The development of subsensitivity to chlorpheniramine

To assess the development of subsensitivity to antihistamines, titrated prick skin test (PSTs) were performed to seven fivefold dilutions of histamine and either morphine or antigen at specific intervals during therapy. Ten subjects received chlorpheniramine, 24 mg per day, and placebo in a double-blind crossover study. Total wheal area was measured at baseline and after 1, 3, 7, 21, and 24 days. The dose of chlorpheniramine (or placebo) was doubled from days 22 to 24 to assess the response to dosage increase. Serum levels of chlorpheniramine were measured at days 3 and 21 in six patients. Maximal skin test suppression was observed on days 3 or 7. On day 21 there was significantly less (p less than 0.01) suppression of all PSTs than on days 3 or 7. Mean serum chlorpheniramine was 48.7 ng/ml on day 3 and 36.1 ng/ml on day 21 (not significant). There was no significant correlation between changes in serum chlorpheniramine levels and changes in PST suppression. Doubling the dose of chlorpheniramine did not achieve the maximal suppression observed at days 3 or 7. We conclude that subsensitivity to antihistamines develops between 7 and 21 days of therapy and cannot be completely overcome by doubling the dose. The decreased effect does not appear to be due to induced metabolism but may be related to increased H1 receptor number.     

Cross allergenicity among grasses determined by tissue threshold changes

Twenty-seven volunteers with grass-pollen allergy who had not received prior immunotherapy had titrated prick tests with fivefold dilutions of 10 grasses (timothy, Bermuda, smooth brome, grama, salt, quack, western wheat, Johnson, June, and Bahia) to a final dilution of 1:3,906,250 w/v. Ten subjects served as untreated control subjects. Seventeen subjects received immunotherapy with an extract containing equal parts of timothy and Bermuda. Twelve months later subjects had repeat titrated skin testing with reconstituted aliquots of the same lyophilized extract, at the same time of day, and at the same location on the back as in the initial testing period. Nine treated subjects and eight control subjects completed the study protocol. The skin test areas with all 10 grass extracts were significantly decreased in the treated group compared to the control group (p less than 0.01), and there was no difference in the extent of the reduction among the 10 grasses by analysis of variance. We conclude that immunotherapy to timothy and Bermuda alone is capable of reducing to a similar degree the clinical sensitivity to all 10 grasses studied. The results of this study suggest that treatment with timothy and Bermuda alone may be sufficient in most grass-sensitive individuals.     

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.     

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.     

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.     

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.     

Aerosolized terbutaline in asthmatics. Comparison of dosage strength, schedule, and method of administration.

Sixteen patients with bronchial asthma participated in three studies of inhaled terbutaline. Onset of action, duration, and peak effects were compared for a dose of 0.5 mg given in one, two, or four inhalations at 1 min intervals from a freon-propelled, metered-dose aerosol. There was no significant difference in the response between the schedules. Dose-response curves were compared for terbutaline from a metered-dose aerosol, and pressure nebulized with and without intermittent positive pressure breathing (IPPB). There was no difference between the response with IPPB and simple nebulization. Improvement continued to the total dose administered of 9.0 mg. For a given bronchial response, six to eight times as much terbutaline was required by pressure nebulization as from the metered-dose aerosol.     

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.     

Incidence of IgG short-term sensitizing antibodies in an allergic population.

Heat-stable, immunoglobulin G, short-term sensitizing antibodies (IgG S-T S) were sought in serum from 149 allergic patients who had strongly positive immediate skin tests to inhalant allergens. The sera were tested by passive cutaneous anaphylaxis (PCA) in monkeys. No IgG S-T S antibodies were demonstrated in 169 tests with a variety of allergens. Antibody with the characteristics of IgE was demonstrated in 47% of monkey PCA tests and, in an additional 34% of sera. IgE antibody to the same allergen was demonstrated by radioallergosorbent testing (RAST).     

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.     

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.     

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.     

Further studies on the mechanism of human histamine-induced asthma : The effect of an aerosolized H1 receptor antagonist (diphenhydramine)

This study was designed to better define the mechanism of histamine-induced bronchoconstriction in humans by pharmacologic manipulation of the postulated bronchial histamine receptor sites. Histamine challenges were performed on a heterogeneous group of adult asthmatic subjects. The cumulative units of histamine required for induction of a sustained 20% or greater decrease in FEV1 from baseline were determined. The effect of pretreatment with an aerosolized H1 receptor antagonist, diphenhydramine hydrochloride, was then studied. Analysis of the data showed that the administration of an H1 receptor antagonist prior to histamine challenge significantly blocked the bronchial response to histamine (p less than 0.005). This effect was considered to be due to specific competitive antagonism at the H1 receptor site and suggests the presence of H1 receptors in human bronchial mucosa.     

