The effect of atropine and albuterol aerosols on the human bronchial response to histamine.

This study was designed to determine whether histamine-induced bronchoconstriction in human asthmatics is mediated by the parasympathetic nervous system and involves cholinergic pathways. Inhalation challenges were performed on 14 adult asthmatic patients using the standardized procedure for inhalation challenge recently recommended by the Asthma and Allergic Disease Centers panel. The effect of pretreatment with either aerosolized atropine sulfate or aerosolized albuterol, a specific beta-2 adrenergic agonist, was studied. The comulative units of histamine required for induction of a positive bronchial response (20% or greater drop in FEV1 from baseline) was used as the basis of comparison of the effects of these drugs. This value was expressed as the PD20-FEV1 to histamine. Analysis of the data showed that aerosolization of sufficient atropie to effect a cholinergic blockade, as shown by inhibition of the bronchial response to inhaled methacholine, only minimally affected the bronchial response to histamine (p less than 0.05). However, the administration of albuterol markedly shifted the response to histamine (p less than 0.005). Although there was a statistically significant change in the mean PD20-FEV1 to histamine following atropine blockade, this effect was small in comparison to that which could be demonstrated with a beta agonist. It would thus appear that the major influence of histamine is not through cholinergic pathways.     

Suppressor cell function in atopic dermatitis associated with elevated immunoglobulin E.

Suppressor cell function was evaluated in 11 patients with atopic dermatitis (AD) and elevated IgE levels (mean, 4,554 IU/ml +/- 1,825 SEM) and compared to 11 matched nonatopic controls (135 IU/ml +/- 52 SEM). Two assays were employed to evaluate suppressor cell function. In the first assay, concanavalin A--activated suppressor cell activity of AD and control subjects were compared. In the second assay, peripheral blood mononuclear cells (PBM) from the same AD and control subjects were stimulated with varying doses of mitogen at day 0 and after 24 hr of preculture. In this system, increased proliferative response of precultured cells as compared to 0-hr cells has previously been shown in normals to represent loss of suppressor cell function in vitro. The lack of such an increase implies aberrant suppressor cell function. The data from both assays showed no significant difference in the degree of suppressor cell function of the patient population vs the control population. Thus, suppressor cell function as tested in these proliferative assays appears normal in AD patients with increased IgE.     

Evaluation of the adverse effects of long-term hyposensitization.

This study was undertaken to determine if long-term hyposensitization causes late sequelae, particularly those reflecting aberrant immunologic responses. Atopic individuals receiving five or more years of hyposensitization with allergenic extracts showed no increased autoimmune, collagen vascular, or lymphoproliferative disease. In addition, chronic hyposensitization did not have adverse effects on immunologic reactivity as assessed by a number of immune parameters. Particularly noteworthy was the absence of immune complexes in the serum of patients undergoing long-term hyposensitization. This study represents the first systematic investigation of potential adverse effects of long-term hyposensitization.     

Severe persistent biphasic local (immediate and late) skin reactions to insulin.

A patient with adult-onset insulin-requirging diabetes mellitus had persistent severe local reactions to all available insulins of animal origin. Skin reactions were biphasic in nature with both immediate and late characteristics. An extensive immunologic investigation of this problem was undertaken, revealing evidence of reaginic antibody involvement in the reactions. Routine histologic studies suggested the possibility that Arthus-type mechanisms played a part, although this impression was not confirmed by immunofluorescent microscopy. A program of medical management provided some relief of symptoms.     

Cholinergic nervous system and immediate hypersensitivity: II. An analysis of pupillary responses

We studied the pupillary responses of various subjects to carbamylcholine chloride (CCC) in order to assess cholinergic responsiveness. Using the concentration of topical CCC required to induce ≧1 mm miosis in the dark as the end point, we compared the responses of five groups of subjects: normal controls; patients with allergic asthma, allergic rhinitis, or intrinsic asthma; and a group who had reproducibly positive skin tests in the absence of symptoms. Subjects with allergic rhinitis or allergic asthma were significantly more sensitive than were normal controls. The patients with positive skin test and negative history were as sensitive as their symptomatic cohorts, suggesting that pupillary cholinergic hyperresponsiveness exists in atopic individuals regardless of symptoms. A small group with intrinsic asthma was examined and found to be even more sensitive than any of the atopic subjects. Thus abnormal hyperresponsiveness of the pupillary constrictor muscles to a topically instilled cholinomimetic has been found in all groups of atopic subjects plus nonallergic asthmatics. Analysis of pupillary responses may prove useful in assessment of autonomic responsiveness.     

