Disodium cromoglycate in ragweed-allergic rhinitis.

This study was designed to test the effectiveness of disodium cromoglycate when compared to placebo in a double-blind study in patients with ragweed allergic rhinitis. Patients were selected on the basis of a clinical history and a 4+ reaction to the intradermal injection of water-soluble ragweed, 0.02 c.c. of 500 PNU/c.c. Active agent/placebo groups were selected at random and were on the drug for approximately 8 wk, commencing 1 wk prior to the onset of the ragweed pollen season. Patient response was evaluated using patient diary cards, number of antihistamine tablets taken, and patient interviews. In the Toronto study, of 17 patients on the active drug, 15 were graded as improved, compared to only 6 of 21 placebo-treated patients who were improved. However, in the Hamilton study, results were less impressive. Nonetheless, it appears that intranasal insufflation of disodium cromoglycate was more effective in reducing ragweed hay fever symptoms than placebo.     

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.     

Comparison of bronchial responses to prostaglandin F2α and methacholine

We examined bronchial responsiveness to prostaglandin (PG) F_2α to determine its applicability in clinical practice and to compare it with bronchial responsiveness to the pharmacologically dissimilar agent, methacholine. Inhalation tests with twofold increasing concentrations of the two agents were carried out in 19 asthmatic and four normal subjects. The results were expressed as the provocation concentration causing a 20% fall in forced expiratory volume in 1 sec (PC₂₀). The range of concentrations required to determine the PC₂₀ was greater with PGF_2α (0.0001 to <5 mg/ml) than that with methacholine (0.07 to 30.96 mg/ml). Side effects of cough, retrosternal irritation, and expectoration of sputum were more frequent after PGF_2α. Repeat measurements in the same subjects showed that responses to PGF_2α were as highly reproducible (r = 0.98, p < 0.001) as previously reported with methacholine, and there was a cumulative dose effect (p < 0.001). PC₂₀PGF_2α correlated with PC₂₀ methacholine (r = 0.5, p < 0.01), but to a lesser degree than was previously demonstrated between histamine and methacholine. The poorer correlation was explained by the results of four subjects tolerant to PGF_2α relative to methacholine, three of whom were aspirin (ASA) intolerant; the correlation was much stronger when these subjects were excluded from analysis (r = 0.91, p < 0.001). The results suggest that (1) PGF_2α is not a suitable agent to use in clinical practice to measure nonspecific bronchial responsiveness because of the wide dose range and unpleasant side effects, (2) the bronchial responsiveness of different individuals to PGF_2α and methacholine is usually well correlated and is thus unrelated to specific receptor activity, and (3) there is a relative reduction in responsiveness to PGF_2α in some asthmatics, particularly those with ASA intolerance.     

Bronchial responsiveness to inhaled histamine and exercise.

Bronchial responsiveness to inhaled histamine and exercise was measured in 19 asthmatics. Histamine aerosol was inhaled to determine the provocative concentration producing a 20% fall in forced expired volume in one second (FEV1) (PC20). Exercise was performed on a treadmill and a cycle ergometer; following each procedure the percent fall in the FEV1 (delta FEV1) and the exercise lability (percent rise in FEV1 plus percent fall in FEV1) were calculated. Delta FEV1 and exercise lability after both forms of exercise were similar. PC20 correlated with delta FEV1 and exercise lability in both forms of exercise; however, the correlation with exercise lability was better. PC20 was more sensitive in demonstrating bronchial hyperresponsiveness. The close correlation between the level of bronchial responsiveness to histamine and exercise supports the view that release of endogenous chemical mediators is an important determinant of exercise-induced asthma. The treadmill exercise and cycle ergometry protocols were equally effective in producing exercise-induced asthma.     

A comparison of the bronchodilator activity of Sch 1000 and salbutamol.

The effects of the beta 2-adrenergic agonist, salbutamol, 200 mug, and the cholinergic antagonist, Sch 1000, 40 mug, have been compared in 25 asthmatic patients using a single dose, double-blind, crossover trial design. Salbutamol aerosol produces a greater degree of bronchodilatation than Sch 1000 aerosol during the initial three hours following drug administration. There is no significant difference in the bronchodilator effects of the two drugs in the interval four to eight hours after drug administration. Nonatopic patients showed less difference in bronchodilator response to each of the two drugs than atopic patients. Neither drug showed any significant adverse effect on blood pressure, pulse rate, or electrocardiogram. In six asthmatic patients the effect of the combination of salbutamol, 200 mug, and Sch 1000, 40 mug, was evaluated. The combination produced a longer duration of bronchodilatation than either drug alone when compared to placebo.     