Nonallergic rhinitis with eosinophilia (NARES syndrome): Clinical and immunologic presentation

Fifty-two patients with perennial nasal symptoms of sneezing paroxysms, profuse watery rhinorrhea, and pruritus of the nasopharyngeal mucosa in an “on-again-off-again” symptomatic pattern have been clinically and immunologically characterized. Historically, age at onset of symptoms showed equal distribution from the first through the fifth decades, and the duration of symptoms at diagnosis ranged from 3 mo to 40 yr (mean 9 yr). Trigger factors associated by the 52 patients with the acute onset of nasal symptoms were none or unknown in 22 (42%), weather changes in 16 (31%), odors in eight (15%), and noxious or irritating substances in six (12%). No patients had a history or physical examination consistent with nasal polyposis, bronchial asthma, recurrent sinusitis, nor otitis media. Fifty percent had a negative family history for either chronic rhinitis or bronchial asthma. Nasal secretion smears revealed marked eosinophilia during symptomatic periods. Intradermal skin tests were negative in 49 patients. Serum radioallergosorbent test (RAST) confirmed immediate hypersentitivity skin tests in two of the three patients with positive skin tests. Mean total eosinophil count was 218/mm³. Quantitative immunoglobulins were normal in all patients. Mean serum IgE was 74 IU/ml. Methacholine bronchial challenge was negative in 37 of 37 patients tested. An open aspirin challenge was negative in 13 of 13 patients tested. Spontaneously collected nasal secretions or 0.9% saline nasal washes were analyzed for percent eosinophils, total protein, IgG, IgA, IgE, and RAST to six perennial aeroallergens in 31 of the 52 patients. Neither elevated total IgE nor evidence of specific IgE was found in the study patients' nasal secretions. This report describes 52 patients with symptoms similar to those seen in perennial allergic rhinitis. A characteristic pattern of symptomatic presentation and a paucity of the in vivo and in vitro findings associated with IgE-mediated nasal disease distinguishes this homogeneous disorder from perennial allergic rhinitis.     

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.     

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.     

Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade

Anaphylaxis to known allergens occurred in two patients under treatment for hypertension with propranolol. The clinical course of both cases was similar. Bradycardia associated with an undetectable blood pressure, unusual severity, and sluggish response to treatment were major common factors in which blockade of the beta-adrenergic system may have had a role. Propranolol, a beta-adrenergic antagonist that acts competitively by blocking the adenylate cyclase receptor on efferent cells, is well recognized to cause increased airways resistance in some asthmatic and normal subjects. It is postulated that propranolol potentiated anaphylaxis in these patients by inhibition of adenylate cyclase, resulting in lowered intracellular cyclic AMP and a lowered threshold of mediator release. The bradycardia during profound hypotension is attributed to an unopposed cholinergic action caused by blunting of the normal endogenous beta-adrenergic response by propranolol.     

Normalization of the dexamethasone suppression test at discharge from hospital. Its prognostic value

Fourteen patients with RDC diagnosis of primary, endogenous, major depressive disorder were studied in an inpatient setting. All were non-suppressors on the Dexamethasone Suppression Test on admission to hospital and were retested at discharge. Over 70% of patients continued to be non-suppressors at discharge, when in clinical remission. Four out of 14 patients converted to normal suppression. All 10 of the non-normalizers did poorly on follow-up: 3 patients committed suicide. All normalizers did well. Non-normalization of the DST at discharge from hospitalization may be more common than previously suspected and predicts poor clinical outcome.     

Nonfamilial, vibration-induced angioedema

Vibratory angioedema is a rare form of physical angioedema. A Mexican-American boy presented with vibration-related prolonged angioedema of the hands at age 16. After the use of a controlled vibratory stimulus, 10 volunteers and seven members of the family (three generations) developed expected transient erythema and whealing reaction of the skin at the site of contact. However, with the same vibrating stimulus the patient developed large erythematous swelling that lasted for 12 hr. Vibratory challenge study revealed a rapid rise and fall in plasma histamine. No increase in levels of plasma histamine were detected from the nonstimulated arm. Prausnitz-Küstner testing was negative. Light and electron microscopic study of the mast cell revealed degranulation and extensive fragmentation of the granules from the stimulated site. No degranulation was seen in the contralateral unstimulated site. A state of tolerance to vibration was induced by graded increased exposure to vibratory stimulus and the patient's clinical problem was eliminated.