Effects of dog ownership in early childhood on immune development and atopic diseases.

BACKGROUND: Exposure to pets in childhood has been associated with a reduced risk of wheezing and atopy. OBJECTIVE: Our objective was to determine whether the effects of pet exposure on immune development and atopy in early childhood can be explained by alterations in exposure to innate immune stimuli in settled dust. METHODS: Two hundred and seventy-five children at increased risk of developing allergic diseases were evaluated to age 3 years for pet ownership, blood cell cytokine responses, and atopy. Can f 1, Fel d 1, endotoxin, ergosterol, and muramic acid were measured in settled dust from 101 homes. RESULTS: Dog exposure at birth was associated with decreased atopic dermatitis (AD) (12% vs. 27%; P=0.004) and wheezing (19% vs. 36%; P=0.005) in year 3. The rates of AD (23%) and wheezing (42%) in year 3 were relatively high in children who acquired dogs after birth. The prevalence of dog sensitization (10-12%) did not vary according to dog exposure. Can f 1 levels in bedroom dust were positively associated with IL-10 (r=0.26; P=0.01), IL-5 (r=0.34, P<0.001), and IL-13 (r=0.28; P=0.004) responses at age 1, and IL-5 (r=0.24; P=0.022) and IL-13 (r=0.25; P=0.015) responses at age 3. In contrast, endotoxin was associated with IFN-gamma (r=0.31; P=0.002) and IL-13 (r=0.27; P=0.01) responses at age 3 but not at age 1, and similar relationships were present for muramic acid. Adjustment for levels of innate immune stimuli in house dust did not significantly affect the relationships between Can f 1 and cytokine responses. CONCLUSIONS: Exposure to dogs in infancy, and especially around the time of birth, is associated with changes in immune development and reductions in wheezing and atopy. These findings are not explained by exposure to endotoxin, ergosterol, or muramic acid.

Bronchodilation and inhibition of induced asthma by adrenergic agonists.

In asthma, adrenergic agonists alleviate airflow obstruction and prevent obstructive responses to a variety of stimuli. A rapidly and a slowly metabolized agonist were compared to determine whether bronchodilation is the major mechanism by which these drugs prevent exercise-induced asthma (EIA). A 200-microgram inhaled dose of the rapidly metabolized agonist, isoproterenol, induced bronchodilation of the same order as terbutaline 500 microgram (1-sec forced expiratory volume [FEV1] increased 9.5% and 10.2%). An hour after isoproterenol, FEV1 was still above baseline (p less than 0.02) but EIA was only partially inhibited; the 23% fall in FEV1 was of the same order as the 32% fall after placebo (p greater than 0.05). One hour after terbutaline, mean resting FEV1 was in the range of that after isoproterenol, but the 10% change after exercise was less than that after placebo and isoproterenol (p less than 0.005). Our findings suggest that the two effects have different dose-response relationships, with higher doses of adrenergic agonists needed to prevent EIA than to maintain bronchodilation.

Exercise-induced asthma in children with intrinsic and extrinsic asthma.

The significance of intrinsic asthma as a diagnosis has been questioned since, except for the lack of evidence of allergy, there is no pathophysiologic distinction from extrinsic asthma. Following a standardized exercise stress, allergic (extrinsic) asthmatics respond with more severe asthma than do nonallergic (intrinsic) asthmatics. The incidence of significant exercise-induced asthma is greater in a group of extrinsic asthmatics than in intrinsic asthmatics. Extrinsic asthmatics show increased airway sensitivity during a significant pollen season.

The cycloergometer as a system for studying exercise-induced asthma.

Although bicycle exercise induces less asthma than does treadmill running, the cycloergometer offers definite advantages for quantitative testing of bronchospastic response, extensive knowldge of normal responses, lack of training artifact, and ease of physiologic monitoring. Using maximal heart rate to tailor the exercise load to a given subject, reliable responses can be obtained from subjects as young as 7 years old. To obtain such results, diurnal variations in response to exercise, resting bronchial tone, and previous medication must be controlled, and pulmonary function measurements must be taken frequently after exercise.

Medications used by children with asthma living in the inner city.

