Longitudinal measurement of airway hyperresponsiveness in selected subjects with persisting pulmonary symptoms.

The relationship between airway hyperresponsiveness and pulmonary symptoms was examined longitudinally in 52 subjects. Subjects were part of a larger study, the Natural History of Asthma, and had repeated measures of airway hyperresponsiveness using methacholine. Atopy was determined using skin tests and serum IgE levels. The subjects completed a standardized respiratory questionnaire. Each subject reported respiratory and pulmonary symptoms at either their initial or follow-up visit. The subjects did not, however, have a physician-confirmed diagnosis of asthma. Subjects were divided into groups according to the current status of their respiratory symptoms. The four groups included subjects who were initially normal but developed respiratory symptoms at follow-up; subjects who had symptoms at all visits; subjects with respiratory symptoms at their initial visit but who had no symptoms at follow-up; and subjects who had respiratory symptoms prior to their initial visit and who did not have a recurrence during follow-up. There was no statistical difference in airway hyperresponsiveness, IgE, or skin test scores at the initial visits. Subjects who had airway responsiveness were significantly more atopic than subjects who did not have airway responsiveness. Subjects were classified as "consistently positive," "variable," or "consistently negative" responders according to the pattern of methacholine-induced airway hyperresponsiveness. Overall, among the four groups, 33% were consistently positive at all visits, 43% were variable, and 22% were consistently negative. Airway hyperresponsiveness was statistically associated with atopy, but not necessarily associated with questionnaire-based respiratory symptomatology. These factors need to be considered in epidemiological studies of asthma utilizing respiratory questionnaires.

Effect of terfenadine on neutrophil and eosinophil chemotactic activities after inhalation of platelet-activating factor in vivo and on neutrophil chemotaxis in vitro.

In this double-blind crossover study we evaluated the effect of terfenadine on the rise in neutrophil chemotactic activity (NCA) and eosinophil chemotactic activity (ECA) in serum induced by platelet-activating factor (PAF) inhalation in 8 asthmatics. Additionally, we examined the direct effect of terfenadine on neutrophil chemotaxis in vitro in 7 allergic subjects. NCA and ECA in serum after PAF inhalation and neutrophil chemotaxis were measured using a modified Boyden chamber method. An initial elevation of NCA after PAF inhalation was inhibited by terfenadine, but the effect was diminished after subsequent PAF inhalations. Terfenadine showed no effect on ECA. In vitro PAF- and fMLP-induced neutrophil chemotaxis were significantly inhibited by terfenadine. These results suggest that terfenadine may have antiallergic properties in addition to its H1 receptor blockade.

A controlled, double-blind study of the effect of quazolast on nasal challenge with ragweed antigen.

Quazolast is a potent mediator release inhibitor as determined by in vitro and in vivo testing. A placebo-controlled, double-blind, two-way crossover study compared the safety and efficacy of Quazolast, 400 mg bid orally, with placebo in 23 subjects with ragweed (RW) allergy, out of season. Subjects were assigned to two 7-day treatments in a random sequence with an 8-day washout. Subjects were challenged on days 1 and 7 of each trial with serial dilutions (10, 100, 1000, 1350, and 2700 PNU/0.135 mL) of RW, using metered pump spray bottles, (two sprays delivered 0.135 mL), preceded by saline control. Efficacy evaluation consisted of nasal flow rates measured by rhinomanometry, sneeze counts, nasal itchiness scores, and weight of nasal secretions during challenges. During Quazolast treatment, subjects had significantly lower (P less than .05) mean percent decreases in nasal flow rate at 1350 and 2700 PNU. Nasal itchiness scores were significantly lower (P less than .05) during Quazolast treatment than at placebo at 1000, 1350, and 2700 PNU. Although sneeze counts were lower during treatment with Quazolast than with placebo, the results did not reach statistical significance. No significant improvement was seen in the weight of nasal secretions. Adverse experiences, clinical laboratory results, and physical examinations were unremarkable, posttreatment. Quazolast was superior to placebo in protecting against nasal congestion and nasal itchiness after ragweed nasal challenge.

