Immunologic observations during desensitization and maintenance of clinical tolerance to penicillin

Immunolcrgic okmmations during desensitization and ma~imtemanee of clinical tolermce to peniciltin Robert Naclerio, M.D., Edward A. Mizrahi, M.D., and N. Franklin Adkinson, Jr., M.D. Bultimow, Md., and J~~ck.wnville, Fltr

Judging from the 3% to 6% prevalence of positive penicillin skin tests in unselected populations, IgEdependent penicillin allergy is relatively common.‘, ’ Because of the usual availability of alternative antibiotics and the significant risk thought to be involved in desensitization procedures, only rarely are penicillin-allergic patients subjected to “desensitization” protocols. In this form of therapy for penicillin allergy, clinical tolerance to the drug is induced by gradual, incremental administration of pencillin parenterally or orally. The most generally accepted indication for desensitization therapy is the need for penicillin in a major life-threatening infection for which no satisfactory alternative antibiotic is available.“P5 In Europe, however, nurses and workers in penicillin manufacturing plants have been desensitized to penicillin because of occupational allergy.fi. i

From the Division of Clinical Immunology. Department of Medicine, Johns Hopkins University School of Medicine at the Good Samaritan Hospital, Baltimore, Md. Supported in part by grant AI 11936 from the NIAID. Received for publication July 19, 1982. Accepted for publication Sept. 9, 1982. Reprint requests to: N. Franklin Adkinson, Jr., M.D . Division of Clinical Immunology, Johns Hopkins Universit) School of Medicine at the Good Samaritan Hospital, 5601 Loch Raven Blvd., Baltimore, MD 21239. Vol.

71, No.

3, pp.

294-301

We report here the case of a nurse anesthetist with penicillin allergy who attributed four systemic allergic reactions to penicillin exposure. The patient’s t”r-. treme sensitivity to minute quantities 01’ penicillin, which could not be avoided in either her occupation far home environment, motivated her to seek desensitization therapy. A regimen of rapid parenteral desen~ sitization followed by prolonged oral therltpy with penicillin was successful in reducing occupationally related allergic symptoms. Immunologic data, obtained throughout the patient’s course, provide some insights into the mechanism of the desensitization process.

CASE REPORT A 4”.yr-old white felJl& nurse anesthetist Ironi ~k)r~di~ was referred for evaluation of penicillin allergy. In 1953, ;rt the age of 20, she developed generalized urticari.1 14 to .3(! min after an intramuscular injection of penicillin. Since that time she has not knowingly received penicillin. Wowc\er in her chosen profession as a nurse, she has had frequent WCL~pational exposure to ,!+lactam antibiotics. Occupational ehposure to penicillin or cephalosporin solutions reguiarlg induced pruritus and occasional urticarial lesioni in rrcenf year\. In 1964 she developed urticarm hypotensmn. whcezmp. and gastrointestinal distress 20 to 30 min after mgestion of’ milk and cereal. The patient was treated ror this episode with epinephrine and steroids in an emergency roo~n In

VOLUME 71 NUMBER 3

Ahhreviarinns

MDM: PPL: RAST: BPO-HSA:

Desensitization

itsed

Minor determinant mixture Benzylpenicilloyl polylysine Radioallergosorbent test Benzylpenicilloyl human serum albumin