OBJECTIVE: The purpose of the study was to examine medication use reported by families participating in an urban school-based community intervention program and to relate this use to other social and medical variables. DESIGN: The design of the study was a cross-sectional questionnaire survey. SETTING: Patients and their families recruited from elementary schools in a community setting were interviewed between December 1991 and January 1992. PARTICIPANTS: A total of 508 children with asthma were identified by school health records and teacher surveys. Their families confirmed the diagnosis and agreed to enter the study. Questionnaires were completed by 392 families. INTERVENTION: The 392 families participated in a controlled trial of asthma education after providing the data that are the basis of this report. RESULTS: More than half of the children took two or more medications for asthma. Thirty-one percent took theophylline alone or in combination with an adrenergic agent; 11% took some form of daily antiinflammatory medication, either cromolyn (8%) or inhaled steroids (3%). The pattern of medication use related to measures of severity and to regular visits to physicians or nurses. In general, however, children were undermedicated. A total of 78 children (20%) reported no medication or over-the-counter medication use, although 37% reported asthma severe enough to be associated with >/=20 days of school missed per month, and 37% had had an emergency room visit for asthma in the past 6 months. More than half of children >/=9 years old supervised their own medication. CONCLUSIONS: We concluded that undermedication is common in poor children with asthma living in urban areas. Antiinflammatory medications are used less commonly than in the general population, and theophylline is used more often. School children may be likely to supervise their own medication.

The environment and asthma in U.S. inner cities.

The prevalence and severity of asthma has increased in the last 20 years, and the greatest increase has been seen among children and young adults living in U.S. inner cities. The reasons for this increase are obviously complex, but include environmental exposures to allergens and pollutants, changing patterns of medication, and the psychosocial stresses of living in poor inner-city neighborhoods. This paper presents an overview of environmental, immunologic, and genetic factors associated with asthma morbidity and mortality. This overview can be used to provide a framework for designing an interdisciplinary research program to address the complexities of asthma etiology and exacerbation. The strongest epidemiologic association has been found between asthma morbidity and the exposure of immunologically sensitive asthmatic patients to airborne allergens. Our current understanding of the process of sensitization suggests that there is a strong genetic predisposition to form IgE to allergenic proteins on airborne particles. Much of this work has been conducted with animal models, but in a number of instances, specific confirmation has been reported in humans. Sensitized individuals respond to inhaled exposure with immediate mast-cell dependent inflammation that may be augmented by pollutant particles, especially diesel exhaust particles. Relatively little is known about the methods of assessing exposure to airborne pollutants, especially biologically active particulates. However, to examine the relationship of morbidity in genetically predisposed individuals, it will be important to determine the most relevant method of making this assessment.

The effects of oral doses of theophylline and fenoterol on exercise-induced asthma.

The effects of oral doses of theophylline and a beta-adrenergic agonist, fenoterol, were examined in 18 asthmatic young adults. Significant bronchodilation was seen with high-dose theophylline (FEV1 increased 14 percent) and with full 10-mg doses of fenoterol (FEV1 increased 10 percent). Low-dose theophylline alone (130 mg) increased FEV1 by 5 percent, but when combined with 5 mg of fenoterol, a 14 percent improvement was seen, demonstrating significant (P = .003) additive effects. The ability of the two drugs to prevent the asthmatic response to exercise was not additive. The mean fall in FEV1 was not statistically different when subjects exercised after receiving a placebo (32 percent) 130 mg of theophylline (27 percent), or 130 mg of theophylline with 5 mg of fenoterol (18 percent). Furthermore, side effects associated with the two drugs, such as tachycardia, tremor, or CNS stimulation, were significantly increased when the two drugs were given simultaneously. Thus, little therapeutic benefit was gained from simultaneous therapy. Both bronchodilation and toxicity were equivalent to that seen with larger therapeutic doses of either drug given alone, and protection from the effects of a frequently encountered stress was not significantly enhanced.

A controlled trial of long-term bronchodilator therapy in cystic fibrosis.

To evaluate the effect of long-term bronchodilator therapy in CF patients with demonstrated bronchial hyperresponsiveness, we first performed methacholine challenges to determine responsiveness, then entered 27 patients (16 methacholine responders and 11 nonresponders) into a two-month double-blind crossover trial of albuterol, 90 micrograms by inhalation four times a day vs placebo. Among the responders, daily PEFR measures improved significantly more during treatment with albuterol (12 +/- 32 L/min) than with placebo (-0.4 +/- 19 L/min; p less than 0.05). In addition, a clinically important level of improvement in PEFR (15 percent increase) was reached significantly more frequently in the responders. Methacholine nonresponders had no change in PEFR on either albuterol or placebo. Daily symptom scores as well as spirometry measurements at biweekly visits did not show significant changes. We conclude that long-term therapy with inhaled albuterol improves lung function in CF patients, but only in those with bronchial hyperresponsiveness as demonstrated by methacholine challenge.