The presence of airway reactivity before the development of asthma.

Exaggerated airway reactivity is an essential component of the current asthmatic. It is not clear, however, if airway reactivity is genetically determined or acquired. To examine the possibility that increased bronchial reactivity exists prior to the development of asthma, we report on 20 subjects who were studied before and after the onset of clinical asthma. Subjects were part of a larger on-going study of the Natural History of Asthma. Thirteen subjects indicated by their answers to the National Heart, Lung, and Blood Institute respiratory questionnaire that they were not asthmatic at their initial visit. Seven subjects had pulmonary symptoms on their initial visit, but had not been diagnosed as asthmatic. Bronchial reactivity was assessed using a standardized methacholine challenge. For the 20 subjects, there was a mean interval of 3.5 yr between the initial visit and the diagnosis of asthma. Ten of 13 nonasthmatic subjects had moderate or strongly positive responses (208 breath units or less) to methacholine prior to onset of asthma. These 13 subjects were compared to age- and sex-matched controls, from both asthmatic and nonasthmatic families, who had not become asthmatic. There was a difference in bronchial responses at the initial visit between the 13 study subjects and their control subjects from nonasthmatic families, but not between the subjects and their controls from asthmatic families. Five of 7 subjects with pulmonary symptoms had responses of 100 breath units or less. Overall, 19 of 20 subjects had strongly positive responses to methacholine after the diagnosis of asthma was established. The results show that enhanced airway reactivity usually precedes the development of asthma, which could support a genetic basis for it.

Comparison of ultrasonically nebulized distilled water and cold-air hyperventilation challenges in asthmatic patients.

Cold-air hyperventilation (CAHC) and ultrasonically nebulized distilled water (UNDW) challenges were compared in 11 asthmatic patients who were moderately sensitive to methacholine. The challenges were performed on two separate days within one week of each other. Baseline FEV1 on each test day was greater than 70 percent of predicted. Ten of 11 subjects' FEV1 decreased at least 15 percent, and nine of 11 decreased at least 20 percent during the UNDW. Ten of 11 subjects' FEV1 decreased at least 10 percent, and eight of 11 decreased at least 15 percent during the CAHC. Using a Spearman rank coefficient, the results of the CAHC and UNDW were compared; the best correlation between the various CAHC and UNDW measurements equaled only 0.51. The correlation between UNDW and CAHC suggests that the mechanism of action of each challenge may be different.

Effect of terfenadine on cold air-induced bronchospasm.

Cold air hyperventilation challenge (CAHC) has been shown to induce bronchoconstriction in asthmatics. We investigated whether terfenadine, a non-sedating H1 antihistamine, had a protective effect against CAHC. Twelve mild-moderate asthmatics, sensitive to both methacholine and CAHC, underwent a double-blind 3-way crossover study of terfenadine at doses of 0, 120, and 240 mg. For four hours after administration of the study drug, pulmonary responses were measured, followed by a CAHC. There was a significant improvement in pulmonary function on the 120-mg and 240-mg days. The percent drop in FEV1 to CAHC was determined by comparing the pre-challenge baseline to the challenge responses. There was a significant attenuation in the FEV1 fall immediately after challenge on active drug days, but it was not sustained. Terfenadine appears to have an attenuating effect against CAHC-induced bronchoconstriction.

Bronchial reactivity pattern in nonasthmatic parents of asthmatics.

Genetic mechanisms have been proposed to explain the presence of asthma in families. A methacholine challenge can identify individuals with bronchial reactivity (a hallmark of asthma). It may then be possible to determine whether the presence of non-specific bronchial reactivity, as detected by a methacholine response, has potential as a genetic marker. Thirty-one non-asthmatic parent pairs of asthmatic children were selected from asthma (AF) families enrolled in a Natural History of Asthma study. Parent pairs were chosen if both gave negative responses to a modified National Heart, Lung and Blood Institute questionnaire on asthma. The methacholine response of these parents of asthmatic children had a bimodal distribution. These results show that the methacholine response can mark bronchial reactivity without the presence of clinical asthma and that a familial component of bronchial reactivity exists which may be transmitted from one generation to the next.