A U.S. reference for human immunoglobulin E

The Committee on In Vitro Tests of the American Academy of Allergy has collected a large pool of human serum containing high titers of total lgE.for the purpose of establishing a U.S. reference material. This pool is free from hepatitis B surface antigen. The serum pool has been subaliquoted, lyophilized and tested.for total IgE content. The paper radioirnnuanosorbent test (PRIST) technique was used for this measurement. All laboratories used the same lot of reagents. The Second International Reference Preparation was used as the reference standard in each assay. Multiple replicates of the pooled sera were tested.for total IgE content with one set of reagents by each of the 14 participating committee laboratories. The results,for total IgE content (IU) of the vials were: mean of means, 899; median of means, 901; weighted mean. 898; it with an overall coefficient of variation of 15.3%. This new IgE re ference material is available to call laboratories for use as a primary reference standard from the Research Resources Branch, NIAID-NIH, Bethesda, MD 20205.     

An approach to the patient with a history of local anesthetic hypersensitivity: experience with 90 patients.

We have studied the utility of skin testing and progressive challenge to detect local anesthetic hypersensitivity in patients with histories of reactions to local anesthetics. The likelihood of previous immediate hypersensitivity reactions was determined by history in 90 referrals. Fourteen had histories compatible with immediate hypersensitivity reactions, 24 did not, and the history was uncertain in 52. Of the 14, 12 were negative to lidocaine skin test and challenge, although 5 gave histories of immediate hypersensitivity reactions to it. The other 76 patients also underwent skin testing and progressive challenge. No skin tests were positive with 1:100 local anesthetics but 10 patients had positive intradermal skin tests to undiluted 1% local anesthetics. Proof of false positivity was confirmed in 4 of 10 cases by uneventful challenge to the local anesthetic giving the positive skin test. At least 1 local anesthetic was cleared for use in each of the 90 patients. Skin testing as part of a progressive challenge protocol is a useful approach to the management of alleged local anesthetic hypersensitivity. True immediate hypersensitivity reactions to local anesthetics are rare. Positive skin tests to dilutions of 1:100 local anesthetics are also rare and may suggest the possibility of true immediate hypersensitivity to the agent tested.     

Effects of infused histamine on asthmatic and normal subjects: comparison of skin test responses

The effect of histamine infused intravenously at sequentially increasing concentrations (0.05, 0.1, 0.25, 0.5, and 1 μ/kg/min) on the wheat responses to intradermal histamine and compound 48/80 in eight normal and five asthmatic subjects and to allergen skin tests in five asthmatic subjects was measured. These measurements were repeated following pretreatment with the H-1 antagonist hydroxyzine or the H-2 antagonist cimetidine, either alone or in combination. Histamine infused in progressively increasing concentrations had no effect on histamine, compound 48/80, or allergen skin tests either before or after H-1 or H-2 antihistamine treatment. No significant differene was found in the concentration of histamine or compound 48/80 required to elicit a 10-mm wheat in normal or asthmatic patients. Pretreatment with the H-2 antagonist alone had no effect on histamine or compound 48/80 skin tests in either group. However, the H-1 antagonist significantly reduced the wheat response to histamine (p < 0.05 normal; p < 0.025 asthmatics) and compound 48/80 (p < 0.05 normal; p < 0.025 asthmatics) in both groups. The combination of H-1 and H-2 histamine antagonists was not significantly different from the H-1 antagonist alone. Antigen skin testing was suppressed 82% by the hydroxyzine alone; no significant suppression was induced by cimetidine alone, and the combination of hydroxyzine plus cimetidine was only slightly more effective than hydroxyzine alone. The results indicate that blockade of histamine H-2 receptors with cimetidine has little or no additive effect on H-1 antagonist-suppressed skin test responses to histamine, compound , or antigen. Furthermore, the capacity of histamine to suppress histamine release in vitro from basophils was not demonstrated in vivo assessing skin mast cell responses. This observation combined with earlier studies on the human lung mast cell, which also failed to demonstrate that histamine had an inhibitory action, suggests that the human mast cell may not respond to histamine like the basophil and that this discrepancy may represent a fundamental difference in the cell types.     

The effect of preservatives and dilution on the deterioration of Russian thistle (Salsola pestifer), a pollen extract.

