Alan R. Feinberg

A controlled study of cromolyn sodium sponsored by the Drug Committee of the American Academy of Allergy

Abstract Because of several controversial reports concerning the efficacy of cromolyn sodium in the treatment of asthma, the Drug Committee of the American Academy of Allergy instituted a collaborative study in November, 1969. The protocol was designed to select patients according to age, cooperativeness, severity of asthma, and type of asthma—extrinsic, intrinsic, or mixed. The basic design of the study involved a baseline period of one week in which inert filler (lactose) was administered in the Spinhaler apparatus and during which the patient could be familiarized with the complex record keeping. The basal period was followed by two 4 week crossover periods during which cromolyn sodium was alternated with placebo. Symptom scores, drug intake, physician evaluation, patient preference, and simple pulmonary function tests were subjected to statistical analysis. Results gleaned from 252 completed patients indicated a favorable response for the drug as compared to placebo in patient symptom scoring, ephedrine-like drug scores, physician evaluation, and patient preference. A drug carry-over effect extending over a period of 4 weeks created difficulty in assessing results of the placebo period in patients who received active drug during the first 4 week period. Although a favorable drug effect was usually observed when cromolyn sodium was the first drug in the trial sequence, efficacy was more clear-cut during active drug administration in patients who received placebo during the first 4 weeks of the study. The mechanism of this carry-over effect was not apparent. The amelioration index tended to be higher in the pediatric group and in those patients whose asthma was classified as mixed. No change in the objective indices of one-second forced expiratory volume or peak expiratory flow measured once every 2 weeks was obtained. No serious side effects were noted by the participating investigators. These results indicate that cromolyn sodium will be a useful adjunct to the pharmacological treatment of asthma.

Asthma and rhinitis from insect allergens: I. Clinical importance

Abstract Insects and arthropods probably constitute a major cause of respiratory allergy. This is supported by the frequent reactions to insects on scratch tests, the inability to find other etiological factors to explain completely the symptoms in many of these patients, the probable prevalence of insect substances in the air, and the encouraging results obtained by desensitization. Preliminary findings on immunologic aspects are noted, but extensive work is needed to determine the antigenic relationship and chemical characteristics of the antigens.

Delayed and immediate skin reactivity in man after the injection of antigen in emulsion: Cell transfer of the delayed sensitivity

Abstract In fifteen nonallergic subjects receiving ragweed in repository form, seven developed immediate skin reactivity, nine delayed reactivity, and three both. After six months all still react. In those developing delayed skin reactivity there was an inflammatory swelling of varying degree at the site of the repository injection, beginning several days later and lasting for several weeks. The delayed reactivity to ragweed was transferred locally and systemically by the injection of peripheral leukocytes from three subjects in whom delayed sensitivity had been induced by an injection of ragweed emulsion. Punch biopsy from the delayed reaction produced in the recipient showed histologic changes characteristic (but not pathognomonic) for a delayed hypersensitivity response. The findings point to the advisability of confining repository treatment to antigens to which the patient is known to be sensitive. This investigative model offers an opportunity for basic studies on delayed hypersensitivity and the relationship between the delayed and immediate type.

Leukocytes and hypersensitivity reactions: I. Eosinophil response in skin window to ragweed extract, histamine, and compound 4880 in atopic and nonatopic individuals

Abstract Eosinophil counts were made from coverslips obtained from skin windows after intradermal injections of buffered saline, histamine, compound 4880, and mixed ragweed extract in 17 atopic clinically sensitive, 7 skin reacting but clinically nonsensitive, and 11 nonatopic subjects. The concentration of challenging substance was selected on the basis of equal reactivity by titration and wheal size, but other concentrations were also tried. A challenging dose of a size individualized for the subject was necessary to produce the most effective response. When a potent reaginic serum and a proper dose of antigen are used, the eosinophil response in the passively sensitized site is not much different from that in the atopic individual. The response in the atopic, clinically nonsensitive persons appears to be less than the response in those with a history of pollinosis, although the number of subjects and their degree of sensitivity do not permit a final opinion. The eosinophil response to histamine and compound 4880 was found to be greater in atopic clinical than in atopic nonclinical or nonatopic subjects. The eosinophilia from these solutions is usually moderate, is absent at 45 minutes, begins at about 2 hours, is maximal at 6 hours, and is usually negligible at 24 hours. There is considerable variability and inconsistency in the cosinophil determination by this method, some of which is based on factors not yet recognized or corrected. However, it is concluded that conditions which constitute a minimal requirement are: accuracy of dose of challenging substance, a dose selected on basis of titration, repeated trials in the same subject, the counting of at least 1,000 leukocytes, and an averaging of representative areas on the same coverslip.

Repository antigen injections. Absorption studies by immunologic and radioactive methods.

