergen challenge. Levels of fractional exhaled nitric oxide were also measured. RESULTS: Allergen challenge increased airway responsiveness to methacholine 24 h postchallenge; the geometric mean (95% CI) methacholine PC20 decreased from 5.9 mg/ml (1.8-19.4) to 2.2 mg/ml (0.81-5.89); P = 0.01. This coincided with a significant increase (P = 0.02) in FeNO levels. Conversely, allergen challenge decreased airway responsiveness to mannitol; geometric mean (95% CI) dose-response ratio was significantly higher after allergen exposure (57 mg/% FEV1 fall [27-121] to 147 mg/% FEV1 fall [57-379]; P = 0.03), and FeNO levels were not significantly increased (P = 0.054). CONCLUSION: Allergen-induced changes in airway responsiveness to direct and indirect stimuli are markedly different. The loss in responsiveness to mannitol is likely not explainable by a refractory state. The effect(s) of allergen exposure on airway responsiveness to indirect-acting stimuli require further investigation.

OX40L blockade and allergen-induced airway responses in subjects with mild asthma.

BACKGROUND: The OX40/OX40L interaction contributes to an optimal T cell response following allergic stimuli and plays an important role in the maintenance and reactivation of memory T effector cells. OBJECTIVE: We tested whether treatment with an anti-OX40L monoclonal antibody (MAb) would inhibit allergen-induced responses in subjects with asthma. METHODS: Twenty-eight mild, atopic asthmatic subjects were recruited for a double-blind, randomized, placebo-controlled, parallel-group trial (ClinicalTrials.gov identifier NCT00983658) to compare blockade of OX40L using a humanized anti-OX40L MAb to placebo-administered intravenously in 4 doses over 3 months. Allergen inhalation challenges were carried out 56 and 113 days after the first dose of study drug. The primary outcome variable was the late-phase asthmatic response. Other outcomes included the early-phase asthmatic response, airway hyperresponsiveness, serum IgE levels, blood and sputum eosinophils, safety and tolerability. RESULTS: Treatment with anti-OX40L MAb did not attenuate the early- or late-phase asthmatic responses at days 56 or 113 compared with placebo. In the anti-OX40L MAb treatment group, total IgE was reduced 17% from pre-dosing levels, and sputum eosinophils decreased 75% by day 113 (both P = 0.04). There was no effect of anti-OX40L MAb on airway hyperresponsiveness or blood eosinophils. The frequency of AEs was similar in both groups. CONCLUSION AND CLINICAL RELEVANCE: Pharmacological activity of anti-OX40L MAb was observed by decreases in serum total IgE and airway eosinophils at 16 weeks post-dosing, but there was no effect on allergen-induced airway responses. It is possible that the treatment duration or dose of antibody was insufficient to impact the airway responses.

Single-dose desloratadine and montelukast and allergen-induced late airway responses.

Montelukast and desloratadine synergistically inhibit the allergen-induced early asthmatic response. Montelukast also suppresses the allergen-induced late asthmatic response, but there are no reports on the effect of desloratadine or the combination on the allergen-induced late asthmatic response. Atopic asthmatics (n = 10) completed a multicentric randomised double-blind crossover study comparing single-dose placebo, 5 mg desloratadine, 10 mg montelukast and the combination administered 2 h prior to allergen inhalation challenge. Methacholine challenges were performed 24 h before and after allergen challenge. Exhaled nitric oxide measurements and sputum inflammatory cell counts were also carried out. All active treatments significantly decreased the late asthmatic response area under the curve. Combination therapy provided the greatest inhibition compared to desloratadine and montelukast. Montelukast was nonsignificantly better than desloratadine but not as effective as the combination. There was a trend towards a decrease in airway responsiveness following montelukast and combination. Montelukast, but not desloratadine or the combination, decreased exhaled NO levels 24 h after allergen. The allergen-induced increase in sputum eosinophil numbers was significantly suppressed at 7 h with desloratadine and combination therapy, and at 24 h with montelukast and combination therapy. Single-dose co-administration of desloratadine and montelukast 2 h prior to allergen inhalation clinically abolished the late asthmatic response and eosinophil recruitment.