Changes in corticosteroid usage by chronic asthma patients during a year of cromoglycate treatment

Fifteen chronic asthmatic, steroid-dependent subjects were treated for one year with disodium cromoglycate (DSCG) while their previous maintenance steroid dosage was gradually reduced or withdrawn. Twelve asthma indices were monitored concurrently so that the observed steroid dose reduction could be related to the degree of control of the chronic asthma. In view of the characteristically varying course of the disease, the observed changes over the whole year were expressed in terms of average and maximum values. The timing and duration of the study were such as to obviate the influence of seasonally determined improvement trends that otherwise may confound drug-related change. A statistically significant reduction in steroid usage was observed in this group of patients and sustained during the year of cromoglycate treatment. The average reduction of the group over the year was 29 per cent, and the median reduction was 33 per cent. Within the group 11 of 15 reduced steroid usage; 3 who had required maintenance prednisone doses above 15 mg. daily were successfully reduced to lower dosage; 4 were converted to alternate-day therapy and stabilized there, whereas conversion attempts had previously failed; in 2 the maintenance steroid regimen was terminated. The possibility that the reduced steroid requirements might be due to the natural course of the disease rather than to the DSCG treatment cannot be entirely excluded.     

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

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 < 0.05). Subjective improvement was reported by 67% of the MRTA group and 38% of the placebo group (0.05 < p < 0.1). Serum concentrations of IgE and IgG antibodies to ragweed increased in response to MRTA (p < 0.02) but not in response to placebo. Side effects of MRTA included generalized urticaria in 2, mild asthma in 1, and large late swellings at the injection site which necessitated stopping the injections in 6 patients. MRTA was superior to placebo in reducing the severity of ragweed pollen-induced allergic rhinitis and was associated with a modest incidence of side effects.     

A comparison of the protective effect of fenoterol and Sch 1000 on allergen-induced asthma.

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 (FEV₁) 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 FEV₁ 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 FEV₁ fall. Fenoterol, however, produced a highly significant reduction in the magnitude of the early of 76.4% ± 23.5% (p < 0.001) for the maximum FEV₁ fall, which was significantly greater than that produced by Sch1000 (p < 0.001). These results show that β-adrenergic agonists, such as fenoterol, are more effective than cholinergic antagonists, such as Sch1000, in preventing the early asthmatic response induced by inhaled allergen. Reflex parasympathetic bronchoconstriction is involved to a variable and minor extent in the production of allergen-induced early asthmatic responses.     

Standardization of inhalation provocation tests: Influence of nebulizer output,particle size,and method of inhalation

Standardization of inhalation tests requires a knowledge of factors that will affect the response. We measured the output and particle size of six types of nebulizers used for inhalation tests. Output varied considerably between nebulizers of different types (0.12 to 1.59 ml/min) and to a lesser extent between nebulizers of the same type. Particle size varied between 0.8 and 5.2 μm aerodynamic mass median diameter (AMMD). The influence of these two properties on bronchial response to inhaled methacholine was examined. Nebulizer output but not particle size (between 1.3 and 3.6 μm AMMD) altered the response. We also examined the effect of change in inspiratory time during inhalation from residual volume to total lung capacity on lung deposition of radiolabeled aerosol and on the provocative concentration of histamine required to reduce the 1-sec forced expiratory volume (FEV₁) by 20% (PC₂₀). A reduction in inspiratory time from 8 to 2 sec resulted in a lower total lung dose, relatively more aerosol deposited in central airways, and a higher PC₂₀. The results emphasize the importance of keeping nebulizer output and pattern of breathing constant when performing inhalation provocation tests if consistent results are to be obtained.     

Prolonged asthmatic responses to inhaled methacholine

The pattern of asthmatic response after inhalation of atropine and methacholine was studied in six adult asthmatics. After pretreatment with atropine, the provocation concentration of methacholine to cause a fall in FEV₁ of 20% was increased from 0.66 ± 2.09 to 94.90 ± 1.78 mg/ml. In the subsequent 7 hr, four subjects developed prolonged asthmatic responses. These occurred after concentrations of methacholine higher than those used clinically but did not directly relate to the dose of methacholine or to the increase in dose after atropine. In one subject the prolonged response was not accompanied by increased methacholine responsiveness and was not prevented by pretreatment with cromolyn sodium (40 mg). These results show that high doses of methacholine inhaled after pretreatment with atropine can induce prolonged asthmatic responses but the mechanism is unclear.     