Airway hyperreactivity in cystic fibrosis. Clinical correlates and possible effects on the course of the disease.

To evaluate whether increased airway reactivity affected the course of patients with cystic fibrosis (CF), we categorized 40 CF patients as to methacholine sensitivity and then evaluated their disease activity and natural history. Twenty methacholine reactors had more severe lung disease (lower S-K clinical scores and more impairment of pulmonary function) than did 16 nonreactive patients, and acute bronchodilator response was greater in the methacholine reactors. Thirty-four patients were followed prospectively over a 17- to 24-month period. Among 19 methacholine reactors, there were more pulmonary exacerbations and a more rapid decline in FEV1. In general, increased obstruction was associated with increased reactivity. Although the data are subject to differing interpretations, they are consistent with the hypothesis that in patients with CF, airway hyperreactivity occurs secondary to bronchial damage, age, is associated with more rapid pulmonary deterioration, and is an unfavorable prognostic finding.

Pathophysiology of exercise-induced asthma.

The initiating stimulus for exercise-induced asthma in airway mucosal cooling or drying is caused by heat and water losses during exercise-related hyperventilation. It is not known how this stimulus is translated to bronchoconstriction, but the most convincing evidence is that mast cells are activated and release bronchospastic chemical mediators. The obstructive response appears to depend on the existence of abnormally reactive airways characteristically found in asthmatics. A number of modifying factors may be found during exercise, including plasma changes in catecholamines and metabolite and acid-base status.

Otitis media and the immotile cilia syndrome.

The immotile cilia syndrome appears to be a congenital defect in the ultrastructure of cilia that renders them incapable of movement. Respiratory tract cilia and sperm are predominantly affected. Bronchiectasis, sinusitis and male sterility are the main clinical findings. Situs inversus may be found. To these findings can be added otitis media. The defect appears to be a complete or partial absence of dynein arms which are believed to be essential for generating movement of cilia or sperm tails. Six patients suspected of having immotile cilia were compared to six patients in a control group. In affected patients, no cilia movement in the middle ear or nasopharynx was observed using the operating microscope. Electron microscopy of cilia from the mucosa of the middle ear and nasopharynx appeared to confirm the ultrastructural defect in two of six patients suspected of having the syndrome.

Immunotherapy for allergic respiratory disease.

In summary, immunotherapy is probably a useful treatment for selected cases of allergic airway disease. Patients should be selected who are allergic and who have at least moderately severe illnesses. Using commercially available solutions of antigen extracts, a therapeutic response may be expected in about three quarters of patients in that they will be able to reduce or eliminate medications. The disadvantages of treatment include its inconvenience and cost, its frequent ineffectiveness, and its risks of anaphylaxis; many of these disadvantages are eliminated by newer antigen preparations.

Moving health care education into the community.

The A+ Asthma Club, an educational program developed for elementary school children in inner-city schools, is offered through a series of six sessions during school hours with an additional three booster sessions. This article describes how the program was designed, its theoretical basis, the curriculum and its staffing.

Biological potency of German cockroach allergen extracts determined in an inner city population.

BACKGROUND: Cockroach allergy is an important cause of inner city asthma. To perform valid studies on the diagnosis and treatment of cockroach allergy, biological potencies of test extracts need to be established, and a surrogate in vitro test for biological potency should be chosen. METHODS: Sixty-two cockroach-allergic adult subjects were recruited for quantitative skin testing with three commercial German cockroach extracts. The intradermal D50 values were determined using linear interpolation, and the biologic potencies were determined from D50 data. The extracts were also analysed for relative potency, using a competition ELISA, and for specific allergen content, using a two-site ELISA. RESULTS: Estimates of each extract's D50 were analysable in 48-55 subjects, with D50s between 10.3 and 11.8. All three extracts were bioequivalent using pre-set criteria. The biological potencies of the extracts were 1738-8570 bioequivalent allergy units (BAU)/mL (geometric mean=3300), and these relative potencies were similar to those estimated by competition ELISA and specific allergen content. IgE against cockroach allergens were detected in sera from 34 subjects with analysable D50s, and 17 subjects had IgE directed against specific cockroach allergens. Although the presence of anti-Bla g 5 correlated with the subjects' skin test responses for 2/3 extracts, no single allergen was immunodominant. Antibody responses among the subjects were heterogeneous. CONCLUSIONS: Although commercial cockroach extracts are relatively low in potency, immunotherapeutic doses should be achievable. Biological potency may be estimated using D50 testing, a combination of specific allergen determinations, or by an overall potency assay such as the competition ELISA. CAPSULE SUMMARY: The biological potency of three German cockroach allergen extracts, determined in an inner city population, was 1738-8570 BAU/mL. No one allergen was immunodominant, and surrogate in vitro testing methods were examined.