Calcitonin from ultimobranchial glands of dogfish and chickens.

Acid extracts of thyroid glands from a small shark Squalus suckleyi and domestic fowl Gallus domestica contained no detectable calcitonin activity, while very potent hypocalcemic responses were obtained in rats with similar extracts from the ultimobranchial glands of these two species. The calcitonin concentration was 4 to 40 times that present in hog thyroid, which, as in most other mammals, contains ultimobranchial tissue. The evidence suggests that calcitonin is a fundamental calcium-regulating hormone present in all higher vertebrates and that it is an ultimobranchial rather than a thyroid hormone. It also indicates an important and hitherto unrecognized function for the ultimobranchial glands.

Assessment of endotoxin levels in the home and current asthma and wheeze in school-age children.

UNLABELLED: The relationship between household endotoxin and asthma in children is not clear. To further investigate the relationship between sources of endotoxin and childhood asthma, we conducted a case-control study of children with and without asthma and examined their more frequent household exposures in the home. Children ages 6-13 years with current asthma (n = 70) or wheeze only (n = 19) were sex and age matched (+/-1 year) to 107 controls. Play area and mattress dust were collected for endotoxin analysis. Atopic status was determined by skin prick testing for allergies. A family size of >4 per household was associated with higher endotoxin levels (EU/mg) in the bed dust (P < 0.05). Passive smoking (P < 0.05) and the presence of a cat were associated with higher levels of endotoxin in mattress dust. Endotoxin levels in either the play dust or the bed dust did not differ between cases and controls. Within atopic cases, those with higher endotoxin loads (EU/m2) in bed or play areas were more likely to miss school for chest illness (P < 0.05). In this study, household endotoxin is not a risk factor for current asthma overall but may be associated with increased severity in children with atopic asthma. PRACTICAL IMPLICATIONS: This study did not find that household sources of endotoxin were associated with asthma. However, within atopic asthmatics, asthma severity (as measured by a history of being kept home from school because of a chest illness in the past year) was associated with higher levels of endotoxin in dust from the child's bed. There is a need to further investigate the nature of the relationship between household endotoxin and asthma severity in children which could lead to better management of childhood asthma.

Intracerebral abscess: a complication of severe cystic fibrosis lung disease.

Intracerebral abscess is an uncommon complication of severe cystic fibrosis lung disease. The present report describes a case of fatal multiple intracerebral abscesses in a patient with a severely bronchiectatic, nonfunctioning right lung and chronic low-grade infection. The patient was previously turned down for pneumonectomy. Intracerebral abscess in cystic fibrosis and the potential role of pneumonectomy in the present patient are discussed.

Clinical concerns with inhaled beta2-agonists: adult asthma.

Inhaled beta2-agonists, when used regularly, cause subtle but significant worsening of asthma control. Overuse of inhaled beta2-agonists is associated with increased risk of death from asthma in a dose-response fashion. beta2-Agonists enhance airway responses to allergens, including induced airway hyperresponsiveness and induced airway inflammation. This is a plausible explanation for beta2-agonist-worsened asthma control. These direct effects of inhaled beta2-agonists, including increased airway response to allergen, tolerance, etc., may partially explain the association of overuse with asthma death. However, it is probable that the major reason for the association of beta2-agonists overuse and asthma mortality is an indirect effect. Inhaled beta2-agonists are effective relievers and preventers of bronchoconstriction and asthma symptoms but fail to treat the underlying pathogenesis, namely the airway inflammation. Thus, overuse may mask the true asthma severity and result in both an underappreciation and undertreatment of the disease. This would provide a rational explanation for the relationship of inhaled beta2-agonist use and mortality and also would fit the dose-response pattern. Inhaled beta2-agonists should be used exclusively as needed for relief of symptoms and their requirement should be infrequent: the need for excessive doses of beta2-agonists provides a useful marker of asthma (lack of) control.