May 1978, while exposed to nafcillin and other medications in an operating room, she developed urticaria, bronchospasm, gastrointestinal distress, and hypotension requiring hospitalization for treatment. In October 1980, shortly after eating cheese and croutons made from stale bread, she developed acute anaphylaxis, with significant hypotension requiring emergency treatment and hospitalization. These episodes led to the avoidance of milk, cheese, and operating rooms in which the patients were being treated with penicillin. The patient’s history is negative for eczema, seasonal rhinitis, and other allergic drug reactions. There is some history of asthmatic bronchitis in childhood. The family history is unremarkable for atopic disease except for a maternal cousin with asthma and two family members who developed urticaria after administration of penicillin. lntradermal skin testing to PPL (Prepen; Kremers Urban, Milwaukee, Wis.) and MDM (benzylpenicilloate, benzylpenicillin, and benzylpenilloate, each at 10 mM) was performed without hospitalization of the subject. A 3 mm intradermal bleb (requiring 0.01 to 0.02 ml of reagent) was raised in duplicate on the patient’s forearm. A test was considered positive if the diameter of induration increased to 5 mm or more within 20 min. PPL produced a 6 by 9 mm wheal and was considered positive at the standard concentration (6.0 x IO-“M). The MDM produced an 11 by 10 mm wheal at a 1: 100,000 dilution of the standard skin-test reagent. While each of the individual components of the MDM was also positive, the benzylpenicilloate component was positive at 1 : 100,000 dilution of the standard reagent, whereas the penicillin and penilloate components were only weakly positive at the standard 10 mM concentrations. Skin testing to common inhalant allergens, including Penicillium mold were negative. After discussion of alternatives, including relative risks and benefits, the patient decided to be admitted to the hospital for desensitization. After a thorough medical evaluation, she was transferred to the intensive care unit, where desensitization was undertaken after appropriate precautions, including continuous EKG monitoring and establishment of an intravenous infusion.

RESULTS Desensitization

protocol

Observations during the desensitization protocol are recorded in Table I. Aqueous potassium benzyl-

penicillin freshly diluted in buffered saline was used for desensitization. Incremental doses were initially administered intradermally every 20 to 30 min until

to penicillin

295

evidence of a mild systemic reaction occurred. The first systemic reaction occurred after 10 U were administered. This dose produced mild wheezing, which abated without specific medical treatment. When this dose was repeated approximately 17 hr later no reaction occurred. Four minutes after 100 U of penicillin were administered intradermally, nasal congestion, palmar pruritus, tachycardia, and cough occurred. By 10 min the patient began to wheeze, at which time 0.3 ml of 1: 1000 epinephrine was administered; this terminated the reaction. After 1 hr 100 U of penicillin were readministered without observable reaction. The next dose (300 U) produced generalized erythema and pruritus. When this dose was readministered approximately 2 hr later, severe nasal congestion developed. Increasing the dose to 1000 U intradermally produced some mild flushing and pruritus. A repeat of this dose 50 min later was well tolerated except for persistent nasal congestion and a frontal headache. Nose drops (Neo-synephrine; 0.25%) were administered, with relief of the headache. A subcutaneous dose of 3000 U and an intradermal dose of 10,000 U were tolerated without difficulty or dermal reaction. At this point, skin testing to PPL and to MDM was negative. Continuous intravenous penicillin was started at a rate of 67 U/hr. The number of units of penicillin per hour was gradually increased over the next 24 hr to 250,000 U/hr. During this period the patient had some minor nasal congestion and sneezing. After approximately 24 hr of the intravenous administration of benzylpenicillin, 250 mg of phenoxymethylpenicillin were given orally and were well tolerated. Twelve hours later the dose of oral penicillin was increased to 500 mg q.i.d. and the intravenous penicillin was discontinued. One urticarial lesion was noted on the day prior to discharge, but this resolved spontaneously. The patient was discharged on a dose of phenoxymethylpenicillin (500 mg q.i.d. orally). Follow-up

evaluation

Five days after discharge the patient developed several mild urticarial lesions, which spontaneously resolved over several hours. Skin testing with PPL and MDM performed on the same day was unequivocally negative (Table II). One week after desensitization the dose of oral penicillin was reduced to 250 mg t.i.d., and since there were no allergic manifestations, 2 wk later the dose was further reduced to 250 mg b .i .d. At this dose level there were several transient episodes of mild u&aria occurring shortly after oral doses of penicillin. These episodes resolved within 1 hr without medication. Six weeks after desensitization an episode of

296

Naclerio

J ALLERGY GIN.

et al.

IMMUNOC. MAPICH 2983

----Boseih Total tgE plus PenMloyl !+cmtc IgE

1600.