The potency of Russian thistle extract was compared after 1, 3, and 12 months of storage with that of freshly reconstituted lyophilized extract. Potency was measured by radioallergosorbent test (RAST) inhibition. Aliquots of extracts were maintained in: glycerin, 50%, 25%, and 10%; human serum albumin (HSA), 1%, 0.1%, and 0.03%; polysorbate 80 (Tween 80), 0.2%, 0.02%, 0.002%, and 0.0002%; phosphate-buffered, bicarbonate-buffered, and normal saline. Extracts were stored in dilutions ranging from 1:100 w/v to 1:100,000 w/v. The effects of 0.4% phenol and of siliconizing the vials with Dri-film SC 87 were also assessed. Extracts were either stored continuously at 17 °C or at 4 °C, but placed at room temperature for 13 hr each week. Extracts lost potency equally with the two conditions of temperature storage. Siliconizing had no effect on preservation of extract potency. At concentrations of 1:100, all dilutions of glycerin, HSA, phosphate buffer, and some concentrations of polysorbate 80 maintained extract potency within 1 logarithm (log) dilution of the original strength for 12 months; glycerin was significantly superior to all other extracts at 1, 3, and 12 months; and the deleterious effect of phenol was minimal. At a concentration of 1:10,000 w/v only 50% glycerin maintained potency within 1 log dilution of the original strength for 12 months. The deleterious effect of phenol was more marked at the higher dilution. It was concluded that there may be marked loss of potency of dilute pollen extracts stored for periods of only one month under conditions which may be encountered in normal clinical practice.     

A laboratory evaluation of immune complexes in patients on inhalant immunotherapy

Patients with allergic rhinitis receiving maintenance inhalant immunotherapy and two control groups were studied for evidence of circulating immune complexes. The first control group contained patients with allergic rhinitis who had never received immunotherapy. The second control group contained normal volunteers. Patients in the treatment group had no proteinuria. When compared with the control group, the treatment group had no statistically significant differences in incidence of Clq binding immune complexes, cryoglobulinemia, rheumatoid factor, or complement depletion. This initial study suggests that maintenance immunotherapy does not result in an increase of circulating immune complexes.     

Clinical and immunological studies of timothy antigen D immunotherapy.

The response to preseasonal immunotherapy with aqueous grass extract, timothy antigen D, or water-soluble timothy (WST) in alginate was compared in patients sensitive to grass pollen. Injections of antigen D in alginate produced little evidence of clinical or immunologic response. Treatment with aqueous grass extract or WST in alginate, on the other hand, significantly reduced the seasonal rise in grass-specific IgE. Aqueous extract therapy was also associated with a decline in leukocyte sensitivity during the pollen season, while WST treatment produced the greatest rise in hemagglutinating antibodies.     

The bronchodilator response to inhalation of increasing doses of aerosolized albuterol

Forty-four asthmatic patients were treated on separate days with increasing doses of albuterol in four double-blind studies that included placebo controls. Twenty-six subjects received one, two, four, six, and eight inhalations from a metered dose inhaler; 18 subjects received 1.25, 2.5, 5, 10, and 15 mg delivered by IPPB. There was a significant linear relationship in both groups between the maximum increase in FEV1 and the log dose of albuterol. The response to four, six, and eight inhalations from the metered dose inhaler was significantly greater than the response to one inhalation, and the response to 15 mg by IPPB was significantly greater than the response to any other dose by IPPB. The results suggest that in many patients maximum possible bronchodilation is not achieved by customarily recommended doses.     

Evaluation of a patient with cold and cholinergic urticaria.

A-20-year-old male Army paratrooper presented with a history of inducible urticaria associated with exercise as well as cold exposure. Upon evaluation, he not only had a positive ice cube test, but also had a positive mecholyl skin test with numberous satellite lesions and generalized punctate urticaria following exercise challenge. Thus, he appeared to have combined cold and cholinergic urticaria. When mediator release was examined during cold and exercise challenge, histamine release was observed in each instance; a rapid rise and fall of plasma histamine was seen after cold challenge, while a lag phase followed by sustained elevation of plasma histamine was associated with exercise challenge. This represents the fourth reported case of combined cold and cholinergic urticaria and is the first in whom mediator release was assessed. The time-course of histamine release was characteristic of each disorder.     

Subsensitivity to epinephrine following the administration of epinephrine and ephedrine to normal individuals.