Airway hyperresponsiveness and late asthmatic responses.

Late inflammatory sequelae following allergen (and occupational low molecular weight sensitizing chemical) exposure, including the late asthmatic response and increased nonallergic airway responsiveness, are now felt to be more important in the pathogenesis of atopic allergic and occupational asthma than are the early bronchospastic responses. These late sequelae can be inhibited by sodium cromoglycate and by corticosteroids but not by bronchodilators. Recognition that allergic and occupational (and likely all forms of) asthma are inflammatory conditions underscores the rationale for the early use of anti-inflammatory therapeutic strategies in the management of asthma. Such "anti-inflammatory" therapeutic strategies include environmental control, sodium cromoglycate, and both inhaled and oral corticosteroids.

Standardization of inhalation provocation tests. Dose vs concentration of histamine.

The importance of histamine dose vs histamine concentration in determining the response to inhaled histamine was evaluated by comparing the effect of 30 sec and two min inhalation times on duplicate histamine inhalation tests in 15 asthmatic patients. The histamine provocation concentration required to produce a 20 percent FEV1 fall after 30 sec inhalations (30 sec PC20) was on average 3.6-fold greater than the two min PC20. Individually, ten of the 15 fell within the range of dose reproducibility (+/- one doubling dose), while five subjects fell outside this range, three with 30 sec PC20 less than twice two min PC20 and two with 30 sec PC20 greater than 8 X two min PC20. Seven subjects had duplicate measurements of both 30 sec PC20 and two min PC20; the two min PC20 was more reproducible than the 30 sec PC20 in all seven. The better reproducibility of the two min PC20 is likely due to a more reproducible inspiratory time over the two-minute breathing period. These findings have relevance in standardization of inhalation challenge tests, and in comparing results of such tests done by different techniques.

Calculation of provocative concentration causing a 20% fall in FEV(1): comparison of lowest vs highest post-challenge FEV(1).

BACKGROUND: Considerable, unexamined controversy exists surrounding the use of the highest vs the lowest FEV(1) for calculating the provocative concentration causing a 20% fall in FEV(1) (PC(20)) during direct bronchoprovocation challenges. OBJECTIVE: To compare the PC(20) calculated using the lowest FEV(1) post-diluent and post-histamine/methacholine vs the PC(20) calculated using the highest FEV(1) post-diluent and post-histamine/methacholine. METHOD: Retrospective analysis of 225 challenges: 75 research methacholine challenges, 75 research histamine challenges, and 75 clinical methacholine challenges. For each test, the PC(20) was calculated twice, first using the lowest post-diluent FEV(1) to the lowest post-histamine/methacholine FEV(1), and then using the highest to the highest. RESULTS: The intraclass correlation coefficients for methacholine research, histamine research, and methacholine clinic challenges were 0.99, 0.98, and 0.95, respectively. The PC(20) calculated using the lowest to lowest FEV(1) was slightly and significantly lower in all three groups (paired t test p < 0.0001). CONCLUSIONS: The PC(20) values calculated using the highest FEV(1) are almost identical to the PC(20) values calculated using the lowest FEV(1). The difference, although clinically irrelevant, holds statistical significance.

Volume adjustment of maximal midexpiratory flow. Importance of changes in total lung capacity.

