D.W. Cockcroft

Bronchial reactivity to inhaled histamine: a method and clinical survey

An easy and safe dose‐response histamine‐inhalation test is described, to measure the level of non‐specific bronchial reactivity.

Allergen‐induced increase in non‐allergic bronchial reactivity

Non‐allergic bronchial hyper‐reactivity is a feature of most patients with asthma. We have measured non‐allergic bronchial reactivity to inhaled histamine and methacholine in thirteen asthmatic subjects before and after allergen inhalation in the laboratory. The allergen inhalation produced mild early asthmatic responses (19–40% FEV1 fall) in all thirteen, additional definite late asthmatic responses (17–29% FEV1 fall) in four, and equivocal late asthmatic responses (5–11% FEV1 fall) in five. Following allergen inhalation, non‐allergic bronchial reactivity increased in seven for up to 7 days. The seven included all four with definite late asthmatic responses and three of the five with equivocal late asthmatic responses. We conclude that allergens make asthma worse, partly through non‐allergic mechanisms, and that avoidance of allergens is important in reducing non‐allergic bronchial hyper‐reactivity.

Factors in allergen-induced asthma: relevance of the intensity of the airways allergic reaction and non-specific bronchial reactivity.

Early asthmatic responses (EAR) of similar severity were produced by allergen inhalation challenges in nine asthmatic subjects. The severity of the airways allergic reaction was estimated by measuring the skin test weal size produced by the same dilution of allergen which caused the EAR. The non‐specific bronchial reactivity was assessed by inhalation of increasing concentrations of histamine acid phosphate. Possible relationships between the severity of the airways allergic reaction, the level of non‐specific bronchial hyper‐reactivity and the pattern of asthmatic response were examined.

Beclomethasone dipropionate aerosol in perennial rhinitis

Beclomethasone dipropionate aerosol (BDA), 50 mug four times daily sprayed into each nostril, was compared with placebo in a double-blind crossover trial in 26 patients with perennial rhinitis. Patients received BDA for 3 weeks and placebo for 3 weeks; the order of administration was randomized. Response was assessed with daily symptom score cards and twice weekly measurements of nasal airway inspiratory resistance at a standard flow rate of 0.4 L/sec. Symptom score and nasal resistance during BDA treatment were significantly lower than those duirng placebo treatment (p less than 0.02 and p less than 0.05, respectively) in the third week. Eighteen of the patients expressed a preference for BDA, 6 for placebo, and 2 for neither (p less than 0.05). Acceptable symptomatic improvement (moderate or marked) was achieved by 54%. Mild side effects were noted by 5 patients; these included nasal irritation and bleeding in 2, aerosol-induced sneezing in 2, and headache in 1. These side effects occurred in 3 patients who used BDA, 1 who used placebo, and 1 who used both. After a 6-mo follow-up period, in which the dose of BDA was adjusted and concurrent initial oral prednisone was administered to patients who were treatment failures, 73% of the patients obtained moderate or marked symptomatic improvement. No further side effects were noted during this time. Results in those in whom a possible allergic component could be identified were not different from those of the whole group. We conclude that BDA is a useful addition to the therapy of perennial rhinitis.

A comparison of the protective effect of fenoterol and Sch1000 on allergen-induced asthma

Abstract The protective effects of inhaled Sch1000 (80 μg), inhaled fenoterol (800 μg), and placebo on the early asthmatic response induced by inhaled allergen were compared in 10 subjects in a single-blind investigation. Allergen inhalation produced early asthmatic responses in all 10 subjects, with a mean 1-sec forced expiratory volume (FEV 1 ) fall of 31.1% (range, 23% to 40%). The similarity of the responses to allergen inhalation following no pretreatment and following placebo showed that the allergen-induced response was highly reproducible, with coefficients of variation for the maximum percentage FEV 1 fall of ± 7.2%. Sch1000 produced a slight nonsignificant reduction in the magnitude of the early asthmatic response of 20.7% ± 39.7% ( p > 0.10) for the maximum FEV 1 fall. Fenoterol, however, produced a highly significant reduction in the magnitude of the early of 76.4% ± 23.5% ( p 1 fall, which was significantly greater than that produced by Sch1000 ( p

Asthma caused by occupational exposure to a furan-based binder system

A 50-yr-old mold maker developed severe asthma a few weeks after commencing work with a furan binder. Asthma recurred within hours of subsequent exposure and was confirmed by measurements every 2 hr of peak flow rate. The molds were prepared by mixing sand with a resin (containing furfuryl alcohol, paraformaldehyde, and xylene) and a catalyst (containing sulfuric acid, phosphoric acid, and butyl alcohol). Occupation-type exposure in the laboratory to the resin mixed with catalyst, and to pure furfuryl alcohol mixed with sulfuric acid or butyl alcohol, provoked late asthmatic responses and heightened nonallergic bronchial responsiveness to inhaled histamine. No changes were produced by the same exposures in an asthmatic volunteer with a similar degree of histamine bronchial responsiveness, or in the worker after exposure to resin alone and catalyst alone. Avoidance of exposure was followed by clearing of symptoms and return of histamine bronchial responsiveness towards normal. The findings identify the occurrence of specific bronchial responsiveness to volatile reaction product(s) of furfuryl alcohol following reaction with sulfuric acid or with butyl alcohol. The incidence of this problem needs investigation, especially since furan-based binder systems are replacing traditional methods.

