C.Edward Buckley

Does hyperimmunoglobulinemia-E protect tropical populations from allergic disease?

The Waorani Indians of eastern Ecuador have the highest blood concentration of IgE reported in a human population. Evidence obtained by medical history, physical examination, and immediate hypersensitivity skin tests suggests that pollen allergy and other atopic diseases are rare among the Waorani. A similar association between parasite-induced hyperimmunoglobulinemia-E and a low prevalence of conventional atopic disease has been reported in numerous other tropical populations. Saturation of mast cell IgE receptors with antibodies directed to the parasite and/or other antigens and competitive inhibition of passive binding of pollen allergen-specific IgE is one hypothetical cause of this association. We have tested this interesting conjecture by passively sensitizing the skin of Waorani Indians with serum containing pollen allergen-specific IgE antibodies. Waorani Indians with hyperimmunoglobulinemia-E can be adoptively sensitized with human ragweed or rye grass hyperimmune IgE antisera. This suggests that the cutaneous mast cells of healthy Waorani have active IgE receptors. The high circulating plasma concentrations of IgE in the Waorani do not prevent adoptive cutaneous sensitization with pollen-specific IgE antibodies.

The Relationship Between Cutaneous Cellular Immune Responsiveness and Mortality in a Nursing Home Population

The survival over 18 months of 29 nursing home residents was compared with results of cutaneous testing of cell‐mediated immunity at the start of the period of observation. Eight antigens were used to evaluate immunity by intradermal injection of each antigen and measurement of the areas of induration at 48 and 72 hours. A difference in responses was seen between the survivors and those who died, although this difference was statistically significant at 72 hours only. As expected, survivors had more (3.1, compared with 1.47) and larger (8.6 mm, compared with 3.2 mm) reactions at 72 hours than those who died.

Double-blind comparison of terfenadine, chlorpheniramine, and placebo in the treatment of chronic idiopathic urticaria

The efficacy of terfenadine, a nonsedating H1 antihistamine, in the management of chronic idiopathic urticaria was compared with chlorpheniramine and placebo in a parallel multicenter trial. Subjects with symptoms of hives for 3 days per week for at least 6 weeks were initially screened and admitted if no identifiable cause for symptoms could be determined. Patients entered a single-blind placebo period, and if hives of moderate severity were present for at least 3 days during the week, they were randomly assigned in a double-blind fashion to take terfenadine, 60 mg twice daily, chlorpheniramine, 4 mg three times a day, or placebo for 6 weeks. Data were analyzed for 122 patients. Those patients receiving both active treatments noted significant improvement in symptoms: pruritus, redness, number of hives, and waking hours during which hives were present, at the end of the first day of therapy. Symptom control by terfenadine was statistically superior to placebo during all 6 weeks, as rated by both patients and investigators. However, statistical significance was not achieved for chlorpheniramine at all observation points. Diphenhydramine was permitted as a relief medication for refractory symptoms and was taken by 52% of subjects receiving placebo, 26% taking chlorpheniramine, and only 9% of patients who were receiving terfenadine. In addition to providing superior symptom control, terfenadine caused less drowsiness and fatigue than chlorpheniramine. Terfenadine is a useful therapeutic agent for primary management of chronic idiopathic urticaria.

Methacholine-induced cutaneous flare response: bivariate analysis of responsiveness and sensitivity

Cutaneous reactions to allergens exhibit a sigmoid dose-response relationship. Available methods for evaluating the allergen skin-test response do not adequately account for the sigmoid curve. Methodologic factors handicap quantitative studies of allergens based on skin-test reactivity. This problem was evaluated with a pharmacologic agonist that mimics cutaneous reactivity. Epicutaneous tests with appropriate concentrations of methacholine were used to provoke flare responses in 84 healthy subjects. A novel hyperbolic tangent model of the sigmoid dose-response curve was used to estimate responsiveness (R) as the midpoint of the sigmoid curve. Sensitivity (C) was estimated as the agonist concentration yielding a flare response equivalent to R. Estimates of sensitivity were independent of estimates of responsiveness (r=-0.0565, p=0.6642). The geometric mean methacholine sensitivity among health subjects was 287 mM/L, and average methacholine responsiveness was 4.9 mm. The mathematic model used in these studies fitted observations surprisingly well (X2(84)=37.044, p greater than 0.95). Differences in methacholine sensitivity and responsiveness related to race, sex, and allergic and/or vasomotor tendencies were detected but were subtle and did not account for a significant portion of the variation among healthy subjects. This model may provide a useful method for quantifying cutaneous immediate hypersensitivity reactions in patients.