Totol I6E (rig/ml)

0

Symptoms

Psniclllln

Doss

a0

0

m

ca

-

2 ,

(g/day) 0

Dssms~titation

Days FIG. 1. Graphic representation tests, numbers refer to mean reagent. c, Hives; l , wheezing;

of postdesensitization course. skin-test wheal in millimeters. i, scaly abdominal rash.

wheezing and urticaria occurred unrelated to known work exposure to penicillin. This episode lasted approximately 1 hr and was treated by the patient with 50 mg of hydroxyzine and 10 mg of oral metaproterenol. As a result of this apparent breakthrough, the oral dose of penicillin was increased to 250 mg t.i.d., where it has remained through 18 mo of postdesensitization follow-up. The next 3 mo (Feb. to April 198 1) were marked by transient pruritus, itching, and/or urticaria occurring on an average of three to four times per month. The following 3 mo were completely asymptomatic. In August 198 1 the patient developed urticaria after eating tomatoes and at other times unrelated to her penicillin doses. Toward the end of the month she developed a scaly pruritic rash on her abdomen, which spontaneously disappeared after about I wk. In the tenth month after desensitization, episodes of urticaria unrelated to penicillin doses or occupational exposure began to occur with increasing frequency and sever-

See text for elaboration. For skm Asterisk, 1 : 10 dilution of standard

ity. On Sept. 26, 1981, the patient experienced urticaria nasal congestion, angioedema, and some wheezing within 1 hr of ingestion of her daily 0.625 mg tablet of conjugated estrogens (Premarin‘), which had been restarted 6 wk earlier. The estrogens were stopped, and the patient remained asymptomatic for the next 3 mo. The patient had been placed on estro gens in March 1981, continued use for 3 mo, and then discontinued it until the drug was reinstituted in August 198 1. In December 198 1 the patient began taking medroxyprogesterone acetate (Provera) and estradiol (Estrace). Shortly after beginning this medical regi-. men she developed a dry scaly erythematous rash on her abdomen, similar to the rash that she developed previously while taking conjugated estrogens. When hormonal therapy was again discontinued, all allergic signs and symptoms disappeared. The patient has been pleased with her progress to date. Except for the estrogen-associated reaction 9 mo after desensitization, all allergic symptoms have been

VOLUME 71 NUMBER 3

TABLE

Desensitization

I. Schedule

of desensitization

to potassium

to penicillin

297

benzylpenicillin

Skin test

Day 1

Day

2

Date

Time

PPL

MDM

Dose W)

Route

12/3 12/3 12/3 I2/4 I2/4 I2/4 I2/4 12/4 I2/4 12/4

1615 1635 1655 1004 1030 1130 1200 1356 1424 1513 1539 1614 1645 I748 1841 924 1002 1105 1415 1600

+

+

O.ll1.0 10

SC ID ID

+

+

10

ID

12/4 12/4 12/4 I2/4 I2/4

Day 3

l2/5 I2/5 12/5 12/5 l2/5

Day 4

l2/6

100 100

300 300 1,000 1,000

3,000 -

-

10,000

1O/hr 67/hr 1OO/hr

-

-

700/hr

I O,OOO/hr 50,00O/hr

250,00O/hr 50,00O/hr 500 mg q.i.d.

Observed

response*

W’ EJ

E,W,P

ID

NC,P,W,Cough, Epi

ID ID ID ID ID

EJ’ NC E,NC,P Headache,NC (severe)Neo-Syn.

