R E Schoeffel

Bronchial hyperreactivity in response to inhalation of ultrasonically nebulised solutions of distilled water and saline.

To assess non-specific bronchial reactivity the effect of inhaling ultrasonically nebulised solutions of distilled water and hypotonic (0.3%), isotonic (0.9%), and hypertonic (2.7%, 3.6%) saline was investigated in 10 asthmatic patients and nine normal subjects. Expired ventilation and the maximum percentage fall in forced expiratory volume in one second (FEV1) were recorded. The sensitivity to the inhaled solutions was determined by measuring the ventilation required to induce a fall in FEV1 of 20% from the prechallenge value. Hypotonic and hypertonic but not isotonic solutions caused a significant fall in FEV1 in the asthmatic subjects. Normal subjects showed no response to either distilled water or 3.6% saline, the only solutions with which they were challenged. The method used for this challenge is rapid, simple, and inexpensive and provides a new means of diagnosing non-immunologically mediated bronchial hyperreactivity.

Prevalence of bronchial hyperresponsiveness and asthma in a rural adult population.

The prevalence of bronchial hyperresponsiveness in adult populations is not known. To document its prevalence and distribution and to determine the factors associated with it, a random sample of the adult population of Busselton, Western Australia, was studied. Spirometric function, bronchial responsiveness to histamine, and atopic responses to skin prick tests were measured. Respiratory symptoms were determined by questionnaire. Data were obtained from 916 subjects. Of these, 876 underwent a histamine inhalation test and bronchial hyperresponsiveness to histamine (defined as a dose of histamine provoking a 20% fall in FEV1 equal to or less than 3.9 mumol) was found in 10.5%. Another 40 subjects with poor lung function were tested with a bronchodilator and 12 were found to have bronchial hyperresponsiveness (defined as a greater than 15% increase in FEV1), making the total prevalence of bronchial hyperresponsiveness 11.4%. The prevalence of current asthma, defined as bronchial hyperresponsiveness plus symptoms consistent with asthma in the last 12 months, was 5.9%. The distribution of bronchial hyperresponsiveness in the studied population was continuous. There was a significant association between it and respiratory symptoms, atopy, smoking, and abnormal lung function (p less than 0.001 for all associations). There was no association with age, sex, or recent respiratory tract infection.

Evaluation of ultrasonically nebulised solutions for provocation testing in patients with asthma.

The airway response to the inhalation of ultrasonically nebulised distilled water was determined in 55 asthmatic patients and 16 normal subjects. We calculated the dose of water required to induce a 20% reduction (PD20) in forced expiratory volume in one second (FEV1) by measuring the output of the nebuliser and the volume ventilated by each subject. Forty-eight of the asthmatic patients had a PD20 of 9 ml or less but three patients required as much as 24 ml. A PD20 was not recorded in the normal subjects and the challenge was stopped after 33 ml. In 12 patients the challenge was repeated within six months and the airway response was shown to be reproducible at equivalent doses of water. In a separate group of 11 patients there was, however, a highly significant reduction in the percentage fall in FEV1 when equivalent doses of water were given on two occasions 40 minutes apart. When the temperature of the inhaled water was increased from 22 degrees C to 36 degrees C eight of 10 patients had a similar change in FEV1 with equivalent doses of water. The airways obstruction induced by the inhalation of water was readily reversed with salbutamol administered by aerosol. In some patients a challenge with water or 3.6% saline was repeated after pretreatment with sodium cromoglycate, atropine methonitrate, and verapamil hydrochloride, all given as aerosols. The airway response to the equivalent dose of water or saline was significantly reduced after treatment with sodium cromoglycate but not atropine or verapamil.

An evaluation of pharmacotherapy for exercise-induced asthma

It is 15 yr since Jones et al.’ first described the effects of isoproterenol on the postexercise increase in airway resistance in patients with asthma. Studies of the incidence, severity, and reproducibility of exercise-induced asthma (EIA) have established that in 70% to 75% of patients with clinically recognized asthma, the postexercise fall in peak expiratory flow rate (PEFR) or forced expiratory volume in 1 set (FEV,) exceeds 10% of the preexercise value.2. I’ Changes in lung mechanics and blood gas tensions seen during EIA are similar to those observed in patients with asthma provoked by other stimuli.“. Irk II Consequently EIA has been used as a model for the investigation of drugs used in treatment of asthmatics. During the past 10 yr many studies have been carried out to determine the effect of a wide variety of pharmacologic agents on EIA. The drug groups studied include

Arterial plasma histamine levels at rest, and during and after exercise in patients with asthma: effects of terbutaline aerosol.

