The Immediate Urticarial Reaction to Intradermal Testing in Penicillin Hypersensitivity1,2

THE IMMEDIATE URTICARIAL REACTION TO INTRADERMAL TESTING IN PENICILLIN HYPERSENSITIVITY12 JOSEPH FARRINGTON, M.D.,' AND JOSEPH TAMURA, PH.D.

The relative ease with which penicillin hypersensitivity can be induced by repeated intradermal injections (1) should caution against indiscriminate testing. In a previous report (2) we described the tuberculin-type reaction encountered in cutaneous testing of a patient hypersensitive to penicillin. Strongly positive cutaneous tests obtained with the purest crystalline fractions and with the amorphous commercial penicillin, and negative tests obtained on cutaneous testing with the autoclaved solution and to penicillin plus penicillinase mixture would indicate that the reaction of hypersensitivity was elicited by the active principle itself. The tuberculin type reactions appeared 24 to 48 hours after the intradermal injection of penicillin. This finding was in accord with those of Welch and Rostenberg (3) and others (4). The 24 to 48 hour period required to read this test in order to determine the existence of this type of hypersensitivity to the antibiotic could prove to be a costly delay for the patient if the drug were withheld pending the result of such testing. Further study of responses to intradermal tests with solutions of the crystalline fractions G and K reveals a second type of reaction which may also occur at the test site. This consists of an accentuation of the original injection wheal manifested by a slight central edema, spreading of erythema with pseudopodia and red areolae of varying intensity. This immediate reaction appears in 2 to 5 minutes, attains a diameter of 3 to 6 centimeters (or more) within 10 to 20 minutes and usually recedes within 1 hour. Frequently an intensification of this reaction is noted in 6 to 8 hours. Using the proper dilutions, we have never encountered an associated generalized urticaria, and few of our subjects have complained of pain or itching at the test site. No constitutional symptoms have been attributed to this type of intradermal injection of penicillin. We originally regarded this reaction as a manifestation of primary irritation from penicillin or its impurities, but experience with the purer crystalline products in dilutions as low as 2.5 units per 0.1 cc. has convinced us that this reaction is an indication of specific allergic urticarial hypersensitivity. It is difficult to interpret this reaction in the light of our present knowledge. The concept of circulating antibodies in cases of hypersensitivity to fungus extracts is not new although all types of antibodies may not be demonstrable at the same time. Sulzberger and Kerr (5) in 1930 and Tomlinson (6) 5 years later described such 1

From the Department of Dermatology and Syphilology, College of Medicine University

of Cincinnati and the Laboratory of Antibiotic Research, Cincinnati General Hospital, Joseph Tamura director. 2 These studies made possible under a grant from the Bristol Laboratories, Inc. Work done in part by grant from the William S. Merrell & Co.

'Bristol Fellow in Antibiotics. Received for publication January 2, 1948. 421

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antibodies to trichophytin. Criep (7) has reported a case of allergy to penicillin in which he was able to obtain positive skin tests, passive transfer and precipitin

tests denoting the presence of reagins in the patient's serum. Callaway and Barefoot (8), on the other hand, were unable to demonstrate the presence of circulating antibodies to sodium penicillin in 5 patients who developed urticaria

associated with penicillin therapy. Hypersensitivity may result during the course of penicillin therapy from contact with the penicillin elaborated by other

fungi in vivo during attacks of dermophytosis (9), by cross-sensitization or possibly by conjoint sensitivity (10). The lack of uniformity of response has led many investigators to conclude that pre-administration testing for penicillin hypersensitivity is neither reliable nor practical. If the limitations of the test and the factors influencing the responses in cutaneous testing with penicillin are realized, the immediate type reaction may be useful and time saving in many circumstances. The reliability and importance of this reaction, however, should not be overemphasized. In a choperative study of reactions to penicillin encountered in the hospitals of Cincinnati, Ohio, from April 1, 1946 to December 30, 1946 cutaneous testing was done in 147 cases. 47 of these patients showed a contact eczematoid or dermatitis venenata type of reaction. One hundred of these cases exhibited so-called endogenous type of dermatoses. Of the latter group 24 patients gave an immediate urticarial reaction while 23 additional patients exhibited a delayed or tuberculin-type response to intradermal testing with 0.1 cc. of normal saline containing from 2.5 to 2,000 units of crystalline penicillin G or K. Sixty-seven of these patients showed only a control type reaction to the penicillin solutions. In our experience, therefore, we have found the immediate reaction helpful in about 24 per cent of the cases coming under our observation. The correlation of cutaneous testing, penicillin therapy- and reactions of hypersensitivity are dependent upon many factors among which are the site, the rate,