Effect of Sch1000 in allergen-induced asthma

Carefully controlled allergen inhalation tests were carried out in twelve subjects to provoke early asthmatic responses with a mean maximum FEV1 fall of 30·7 ± 5·2% (mean ± s.d.). Four subjects had additional late asthmatic responses with a maximum mean FEV1 fall of 21·0 ± 5·9%. The tests were repeated at intervals of 7 days in an identical way, following inhalation of Sch1000 (80 μg) and placebo, each given 45 min before the onset of the early asthmatic response. This dose of Sch1000 produced a marked and uniform inhibition of methacholine‐induced bronchoconstriction in the same subjects. The allergen‐induced responses were reproducible in eleven out of the twelve subjects; the coefficient of variation for the decrease in FEV1 in the early responses being ±7% and in the late response ±43%. Sch1000 produced a slight and variable inhibition of early asthmatic responses (P<0·02) and no inhibition of late asthmatic responses. We examined the relationship between the degree of inhibition of the early asthmatic response by Sch1000 and: (a) the degree of inhibition produced by Sch1000 on histamine‐ and methacholine‐induced bronchoconstriction; (b) the level of non‐specific bronchial reactivity measured by inhaled histamine and methacholine; and (c) the degree of bronchodilatation produced by Sch1000. No relationship was found.

Allergen injection therapy with glutaraldehyde-modified—ragweed pollen-tyrosine adsorbate: A double-blind trial

Abstract The effect of a preseasonal course of four injections of glutaraldehyde-modified—ragweed pollen-tyrosine adsorbate (MRTA), in a total dose of 7,000 Noon pollen units, was compared with a tyrosine base placebo in a double-blind trial in 43 matched patients with ragweed pollen-induced allergic rhinitis. During the pollen season, troublesome symptoms were treated with a standardized therapeutic regimen. The minimum medication requirement that adequately controlled symptoms was used as the main indicator of severity of the allergic rhinitis. Consequently, the symptom scores were similar in both treatment groups; however, the MRTA-treated group required approximately 50% less medication than the placebo group (p

Appearance of allergen‐induced increases in airway responsiveness only after repeated allergen inhalations in two subjects

Observations in two subjects undergoing three allergen challenges for a drug study suggested ‘priming’ of the late sequelae, namely allergen‐induced increase in airway responsiveness. Both subjects had rhinitis and asthma limited to the ragweed season, near normal out‐of‐season histamine PC20, and extreme IgE sensitivity to ragweed. Both had an isolated early response with no change in histamine PC20 after the first allergen challenge. Significant (3.5‐ to 5.8‐fold) reductions in histamine PC20 occurred after the second and third allergen challenge in Subject 1, and after the third challenge in Subject 2; this was associated with equivocal 5–8% late responses. Such a ‘priming’ effect, the prevalence of which is not known, may be important in the pathogenesis of naturally occurring allergic asthma, and in the design of clinical trials involving repeated allergen inhalations.

Sporobolomyces: a possible cause of extrinsic allergic alveolitis

A 28-year-old horseback rider presented with symptoms, chest radiograph, and pulmonary function tests suggestive of extrinsic allergic alveolitis related to exposure to a horse barn. Exposure to the barn produced symptoms, fever, and a fall in VC commencing 4 hr after exposure. Precipitins were positive against Sporobolomyces, suggesting this might be the causative agent; precipitins were negative against other fungi and horses. Lymphocyte stimulation to Sporobolomyces in vitro was positive in the patient and negative in two control subjects. Sporobolomyces was grown from straw in the barn. Cessation of exposure to this barn (but continued exposure to horses) has resulted in improvement in clinical condition. A survey for immunologic sensitivity to Sporobolomyces revealed that eight of 30 atopic subjects had positive wheal-and-flare prick skin tests to Sporobolomyces antigen, whereas none of 30 laboratory controls or 30 grain handlers had precipitins against Sporobolomyces. Sporobolomyces is a common fungus in cereal grain growing areas. Its spore size is less than 5 micron, consistent with other causative agents of this disorder. In this patient, positive precipitins and lymphocyte stimulation to Sporobolomyces and negative precipitins to other known causes of extrinsic allergic alveolitis provide circumstantial evidence that Sporobolomyces was the cause of the syndrome.