Late cutaneous allergic responses in isolated IgE-dependent reactions

Relationships between IgE-dependent reactions and late cutaneous allergic responses were examined. Heterologous whole antihuman IgE or its pepsin digest F(ab′)2 product injected intracutaneously produced “immediate” wheal and flare responses followed by late responses. Prausnitz-Küstner reactions were similar in appearance. The late responses were studied morphologically by conventional microscopy and by direct immunofluorescent techniques. The results support the thesis that in man, late cutaneous allergic responses can occur in reactions with an isolated involvement of IgE. There is a discussion of the possible relevance of these observations to antigen-induced allergic reactions in skin and in the respiratory tract.     

Relative refractory state for late cutaneous allergic responses.

The late cutaneous allergic response (LCAR) is a usual sequel to the wheal-and-flare (early) response in sufficiently intense cutaneous allergic reactions. Allergic reactions with early and late components were produced in the skin of the forearm by the intracutaneous injection of anti-IgE or allergen. One week later, these sites, which were normal in gross appearance, and separate control sites on the opposite forearm, were injected. At the sites of repeat reactions, the wheal diameter of the early response was the same but the LCAR was considerably smaller than at simultaneously injected control sites. This local relative refractory state for LCAR is immunologically nonspecific in the sense that it was manifest even when the antigen injected the second time had no evident immunologic relationship with the antigen injected initially. The refractory state for LCAR was present at 2 wk after the initial reaction, but it was no longer demonstrable after 3 wk. This local relative refractory state for LCAR may represent an inhibitory control mechanism for allergic reactions in man.     

The effect of inhaled hexamethonium bromide and atropine sulphate on airway responsiveness to histamine

The degree of protection against inhaled histamine achieved by inhalation of the ganglion blocker hexamethonium bromide plus placebo, hexamethonium plus atropine sulphate, and placebo plus placebo was examined in six atopic subjects, four of whom had current asthma. Hexamethonium was administered until there was systemic evidence of ganglionic blockade with a postural drop in blood pressure of 31 +/- 7.5 mm Hg (mean +/- SD) (p = 0.01) and an increase in heart rate of 30 +/- 3.1 bpm (mean +/- SD) (p = 0.01). Atropine was inhaled in a dose (18 mg nebulized during tidal breathing) known to produce systemic inhibition of cardiac and salivary cholinergic (muscarinic) receptors. The airway effects were measured by FEV1. Hexamethonium caused bronchoconstriction in all four subjects with asthma, which was reversed by atropine. The mean provocation concentration of histamine to provoke a 20% fall in FEV1 was 2.97 mg/ml after premedication with placebo, it was not different at 2.84 mg/ml after hexamethonium alone, and it increased slightly to 5.31 mg/ml after both hexamethonium and atropine (p = 0.06). The results suggest that the main effect of inhaled histamine is not by reflex bronchoconstriction but rather through stimulation of H1-receptors on airway smooth muscle. Therefore, histamine hyperresponsiveness in asthma is not primarily caused by a defect in the parasympathetic nervous supply to the airway.     

Allergy to a product(s) of ethylene oxide gas: demonstration of IgE and IgG antibodies and hapten specificity.

Patient D.H., on chronic hemodialysis, developed severe allergic reactions after exposure to articles such as plastic tubing and hemodialysis supplies which had undergone cold sterilization with ethylene oxide (EO) gas. It was shown that human serum albumin (HSA) exposed to EO (EO-HSA) in the usual sterilization procedure selectively elicited positive skin tests and in vitro histamine release. It is now demonstrated that D.H. serum reacts selectively in a radioallergosorbent test (RAST) which utilizes discs coated with HSA and exposed to EO gas. In addition, D.H. serum contained IgG antibodies reactive with EO-HSA. This antibody activity was not detected in the sera of 27 normal subjects and 25 chronic hemodialysis patients. EO-HSA and ragweed RAST inhibition tests with a number of proteins in native form and after exposure to EO demonstrated the EO hapten specificity of the IgE antibody.     