Abstract 1.1. Methods employed to study the degree of immediate release of ragweed pollen antigen from emulsions have consisted of the ability of emulsified and injected antigens to produce reaction in passively sensitized sites, the reaction on scratch test in allergic subjects after titration with aqueous extracts, the radioactivity of the blood and urine shortly after the injection of radioiodinated emulsion, the local reaction of the emulsion in allergic persons, and the radioactivity release from the emulsion placed in an aqueous solution. 2.2. With the emulsions studied, such immediate release varies from about 1 to 3 per cent, depending on the method used and the batch of the emulsion. 3.3. Persistence of the antigen at the site of injection has been studied in relation to the persistence of radioactivity of radioiodinated pollen extract. Traces of the radioiodination can be shown to exist for as long as four weeks with the emulsion and three weeks with the aqueous preparation. It is possible that longer persistence might be shown with our use of more potent radioactivity. 4.4. By the method of reagin neutralization, it could not be proved that antigen is released from the emulsion in active form beyond the twenty-four-hour period. It is admitted that this is not final evidence that the antigen is unavailable. 5.5. The production of delayed hypersensitivity with the emulsified antigen in nonallergic subjects is of basic and clinical significance. 6.6. Further amplification of these and other studies is needed to perfect the antigenic preparation and to understand the immune mechanisms involved.

Cell transfer of delayed hypersensitivity to ragweed from atopic subjects treated with emulsified ragweed extracts

Abstract 1.1. Four of 10 spontaneously ragweed-sensitive subjects who received an injection of emulsified ragweed extract and who failed to show delayed skin reactivity were capable of transferring delayed reactivity by their peripheral blood leukocytes. 2.2. Twenty ragweed-sensitive subjects, 6 of whom had never been treated and 14 who had had long-term conventional treatment with aqueous ragweed, failed to show a cellular transfer. 3.3. Nonspecific inflammation from a wheal and erythema reaction due to Compound 4880 or an unrelated immediate antigen-antibody reaction resulted in only moderate diminution in the delayed response to a delayed reacting antigen. 4.4. Skin tests in nonatopic persons possessing delayed skin reactivity to ragweed, who were passively sensitized with ragweed reaginic serum and subsequently injected with ragweed antigen, failed completely to give a delayed reaction. 5.5. Although the findings suggest a mechanism of consumption or modification of the antigen by the immediate antigen-antibody reaction, thus removing its availability for the production of a delayed reaction, other observations suggest that such a mechanism may not be present under all circumstances.

Hydroxyzine (Atarax) in chronic urticaria and in allergic manifestations: Clinical observations in man and experimental studies on asthma in guinea pigs produced by several agents

Abstract 1.1. Atarax gives relief in the majority of cases of chronic urticaria and dermographia. 2.2. Atarax is less effective in other allergic diseases. 3.3. Indirect evidence points to the possibility that there is a mediating mechanism in chronic urticaria besides the possible ones of histamine, acetylcholine, or serotonin. 4.4. Experimental studies in the guinea pig indicate that Atarax is a longacting, potent, antianaphylactic, antihistaminic, antiserotonin, and antiacetylcholine agent. For the most part, other tranquilizing or antihistaminic drugs have only part or none of these effects. 5.5. The antihistaminic activity of these drugs appears to be the most important feature determining its antianaphylactic action in guinea pigs.

The sensitizing effects of emulsified pollen antigens in atopic subjects naturally sensitive to an unrelated antigen.

Abstract 1.1. Atopic individuals develop immediate and delayed skin reactivity to emulsified pollen antigens to which they have had no previous sensitivity. 2.2. The development of such new sensitivity is not hampered by the production of a nonspecific inflammatory reaction (from histamine) or a specific antigen-antibody reaction at the site of injection of the emulsified new antigen. 3.3. With the type of antigen, dose, and method used, the atopic person almost regularly develops immediate skin reactivity and less often delayed reactivity. Nonatopic individuals, on the other hand, have a greater tendency to develop delayed sensitivity. 4.4. Our findings do not support the contention that delayed hypersensitivity is a necessary step in the process of development of the immediate type in all instances and with all techniques. 5.5. The reason for the failure of the atopic person to develop induced delayed skin hypersensitivity to the antigen to which he is spontaneously sensitive still remains unsolved. Some possible explanations are offered, but these must await further study.

Aspirin sensitivity—Experimental studies

Abstract 1.1. Guinea pigs were sensitized to aspirin by the use of aspirin-protein conjugates. Uncombined aspirin even when incorporated with various adjuncts failed to produce this sensitivity. 2.2. Rabbits showed precipitating antibodies to aspirin when immunized with aspirin-protein conjugates. 3.3. The sera of aspirin-sensitive human beings as well as that of immune rabbits and guinea pigs failed to show an increase in the amount of salicylate normally bound, as determined by our technique. 4.4. Guinea pigs passively sensitized by serum from aspirin-sensitive patients gave distinct though mild anaphylactic reactions when challenged with heterologous aspirin-protein conjugate.

Immunologic and clinical studies on allergenic fungi.

Abstract A dialyzable and a nondialyzable principle were obtained from alternaria grown on a synthetic medium. The antigen in the nondialyzable fraction was purifed by deproteinization, precipitation as the uranyl salt, and low-temperature centrifugal ultrafiltration. The nondialyzable fraction reacted by skin test in allergic individuals and was precipitated with rabbit antiserum. The dialyazble fraction also reacted on skin tests. It failed to precipitate with antiseurm but acted as a hapten in specifically inhibiting precipitation of the nondialyzable fraction.