Mouse allergen-specific immunoglobulin G4 and risk of mouse skin test sensitivity.

BACKGROUND: High serum levels of cat-specific IgG and IgG4 are associated with protection against allergic sensitization to cat, but whether this association applies to other animal allergens remains unclear. OBJECTIVE: To determine if high levels of mouse-specific IgG and IgG4 are associated with a decreased risk of mouse skin test sensitivity. METHODS: Two hundred and sixty workers of a mouse facility underwent skin prick testing and completed a questionnaire. Serum levels of mouse-specific IgG and IgG4 were quantified by solid-phase antigen binding assays. Room air samples were collected and airborne Mus m 1 was quantified by ELISA. RESULTS: Forty-nine participants had a positive skin prick test to mouse. Mouse-specific IgG was detected in 219 (84%) participants and IgG4 was detected in 72 (28%) participants. A detectable mouse-specific IgG4 level was associated with an increased risk of mouse skin test sensitivity (odds ratios (OR) 6.4, 95% confidence intervals (CI) 3.3-12.4). Mouse-specific IgG and IgG4 were both positively correlated with mouse allergen exposure (r(s)=0.31, P=0.0001, and r(s)=0.27, P=0.0006, respectively). The odds of skin test sensitivity peaked at moderate levels of IgG4, but decreased at the highest levels of mouse-specific IgG4. In contrast, the odds of skin test sensitivity increased monotonically with IgG levels. CONCLUSIONS: A detectable level of mouse-specific IgG4 is associated with an increased risk of skin test sensitivity to mouse. However, the highest IgG4 levels appear to be associated with an attenuated risk of mouse skin test sensitivity, suggesting that induction of high levels of IgG4 through natural exposure may protect against the development of allergic sensitization.

Mouse allergen-specific immunoglobulin G and immunoglobulin G4 and allergic symptoms in immunoglobulin E-sensitized laboratory animal workers.

BACKGROUND: High levels of allergen-specific IgG have been associated with clinical efficacy in immunotherapy studies, but whether this antibody isotype is associated with clinical tolerance in the setting of environmental exposure remains unclear. OBJECTIVE: To determine if mouse allergen-specific IgG (mIgG) and IgG4 (mIgG4) levels are associated with mouse-related symptoms among IgE-sensitized laboratory workers. METHODS: Fifty-eight workers with either skin test or serologic evidence of IgE-mediated mouse sensitization were studied. Symptom data were obtained by a questionnaire. Serum levels of mouse-specific IgG, IgG4, and IgE were quantified by a solid-phase antigen-binding assay (IgG) and RAST (IgG4 and IgE), and the relationships between mouse-specific serologic responses and mouse-related symptoms were analysed. RESULTS: Twenty-three (39.7%) participants reported mouse-related symptoms. Mouse-specific IgG and IgG4 levels were not associated with mouse-related symptoms among the study population as a whole. Among the 29 (50%) participants with detectable mouse-specific IgE (mIgE), higher mouse-specific IgG and IgG4 levels were associated with a decreased risk of symptoms, after adjusting for mIgE level (odds ratio (OR) 0.3, 95% confidence interval (CI): 0.1-1.4, and OR 0.3, 95% CI: 0.04-2.6, respectively). Higher levels of mIgG and mIgG4 remained associated with a decreased risk of symptoms after additional adjustment for sex and handling of mice (OR 0.1, 95% CI: 0.02-0.7, and OR 0.2, 95% CI: 0.02-2.1, respectively). Higher mIgG : IgE and mIgG4 : IgE ratios were also associated with a decreased risk of symptoms after adjusting for these confounders (OR 0.1, 95% CI: 0.02-0.7, and OR 0.2, 95% CI: 0.02-0.92, respectively). CONCLUSION: Among workers with detectable mIgE, higher mIgG and mIgG4 levels are associated with a decreased risk of mouse-related symptoms. High serum levels of mIgG or mIgG4 may be markers for clinical tolerance among laboratory mouse workers with detectable mIgE, but these findings need to be confirmed in larger, prospective studies.