and the number of antibodies formed. The penetration of the body by an

antigen such as penicillin results in the production of antibodies which in time appear in the circulation where they remain for varying periods of time. The antibodies may then become fixed in the tissues. This may result in a localized hypersensitivity which is usually greatest at the point where the antigen has been introduced or at the site primarily contacted by the antigen. Intradermal tests, therefore, may be positive only at the site of previous contact. After the antibodies are anchored to the cells, when the antibiotic is again introduced into the body a prompt allergic reaction, either local or general, may follow.

It is safest to begin testing with dilute solutions. The smallest amount of penicillin which we have found to provoke a cutaneous response has been 2.5 units. Quantitative tests (11), using from 2.5 to 2,000 units per 0.1 cc. of normal saline, will afford some idea of the degree of hypersensitivity. An immediate erythema-edema reaction with a diameter of over 1.5 cms. with 2.5 units of crystalline penicillin indicates, in our experience, a significant degree of hyper-

sensitivity. This must be differentiated from the immediate reaction of the control type described by Cormia and others. Cormia and Lewis (10)

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in an experiment with infants and young children who were given intradermal tests with commercial penicillin sodium, 1,000 units per 0.1 cc., found immediate reactions invariably occurred and were manifested by "a central wheal surrounded by a zone of solid erythema and with a peripheral zone of mottled erythema. The reaction never exceeded 0.7 cm. in diameter. There were no delayed 48 hour (tuberculin type) reactions." A significant positive immediate reaction is usually—but not always—followed by a tuberculin type reaction. It should furthermore not be construed that these two types of responses can be used interchangeably. Patients exhibiting a truly positive immediate reaction to this quantity of penicillin dissolved in 0.1 cc. of normal saline has, or almost invariably develops, one of the recognized types of hypersensitivity reactions (12) if the antigen is administered in effective therapeutic dosages by any route. The immediate reaction is also useful in determining readily periods of hyper-

activity and periods of anergy. Kalodny and Denhoff (13) found even in a group of consistent reactors to penicillin "that a phase of relative anergy existed for a period of 5 to 7 days" and noted that skin tests might be negative during this period. Zeller (14) has reported a case showing that as little as 50 units of commercial penicillin will produce urticaria during the reactive phase but that during the anergic state larger dosages up to 25,000 units are tolerated without reactions of hypersensitivity. Farrington et a!. (15) have shown that this anergic phase may be utilized in penicillin therapy and reactions of hyper-

sensitivity avoided. Although this period usually lasts from 5 to 7 days its duration is unpredictable and uncontrollable. If therapy is to be carried out during this period it is well to follow the patient's degree of reactivity with intracutaneous tests. Simultaneous testing with crude amorphous commercial penicillin and the crystalline products, or with a specific fraction, will at times show which will be

best tolerated. Barefoot and Olansky (16) have recently reported a patient who exhibited repeated, immediate, generalized urticarial reactions to amorphous penicillin but tolerated large dosages of crystalline penicillin G without untoward

effects. The cutaneous tests parallel these results. By careful physical examination and simultaneous testing with other fungus extracts, expecially trichophytin, as well as penicillin, reactivation of other latent fungous infections may be anticipated. Prophylactic treatment of old fungous infections may be instituted early or done before elective penicillin therapy is undertaken. In patients showing reactions during the course of penicillin therapy, simul-

taneous testing with several different commercial brands will often indicate a brand to which the patient does not react untowardly making further penicillin therapy possible.

The duration of penicillin sensitivity has not been determined. In a group

of six patients coming under our observation, all of whom had shown severe reac-

tions to penicillin correlated with strongly positive intradermal tests, retesting was done at intervals of 1 month, 3 months and 6 months. Three gave consistently positive immediate erythema-edema reactions followed by a delayed

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or tuberculin type reaction at each test interval. One gave a positive tuberculin type reaction only and two showed oniy a control type reaction at the end of 48 hours. CONCLUSIONS

1. An immediate erythema-edema reaction to intradermal testing with crystal-

line penicillin G and K elicitable in sensitized individuals is described and is thought to be an indication of specific allergic urticarial hypersensitivity. 2. Some clinical applications of this reaction are described. REFERENCES 1. ROSTENBERG, A., Jil.: Local penicillin therapy. Arch. Dermat. & Syph., 50:330 (Nov.) 1944.

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