ASPIRIN, SALICYLATE, SULFITE AND TARTRAZINE INDUCED BRONCHOCONSTRICTION. SAFE DOSES AND CASE DEFINITION IN EPIDEMIOLOGICAL STUDIES

Allergic-like reactions to chemical components of foods and medicines may be common. The prevalence of idiosyncratic reactions to aspirin, salicylate, metabisulfite and tartrazine is not known. We used a tertiary referral clinic population to estimate safe exposure doses for epidemiological studies. A 15% decrease in the amount of air expired in one second was defined a positive response. The median effective molar doses of the agents were remarkably similar: metabisulfite 0.19 mM, 34.4 mg [95% confidence interval (CI) 0.14, 0.27 mM]; tartrazine 0.10 M, 55.0 mg (95% CI 0.05, 0.21 mM); aspirin 0.09 mM, 16.5 mg (95% CI 0.04, 0.19 mM); and salicylate 0.11 mM, 15.3 mg (95% CI 0.05, 0.27 mM). Doses to which the most sensitive (5%) and practically all (95%) susceptible persons might respectively respond are: metabisulfite 4.6 mg, 255.8 mg; tartrazine 3.4 mg, 885.6 mg; aspirin 0.8 mg, 332.3 mg; and salicylate 2.6 mg, 89.9 mg. Doses within these ranges can be used in epidemiological studies.

A novel Candida albicans skin test antigen: efficacy and safety in man

Yeast phase Candida albicans (ATCC No. 10231) was grown in a nonantigenic medium, harvested and lyophilized. Ammonium sulfate fractions of an aqueous extract of the lyophilized cells were evaluated and the fraction yielding the highest specific delayed cutaneous reactivity in sensitized guinea-pigs was used to prepare a C. albicans skin test antigen (CASTA). The safety of the antigen was evaluated by measuring immediate and delayed (0.25, 6, 24, 48 and 72 h) cutaneous reactions in atopic and nonatopic human subjects. The outcome of three repetitive monthly Mantoux skin tests with 0.01-1 microgram antigen doses was used to test for booster effects in 14 subjects and to estimate a safe initial test antigen dose. The utility of a single skin test as a measure of cell-mediated immunity was evaluated in 40 healthy subjects. Reactor rates (greater than or equal to 2 mm, 48 h) of 40% and 85% were detected, respectively, with doses of 0.0316 and 1 microgram. Using a skin test reaction diameter greater than or equal to 5 mm at 48 h, the reactor rate was 50% for the 1-microgram dose. The only adverse reaction (45 mm, 0.25 h) was detected with the 1-microgram dose in an atopic subject who also exhibited exquisite scratch test reaginic hypersensitivity to C. albicans allergen. The prevalence of other adverse reactions to this antigen compared favorably with that to other antigens used for recall antigen testing. These studies suggest the 1-microgram CASTA dose can be used for effective, safe recall antigen skin tests.

Persistent Cutaneous Cellular Immune Responsiveness in a Nursing Home Population

Mantoux‐type skin tests were applied to 29 elderly residents of an intermediate care floor of a nursing home. Eight antigens were used with each resident, and the size of the reactions was measured at 6, 24, 48, and 72 hours. All but one resident had at least one response ≥ 3 mm at 48 or 72 hours, and most had more than one response of that size. At 48 compared with 72 hours, there was one more responder and the mean size of the reactions to each antigen was greatest. However, there were two responders at 72 hours who did not react at 48 hours, and the total number of reactions in the group was greater at the later reading. Only one resident did not produce any response at either 48 or 72 hours. The minimum number of antigens needed to identify all responsive subjects was five (PPD‐Avian, coccidioidin, histoplasmin, streptokinase‐streptodornase, and trychophytin). The purified protein derivative of tuberculin skin test was repeated on subjects who had an initial response < 10 mm, and one increase of more than 6 mm was observed in a resident who was initially unresponsive to that antigen.