Ragweed pollen challenges in a controlled environment

Clinical manifestations of allergic reactions to airborne ragweed pollen have been produced by direct challenge of patients in an Environmental Control Unit. The experiment was so designed and carried out in an effort to eliminate all possible external psychological factors that might interfere with the validity of pollen provocation results. This preliminary study has verified the effectiveness of a newly devised provocation technique using ragweed pollen in quantitative manner in an Environmental Control Unit. In our study group, children with definite clinical symptomatology during the ragweed season developed symptoms on ragweed pollen provocation. The amount of clinical reactivity to pollen challenge directly correlated with the intensity of the intradermal ragweed skin test reaction.     

Antigenic reactivity of inactivated Bacillus subtilis enzyme preparations

The Bacillus subtilis preparations to which detergent industry workers have been exposed contain a number of enzymes including amylase and the alkaline proteinases, SPA, and SPB. Proteinase-dependent properties of these preparations are a potential source of confusion in some immunologic tests, so that the use of inactivated preparations may be preferable. It was shown that a selective chemical blockage of the active site of SPA is associated with a preservation of antigenic reactivity; however, this preparation has not been used in humans. Heat inactivation of the enzyme activities of SPA- and SPB-containing preparations led to a corresponding loss of antigenic reactivity. The macroglobulin inhibitors of rabbit serum represent an example of naturally occurring proteinase inhibitors. SPA mixed with preparations of these serum inhibitors in inhibitor excess suffered complete or almost complete loss of antigenic reactivity. However, when reaction mixtures were formed in enzyme excess, there was at least partial preservation of the antigenic reactivity of macroglobulin-associated SPA. These properties of inhibited B. subtilis enzyme preparations require consideration in their use in immunologic procedures.     

Reactions during hemodialysis caused by allergy to ethylene oxide gas sterilization

In patients receiving long-term hemodialysis (HD), we have examined the presence of IgE-dependent sensitization to ethylene oxide (EO) gas, which is used for sterilization of disposable medical products including dialyzers. Serum was obtained from 25 patients who experienced acute allergic reactions during HD, five patients receiving HD with isolated eosinophilia, and 37 unselected patients receiving HD. Sera from 22 of 25 of the allergic reaction group and from five of 35 of the unselected group were demonstrated to contain IgE antibodies with specificity for EO. Corresponding IgG antibodies were also present. No such antibodies were detected in serum from normal controls or ragweed-allergic patients. The serum from one patient with isolated eosinophilia had a borderline elevated IgE antibody level. These results demonstrate a close relationship between the presence of IgE antibodies to EO and HD-related allergic reactions in this patient population.     

The Merkel cells and the rapidly adapting mechanoreceptors of the salamander skin

We have made correlated physiological and morphological studies of salamander skin to look for a possible relationship between Merkel cells and the mechanoreceptors of the skin. Using electrophysiological techniques, a systematic survey was made of the apparent thresholds to mechanical stimulation over areas of approximately 1 mm₂ of skin surface; the same skin was then serially sectioned for electromicroscopic examination. From an analysis of the physiological findings we could define highly mechanosensitive discrete areas on the skin which indicated the locations of the rapidly adapting mechanoreceptors. The same skin was then examined morphologically to construct a map showing the locations of the Merkel cells. The morphological map was corrected for distortion due to shrinkage, by using as ‘internal markers’ the gland openings which can be identified both in the morphological study and during the physiological survey. The final superimposition of the physiological map with the corrected morphological map revealed a highly significant correlation between the touch-sensitive areas and the Merkel cells. We conclude that each rapidly adapting touch receptor, which we know is only rarely supplied by more than one axon, is comprised of mechanosensory endings in intimate association with a single Merkel cell.     

Dose-response effects of albuterol aerosol compared with isoproterenol and placebo aerosols: response to albuterol, isoproterenol, and placebo aerosols.

Albuterol aerosol was an effective bronchodilator as reflected by indices of pulmonary function obtained from spirometry and flow volume curves; Compared with isoproterenol, there were minimal side effects even at the highest doses, and bronchodilation lasted significantly longer. In addition albuterol was successfully used by a patient with idiopathic hypertrophic subaortic stenosis who was unable to tolerate isoproterenol, as well as by some patients with idiosyncratic responses to isoproterenol; A few patients appeared to derive little benefit from either albuterol or isoproterenol.