In 21 of 100 consecutive subjects demonstrating greater than or equal to 10 percent increase in one second forced expired volume following 200 micrograms inhaled salbutamol, the forced expired flow over the middle half of the vital capacity (FEF25-75% was unchanged (n = 16) or fell greater than or equal to 10 percent (n = 5). Volume adjustment of FEF25-75%, to the same volume below total lung capacity (TLC) before and after administration of the bronchodilator resulted in significant increases in 18 of these 21 subjects. The volume-adjusted FEF25-75% increased more (98 percent) following 1500 micrograms inhaled metaproterenol in ten asthmatic subjects, and decreased more (53 percent) following inhalation of histamine in eight subjects, than did the standard FEF25-75% (44 percent increase and 34 percent decrease respectively). When the small changes in TLC which were seen following metaproterenol (4.4 +/- 4.1 percent reduction, p < 0.01) and histamine (11.0 +/- 7.2 percent increase, p < 0.001) were considered, and FEF25-75% volume adjusted so it was measured at the same absolute lung volume, greater changes were seen (198 percent increase after use of metaproterenol, and 75 percent decrease after use of histamine). When FEF25-75% is being examined following administration of a bronchodilator or a bronchoprovocation challenge, it should be volume-adjusted to absolute lung volume. When TLC cannot easily be determined repeatedly (eg routine pulmonary function studies), volume adjustment to the same volume below TLC is advised.

Right-sided aortic arch presenting as refractory intraoperative and postoperative wheezing.

A 29-year-old woman presented with severe refractory intraoperative wheezing and airflow limitation that resolved spontaneously. Contrast-enhanced computed tomographic (CT) scan of the thorax confirmed a right-sided aortic arch. Variable intrathoracic large airway obstruction that worsened markedly when the patient was in a supine position and slightly more following intravascular volume expansion was shown on flow-volume studies. We postulate the right-sided aortic arch caused airflow obstruction that worsened intraoperatively because of position and intravenous fluids.

Ethnic differences in the prevalence of pulmonary airflow obstruction among grain workers.

World Health Organization data suggest that British males over 45 have a higher death rate from chronic bronchitis, emphysema, and asthma combined than do other Europeans. Although widely supposed that this is due to particularly unfavorable environmental factors in the British Isles, as well as a higher rate of tobacco consumption, ethnicity itself may be a significant factor in determining risk of obstructive airways disease. To test this hypothesis, we have analyzed the prevalence of airflow obstruction (100 x FEV1:FVC less than 68% and FEV1 less than 84 percent predicted) in Saskatchewan grain workers of British, German, and Eastern European ancestry using the Mantel-Haenszel odds ratio (OMH) and stepwise logistic regression. We found that the British grain workers had a significantly greater prevalence of airflow obstruction (OMH = 3.2; p less than 0.01) than the Eastern Europeans. We also found that ethnic origin made a significant contribution to the estimation of risk of airflow obstruction among grain workers independent of the effects of age and smoking.

Occupational asthma caused by cedar urea formaldehyde particle board.

Two carpenters developed asthma and rhinitis related to occupational exposure to a cedar urea formaldehyde (CUF) particle board. One patient developed nasal and chest symptoms and an equivocal early asthmatic response after CUF sawdust exposure, but not after spruce or western red cedar sawdust exposure; possible late asthmatic response may have been inhibited by beclomethasone treatment. The other patient developed marked nasal and chest symptoms and a dual asthmatic response after CUF exposure, but not after spruce or cedar exposure. Both patients developed increased bronchial responsiveness to inhaled histamine, which persisted for at least six days in the first patient, and which was associated with increased asthmatic symptoms of days' to weeks' duration in both. A previously unexposed asthmatic patient, with more markedly hyperreactive bronchi, developed no symptoms, no change on spirometric testing, and no change in histamine response after CUF exposure. Specific IgE antibodies directed against formaldehyde-human serum albumin conjugate could not be demonstrated using the radioallergosorbent test. This investigation documents the occurrence of occupational asthma caused by urea formaldehyde used as a bonding agent in particle boards. Absence of a response in a previously unexposed, more severe asthmatic patient suggests specific sensitization to some component of the urea formaldehyde resin complex had developed.

Increased airways responsiveness in swine farmers.