Population differences in cutaneous methacholine reactivity and circulating IgE concentrations

We evaluated the incidence of allergic and vasomotor symptoms, serum IgE concentrations, and the cutaneous responses to allergens and/or methacholine in 229 Waorani Indians residing at 300 m altitude near the headwaters of the Amazon River, 39 Tibetans residing at 4000 m in the Himalayas, and 84 healthy subjects residing at 150 m in the piedmont region of North Carolina. The Waorani Indians had a high level of intestinal parasitism, an intermediate level of parasitism occurs in Tibetans, and parasitism is rare in the control population. One Waorani Indian (less than 1%), six Tibetans (15%), and 59 North Carolina subjects (88%) had a past history of allergic or vasomotor symptoms. The prevalence of positive epicutaneous allergen skin tests among the Waorani was 40 in 2910 tests and was significantly less (chi-squared = 184.5; p less than or equal to 0.0001) than the 151 in 1344 incidence in the North Carolina subjects. Large highly significant differences (p less than or equal to 0.0001) were detected between the geometric mean IgE concentrations (international unit per milliliter) and methacholine-induced cutaneous flare responsiveness (millimeter) elicited, respectively, in comparisons between the Waorani Indians (9806 IU/ml; less than 1.0 mm), Tibetans (2930 IU/ml; 2.06 mm), and North Carolina subjects (108 IU/ml; 4.49 mm). Differences in methacholine sensitivity were small and not significant. A highly significant inverse relationship (r = -0.50, p less than or equal to 0.0001) was detected between the circulating IgE concentrations and the methacholine-induced cutaneous flare responsiveness in this cross-cultural, cross-environmental comparison of three populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative studies of cutaneous hypersensitivity: The prevalence of epicutaneous flare reactions to allergenic pollen extracts

The flare reactions produced by epicutaneous tests with 68 undiluted allergenic pollen extracts were measured in 550 allergic patients. Skin test reactions greater than or equal to 2, greater than or equal to 5, greater than or equal to 10, greater than or equal to 20, and greater than or equal to 30 mm in diameter, respectively, were detected in approximately 67%, 22%, 10%, 3%, and 1% of the 34,700 skin tests. With the Kolmogorov-Smirnov difference test, the cumulative frequency of reaction diameters and loge-transformed diameters of all reactions and reactions to individual allergenic extracts differed significantly (p less than or equal to 0.01) from a normal distribution. The ability to identify specific differences between reactions to closely related pollen extracts was evaluated. Specific reactions could be reliably identified with greater than or equal to 10 mm diameter flares. This arbitrary conservative threshold was used to estimate the relative prevalence of positive reactions to each allergenic extract. Seven allergenic extracts elicited the first quartile of all positive reactions. Thirteen, 18, and 30 allergenic extracts, respectively, were needed to elicit the second, third, and fourth quartiles of all positive reactions. Reactions to amphiphilous, as well as anemophilous, pollens were detected. Skin test reactions to grasses were more prevalent than reactions to weeds and trees. The most informative allergenic extracts for the detection of patients who exhibited a positive reaction to any extract were from red fescue-grass pollens, mesquite, short ragweed, red clover, and timothy-grass pollens.

The lectin reactivity and lectin-like activity of allergenic pollen extracts

The binding of soluble components of pollen grains to plant-stigma receptors can be inhibited by concanavalin A. This lectin-like activity of pollen components is important in the genetic control of plant reproduction. Aqueous extracts of allergenic pollens also react with concanavalin A. Agarose gel-diffusion precipitates were used to survey and characterize the ability of allergenic pollen extracts to react with concanavalin A and other lectins. Concanavalin A alone precipitated with extracts of plantain, American beech, white ash, and corn pollens. Surprisingly, extracts of the pollen from certain plants also precipitated when the extracts were diffused against pollen extracts from other plants. Pollen extracts of alfalfa, white ash, American beech, burweed marsh elder, redtop grass, corn, plantain, orchard grass, and aspen reacted with one or more other pollen extracts. Extract precipitin activity was reliably obtained after extracting pollens for 20 min with pH 7.5, 0.05M Tris buffer in 0.2M of saline. Optimal agarose gel conditions for detecting the precipitin reactions were pH 8.5 to 9.0, 75 mM borate buffer made to an ionic strength of 1.5M with NaCl for concanavalin A pollen reactions and 0.015M with NaCl for pollen-pollen reactions. The presence of the borate ion was necessary for optimal detection of the agarose gel precipitates. Studies of the inhibition of the lectin-pollen and pollen-pollen reactions with specific mono and disaccharides revealed many similarities and differences between the two types of reactions. The high concentrations of glycerol used to stabilize pollen extracts also inhibit these reactions.