Effect of terfenadine on the bronchoconstriction induced by ultrasonically nebulized distilled water.

Ultrasonically nebulized distilled water (UNDW) has been shown to induce bronchoconstriction in asthmatics. The proposed mechanism is through changes in osmolarity of the airway fluids and subsequent release of mediators from airway mast cells. We investigated whether terfenadine has a protective effect on UNDW challenges. Twelve mild-to-moderate asthmatics responded to screening a methacholine and UNDW challenge. For four hours after the ingestion of 0, 120, and 240 mg of terfenadine pulmonary responses were performed, followed by a UNDW challenge. Nine of 12 subjects dropped 20% after 120 mg and after 240 mg. There was a suggestion of a protective effect at 120 mg (P = .054), which was significant at 240 mg (P = .012) when the areas under the dose-response curves were compared. Bronchoconstriction induced by UNDW may in part be caused by histamine release and was attenuated by an oral antihistamine.

Incorporation and analysis of ultrasonically nebulized distilled water challenges in an epidemiologic study of asthma and bronchial reactivity.

The usefulness of an ultrasonically nebulized distilled water (UNDW) challenge as a screening procedure was tested in an on-going epidemiologic study of asthma and bronchial reactivity. Sixty-six individuals underwent a methacholine challenge, an UNDW challenge, and were administered a standardized respiratory disease questionnaire. To perform the UNDW challenge, subjects inhaled increasing volumes of nebulized distilled water while breathing tidally. Thirty-eight asthmatics, two former asthmatics, 14 normal, and 12 allergic subjects, were included. Sixty-six percent of the asthmatics dropped 20% from their baseline FEV1 during the UNDW challenge. Only one allergic or normal subject had a similar drop. The Pearson's correlation coefficient between methacholine and UNDW challenges was 0.60. If positive, an UNDW seems to be highly specific in supporting a diagnosis of asthma, while methacholine challenges are more useful in verifying the presence of non-specific bronchial reactivity.

Interpretation of the results of methacholine inhalation challenge tests.

Methacholine inhalation challenge studies are conventionally expressed as the provocative cumulative dose of methacholine that causes a 20% fall in FEV1 (PD20). This method is widely used and most suitable for expressing results for challenges in subjects with asthma. However, it is impossible to present results in this manner in other circumstances. Normal subjects and many subjects with allergic rhinitis do not have significant bronchial reactivity and will not reach a 20% fall during standard challenge protocols. This limitation precludes the use of this large population in the quantitative analysis necessary in epidemiologic, genetic, or drug studies. To compound this difficulty, a subset of patients with allergic rhinitis may demonstrate a 20% drop but have a subsequent plateau drop in FEV1. Expressing the results of their methacholine challenge with only a PD20 loses valuable information available in the test. We demonstrate that expressing results as the area beneath a dose-response curve provides useful parametric data on all studied subjects and distinguishes among subjects who might otherwise be classified as equivalent when results are expressed solely as a PD20.

Distribution of methacholine inhalation challenge responses in a selected adult population.

To determine bronchial reactivity patterns in adults, 211 subjects, 22 to 86 years of age, underwent a methacholine challenge in a Natural History of Asthma study. The diagnosis of asthma or nonasthmatic allergic diseases was based on a standardized respiratory questionnaire. Subjects were nonsmokers and had not had an infection for 1 month. Intradermal skin tests were done to a battery of common antigens. The methacholine challenge response was expressed as the area under the dose-response curve integrated to a 35% fall in the FEV1 or 800 breath units. Thirty-three subjects with asthma, 47 normal subjects from normal families (NF), 59 normal subjects from families with asthma (AF), 31 allergic subjects without asthma, 23 subjects with questionable asthma, and 18 subjects with prior asthma were studied. Overall, 50% of the subjects without asthma had a negative response to methacholine. There was a difference (p less than 0.02) in the distribution of log10 methacholine area under the dose-response curve integrated to a 35% fall in the FEV1 or 800 breath units responses in normal subjects from NFs compared to normal subjects from AFs. The allergic subjects from AF had a greater degree of bronchial reactivity compared to normal individuals from NF. The age of the normal subjects had an influence on the degree of bronchial reactivity. Methacholine challenge studies in adult patients need to be interpreted with age and family history in mind.