Eight asthmatic patients and two normal subjects performed two identical exercise tests 140 minutes apart (first test preceded by inhalation of saline and the second by terbutaline sulphate). A ninth asthmatic patient exercised twice after placebo 40 minutes apart. Arterial plasma levels of histamine and cyclic AMP, expiratory flow rates and volumes were measured at rest and during and after exercise. After the first test the mean +/- SEM fall in PEFR was 45.2 +/- 2.6%. In five asthmatics there was an increase in plasma histamine (mean +/- SEM 14.8 +/- 3.3 pmol ml-1) coinciding with exercise-induced asthma (EIA). Histamine levels returned to pre-exercise values within 30 minutes. After terbutaline these five patients had histamine levels greater than those observed before, during, or after the first test. This effect may have been the result of changes in pulmonary microcirculation. After the second test the levels decreased indicating no further release of histamine in response to exercise. No EIA occurred in these patients after terbutaline. The other patients and the two normal subjects had little or no change in histamine throughout the study. The one patient in whom exercise was repeated after placebo demonstrated less histamine release and less EIA after the second test.

Multiple exercise and histamine challenge in asthmatic patients

We studied the effects of repeated exercise and histamine challenge in asthmatic patients to determine the frequency and degree to which a state of refractoriness was induced by these stimuli. Twenty-nine patients performed three exercise tests, and on a separate day 16 of these patients had three histamine inhalational challenge tests. Forty minutes separated each challenge. Changes in airways resistance were measured using the peak expiratory flow rate (PEFR). The fall in PEFR (expressed as a percentage of the pre-challenge value) was used to quantify the response to challenge. Significant “protection” was defined as a fall in PEFR after a repeated challenge less than 50% of the fall observed on the first challenge. All patients had a fall in PEFR greater than 22% on the first challenge of the day. With repeated exercise 28 out of 29 patients had a fall in PEFR less than that observed on the first test and 12 had significant “protection”. The fall in PEFR after the third exercise challenge was not significantly different to the second challenge and a “plateau” effect was observed. There was no significant difference in the fall in PEFR after the first and second histamine challenge although two of the 16 patients were significantly protected. After the third histamine challenge five of the 16 patients were significantly protected from the effects of the same dose of histamine. The degree to which repeated exercise challenge induces a diminished response is variable. With repeated challenge the response to histamine remains relatively constant in most patients though 30% may be expected to be refractory after a third challenge.

Mediators of hypersensitivity and "fog"-induced asthma.

Seven asthmatic and five normal subjects inhaled increasing amounts of nebulized water (“fog”). Neutrophil chemotactic activity (NCA), histamine and FEV1 measurements were undertaken before and at time intervals after challenge. In asthmatics, the mean maximal reduction in FEV1 (± 1 SD) was 46.6%± 11.5; whereas, in normal subjects, the reductions were less than 20% of pre‐challenge values after the inhalation of 33 ml of water. There were no significant differences in the pre‐challenge values for NCA between the asthmatics and the normal controls. When the highest values for NCA during the 30 min after challenge in the asthmatics were compared with controls there was a significant increase (P < 0.02). The percentage change in NCA was also significantly greater in the asthmatics compared with the controls at 10 min after challenge (P < 0.05). Fog‐induced NCA was shown to be associated with proteins with approximate molecular weight of 600,000 daltons (as assessed by gel filtration chromatography on Sephacryl‐S400). There was an increase in plasma histamine in the asthmatics after challenge but this was not significantly greater than the controls. These findings support the view that mediators might be involved in fog‐induced asthma, possibly as a result of mast cell degranulation by “osmotic shock”.

Effect of aerosol and oral fenoterol on histamine and methacholine challenge in asthmatic subjects.

In order to determine the effect of drugs on bronchial hyperreactivity in subjects with asthma, 12 atopic asthmatic volunteers underwent bronchial challenge with either histamine or methacholine on three separate days. Before the challenges no medication was given on the first day, on the second 400 microgram of aerosol fenoterol and on the third 5 mg of oral fenoterol were administered. The aerosol fenoterol caused the dose response curves to both histamine and methacholine to be shifted to the right in all subjects. The oral dose produced no significant change from the control values. The slope of the dose response curves was not altered by either the oral or the aerosol drug. It is concluded that aerosol but not oral fenoterol in the clinical dosage, causes a change in the sensitivity but not in the reactivity of the airway of patients with atopic asthma.

Increased responsiveness to methacholine and histamine after challenge with ultrasonically nebulised water in asthmatic subjects.

Responsiveness to inhaled methacholine was compared before and 40-60 minutes after a challenge with ultrasonically nebulised water (UNH2O) in 16 asthmatic patients. The sensitivity to methacholine increased after UNH2O challenge (p less than 0.001). The mean dose of methacholine producing a 20% fall in forced expiratory volume in one second was 0.4 (95% confidence limits 0.2, 0.8) mumol, compared with 0.9 (95% confidence limits 0.5, 1.6) mumol in the first methacholine challenge. When the study was repeated in six asthmatic patients with histamine substituted for methacholine, five of the patients were significantly more sensitive to histamine after UNH2O challenge. It is concluded that challenge with UNH2O produces an increase in airway responsiveness.