A respiratory questionnaire, pulmonary function tests, and an examination of airways responsiveness were conducted on 20 swine farmers and 20 control subjects. The swine farmers represented almost the complete work force from 13 Hutterite colonies and had worked in confinement buildings with more than 2,000 swine (3,270 +/- 1,221 swine) for at least four hours (6.6 +/- 1.8 hours) per day for more than two years (10.5 +/- 7.5 years). The control subjects were randomly selected from outdoor city workers from the city of Saskatoon and were matched for gender, age (+/- 2 years), and smoking status. Eleven swine farmers (55 percent) had chronic cough, compared with three (15 percent) of the control subjects (p less than 0.01). Eight (40 percent) of the swine farmers had symptoms of wheezing, compared with three (15 percent) of the control subjects (p less than 0.05). The FEV1 was significantly lower in swine farmers (97.2 +/- 11.5 percent predicted) than in control subjects (106.0 +/- 12.0 percent of predicted) (p less than 0.05). Airways responsiveness was measured by methacholine challenge with doubling concentrations ranging from 0.25 to 256 mg/ml. The provocation concentrations resulting in a reduction of 10 percent (PC10) and 20 percent (PC20) in FEV1 were lower in swine farmers than in control subjects (PC10, 77.2 +/- 78.8 mg/ml vs 180.8 +/- 96.5 mg/ml; p less than 0.01; and PC20, 154.5 +/- 99.9 mg/ml vs 229.6 +/- 66.8 mg/ml; p less than 0.05). Twelve swine farmers (60 percent) had PC20 of less than 256 mg/ml, compared with three (15 percent) of the control workers (p less than 0.01). Fewer swine farmers demonstrated atopy as measured by skin prick tests than did control workers (21 percent vs 56 percent; p less than 0.05). These findings suggested that occupational exposure in swine confinement buildings is associated with mild increases of nonspecific, nonatopic airways responsiveness in swine farmers.

Importance of evaporative water losses during standardized nebulized inhalation provocation tests.

Evaporative water losses from jet nebulizers produce temperature drop, reduction in total nebulizer output with increased nebulization time, and increasing concentration of solute remaining in the nebulizer. These were documented and quantitated for the Wright nebulizer which is used for one histamine/methacholine inhalation test method. Indirect determination of nebulizer aerosol output, made by estimation of total sodium lost from the nebulizer, was about 25 percent of total output as determined by weight change. A similar tendency was seen for a De Vilbiss 40 nebulizer for both reduction in total nebulizer output with increasing duration of nebulization, and increased solute concentration remaining in the nebulizer. These data must be taken into account when standardizing inhalation provocation tests. Nebulizers should be calibrated under the same conditions that they are used during the test. Histamine and methacholine solutions should be discarded after a single use in the 2-min tidal breathing Wright nebulizer method.

Airway responsiveness to inhaled histamine in chronic obstructive airways disease. Chronic bronchitis vs emphysema.

Airway responsiveness to inhaled histamine was examined in two groups of carefully selected patients with nonasthmatic chronic obstructive airways disease (COAD). Twelve patients with chronic bronchitis and airflow obstruction but little emphysema and 13 with predominantly emphysema and airflow obstruction but little bronchitis were selected based on history, chest roentgenogram, and diffusing capacity for carbon monoxide (Dsb). Emphysema patients had less cough, less sputum, less chronic bronchitis, lower Dsb, and more radiographic evidence of vascular deficiency. There was no difference in anthropometric features, smoking history, atopic skin sensitivity, hemoglobin, blood eosinophilia, PaO2, PaCO2, ECG, lung volumes, or expiratory flow rates. The two groups had similar airway responsiveness to inhaled histamine; the geometric mean provocation concentrations producing a 20 percent FEV1 fall (PC20) was 0.56 mg/ml for the bronchitis patients and 0.28 mg/ml for the emphysema patients (p greater than 0.20). Regression of log histamine PC20 vs percent predicted FEV1 showed a high correlation in both groups (r = 0.73, p less than 0.01 in bronchitis and r = 0.79, p less than 0.001 in emphysema). The regression lines were almost identical. These data suggest that in COAD bronchial responsiveness to inhaled histamine is mainly due to the altered airway geometry, and that there is no difference in histamine responsiveness between patients with emphysematous COAD and nonemphysematous COAD with chronic bronchitis.