Methacholine inhalation challenge studies in a selected pediatric population.

To determine bronchial reactivity patterns, 400 subjects, 5 to 21 yr of age, underwent a methacholine challenge in a Natural History of Asthma study. The diagnosis of asthma or allergy was based on a respiratory questionnaire. Subjects were nonsmokers and had had no respiratory infections for 1 month. Intradermal skin tests were done. The methacholine challenge response was expressed as the area beneath the dose-response curve (Area 35). Fifty-five asthmatics, 113 normal subjects from normal families, 103 normal subjects from asthma families, 60 normal twins, and 69 allergic subjects without asthma were studied. Overall, 52% of nonasthmatics and 47% of nonallergic subjects had an Area 35 less than 4,000 (800 breath units). There was a difference (p less than 0.05) in the distribution of methacholine Area 35 responses in normal subjects from that in normal families compared with normal subjects from asthma families. The age of the nonasthmatic subjects had an influence on the degree of bronchial reactivity. Methacholine challenge studies in pediatric patients must be interpreted with age, personal atopic status, and family asthma history in mind.

The effect of age on methacholine response.

Bronchial reactivity to inhaled methacholine exists in subjects with asthma but may occur in subjects with allergic rhinitis, chronic lung diseases, and during respiratory infections. In the absence of these factors, we found that age also has a significant effect on the methacholine response. One hundred forty-eight subjects, 5 to 76 years of age, were studied as normal control subjects in a natural history of asthma study. The methacholine response was measured by standard techniques. The analysis demonstrated that age had a significant effect on the methacholine response. In addition to known factors influencing the results of methacholine inhalation, young and older subjects may exhibit bronchial responses that may falsely suggest hyperreactive airway disease.

Specificity and sensitivity of methacholine inhalation challenge in normal and asthmatic children.

The provocative dose of inhaled methacholine required to cause a 20% drop in the forced expiratory volume in 1 sec was evaluated in two selected pediatric populations. On the basis of a standardized respiratory questionnaire, 165 individuals 5 to 21 yr of age were identified. Included were 110 normal nonatopic individuals and 55 current asthmatic subjects. Methacholine inhalation challenges were performed by use of a standard inhalation procedure. Fifty-four (98.1%) of the asthmatic subjects responded to methacholine with a 20% drop in the forced expiratory volume in 1 sec. Seventy (63.1%) of the normal individuals did not respond to methacholine. The specificity and sensitivity of the methacholine challenge was best obtained at a provocative dose of 100 breath units of methacholine.

Genetic analysis of allergic disease in twins.

One hundred seven pairs of twins, sixty-one MZT and forty-six DZT, were investigated for allergic disease by a questionnaire, reaginic antibody levels, bronchial reactivity to inhaled methacholine, and skin test responses. Intrapair correlation coefficients (ri) of measured clinical markers of atopy were determined and a heritability analysis was performed. The intrapair correlation coefficient for serum IgE was 0.82 for MZT and 0.52 for DZT. The methacholine area demonstrated greater correlation in MZT with an ri of 0.67 compared to 0.34 for DZT. The total ISTS had an intrapair correlation coefficient of 0.82 in MZT and 0.46 in DZT. Our analysis demonstrates that methacholine sensitivity, total serum IgE levels, and total skin test scores to be heritable traits and suggests a genetic contribution to their expression.