Cardiovascular and metabolic responses to exercise and consecutive epinephrine infusions 24 hours apart were measured in 7 normal individuals before and following a week's administration of ephedrine sulfate. There was evidence of less beta adrenergic response to the second control epinephrine infusion compared to the first control infusion, and the depression of the rise in blood lactate was significantly different. A week of ephedrine produced more profound depression of the beta adrenergic responses to epinephrine with significant differences in the rise in blood glucose and lactate, and the pulse and blood pressure responses. Furthermore, these same responses remained significantly altered when a second epinephrine infusion was performed 36 hours following the last dose of ephedrine. The alterations in the response to epinephrine induced by ephedrine are consistent with the concept of effector cell "subsensitivity," an adaptive response to prolonged excessive stimulation.     

Incidence of bronchoconstriction due to aspirin, azo dyes, non-azo dyes, and preservatives in a population of perennial asthmatics.

Forty-five patients with moderately severe perennial bronchial asthma were challenged by ingestion of: acetylsalicyclic acid (ASA); 4 azo dyes (tartrazine, sunset yellow, amaranth, and ponceau); 3 non-azo dyes (erythrosine, brilliant blue, and indigotin); sodium benzoate (NaB); parahydroxybenzoic acid (OHBA); butylated hydroxyanisole (BHA); and butylated hydroxytoluene (BHT). A fall in forced expiratory volume is one second (FEV1) greater than 25% from baseline was considered positive. Seven patients who gave an unequivocal history of aspirin intolerance were not challenged with ASA; an additional 13 had positive open challenges to ASA, giving an apparent incidence of aspirin sensitivity of 20/45. The presence of nasal polyps, simusitis, or the regular use of corticosteroids, either singly or in combination, was not associated with an increased incidence of reactions to ASA. Significant bronchoconstriction to open challenges with agents other than ASA was less frequent. Positive open challenges to all substances except aspirin were followed by double-blind challenges which were positive in only 3 instances: 1 each with erythrosine, ponceau, and NaB/OHBA. Our findings confirm that ASA intolerance is relatively common but suggest on the other hand that reactions to dyes and preservatives are uncommon cause of clinically significant bronchoconstriction in moderately severe perennial asthmatics.     

The effect of ephedrine on the response to epinephrine in normal men

The metabolic and cardiovascular responses to epinephrine infusion were measured in 6 normal men following a control period, and one week each of phenobarbital, ephedrine, and theophylline. Following the period of ephedrine administration, there was significantly less rise of the blood-free fatty acids, lactate, and glucose in response to intravenous epinephrine. The pulse rate during the epinephrine infusion following the administration of ephedrine was significantly slower than following the other regimens; the mean blood pressure was higher following ephedrine, but the difference was not statistically significant. These abnormal responses to epinephrine infusion in men who had received ephedrine were similar to those produced by administration of a beta adrenergic blocking agent and to those that have been reported in patients with bronchial asthma.     

Immunologic studies in a case of baker's asthma

A 28-year-old baker with 13 years of occupational experience has developed, over the past several years, sinusitis, rhinitis, contact dermatitis, and asthma. Clinically, all of his symptoms were felt to be related to occupational exposure. Immunologic evaluation consisted of the following tests: intradermal skin testing, leukocyte histamine release, total serum IgE, PK transfer with immunoadsorption, and specific antigen bronchial challenge. Analysis of results would tend to implicate a type I, IgE-mediated immunologic reaction.     

Experience with daily immunotherapy in 59 adult allergic patients

Fifty-nine adult men with seasonal allergic rhinitis received immunotherapy that was administered five to six times per week until maintenance doses were achieved. Immunologic response was monitored with titrated prick skin tests, which revealed increased sensitivity at 2 wk, followed by progressive decline coinciding with a rise in IgG blocking antibody. Specific serum IgE (RAST) did not change. When compared with a group receiving conventional weekly injections, these subjects required the same number of injections to reach maintenance and had the same incidence of adverse reactions.     

Further studies on the safety of polymerized antigens for immunotherapy

Six patients receiving immunotherapy with standard aqueous extracts for the treatment of atopic disease were selected from the patient population of Northwestern University Allergy Clinics for continued immunotherapy with polymerized antigens. These six patients could not tolerate quantities of conventional aqueous extracts considered maintenance doses because of immediate-type local or systemic allergic reactions or both to immunotherapy. These six patients were treated with separate preparations of polymerized ragweed (PRW) and polymerized grass (PG), and each of the six patients was rapidly advanced to previously unobtainable maintenance doses of PRW and PG without local or systemic reactions. Treatment with other aeroallergen standard extracts was continued to maintenance dosage without further systemic reactions. In patients highly sensitive to ragweed and grass aqueous extracts, the substitution of these extracts with PRW and PG allows these patients to receive therapeutic immunotherapy injections with decreased risk of immediate-type local and systemic reactions.