SC

ID IV IV IV IV IV IV IV IV PO

NC (mild) NC (mild) NC (mild) NC (mild) NC (mild) NC (mild)

NC (mild)

-

SC = subcutaneous; ID = intradermal; PO = oral; IV = intravenous; E = erythema; W = wheezing; P = pruritus; NC = nasal congestion; Epi = 0.3 ml epinephrine 1: 1000 given; Neo-Syn. = 0.25% Neo-Synephrine nose drops given *Blood pressure and pulse were monitored prior to and 10 min after each cutaneous dose and more frequently during observed reactions. Throughout the procedure blood pressure remained stable at 130/80 and pulse rate never exceeded lOO/min. tAdministered as 0.1 ml of I U/ml (IO-jM) solution of benylpenicillin diluted in sterile buffered saline.

milder than those episodes occurring prior to desensitization. She is able to handle penicillin in the operating room without sequellae. In addition, she has had no recurrence of allergic reactions associated with dairy products, which she now eats freely. Immunologic

assessment

Throughout the patient’s course skin-test reactivity was determined and serum samples were monitored for penicillin antibodies. Serial skin-test results are shown in detail in Table II. Prior to desensitization, the patient’s intradermal tests were positive to the MDM and to the penicilloate component at 1 : 100,000 dilution of the standard skin-test concentration. The penicilloyl determinant was weakly positive at the routine skin-test concentration. During the period of desensitization the patient’s skin-test responses to both reagents converted to negative. Skin reactivity returned to the major determinant (PPL) within 3 wk of desensitization. The penicilloate minor determinant skin test was again positive at 1 mo, but reverted to negative between the third and sixth months. Benzylpenicilloyl-specific IgE was determined by a RAST, employing BPO-HSA insolubilized to agarose

as previously reported.* Benzylpenicilloyl IgG was measured by a competitive binding radioimmunoprecipitation assay using 12”1-BPO-HSA as ligand. y Penicilloyl-specific antibodies were measured in two to four separate assays, and the results were averaged. Interassay coefficient of variation was 10% to 20% for both assays. Total serum IgE was determined by a noncompetitive agarose-based radioimmunoabsorbent test as previously described.” Pencilloyl-specific IgE in serum was initially undetectable. It increased rapidly, peaking in approximately 3 wk at 213 rig/ml (Table II and Fig. 1). The peak has been followed by a slow steady decline to a level of 10 rig/ml at 1 yr after desensitization. The penicilloyl IgG has fluctuated in a pattern similar to penicilloyl-specific IgE. Total IgE increased significantly from 120 to 1630 rig/ml within 3 wk and then began to decline. Interestingly, the two clusterings of urticarial lesions and scaly abdominal rashes in the ninth and twelfth months after desensitization were associated with rises in total IgE without rises in penicilloyl-specific IgE (Table II and Fig. 1). Basophil histamine release was attempted according to the method of Lichtenstein and Osler.” The

298

Naclerio

TABLE

J ALLERGY CLIN. IMMUNUL MARCH 1813

et al.

II. Immunologic

observations

during

and after desensitization Serum

Days after desensitization

Dat

12/2/x0

_-__

BPO-IgG

(ngiml)

Total

0 A.M. P.M.

6.7

I’0

6.2

I34

5,s 5.5 5.3

107

7 x 70 33

2/3/x I

62

43x

3/10/81

97

351

4Sh

h/17/X1

IYS

145

328

Y/IX/XI

Xc)

Xh

431

IO/l/81

303

I?.

74,

773

l/1.5/82

410

IO

= benzylpenicilloyl:

QNS

= quantity

*Skin test entries are mean cross-sectional specified. Neg = mean wheal diameter

of serum

available

I680

1090

I200

This case illustrates the successful desensitization of a nurse exquisitely sensitive to penicillin. Three systemic allergic reactions were historically related to obscure exposure to putative penicillin contaminants in food or in a hospital operating room where penicillin was being administered. This exquisite sensitivity to penicillin in the environment was paralleled by markedly positive skin response to benzylpenicilloate, which was positive at 10e7M, a 1 : 100,000 dilution of the standard skin-testing concentration. Previous experience indicates that individuals with minor determinant IgE antibodies are at higher risk for allergic reactions if treated or desensitized than are those with isolated penicilloyl-specific IgE. ‘*-I3 Thus both historical and skin-test data placed this patient in a high-risk category for desensitization therapy. However, the patient had been unable to avoid two serious

-_-.

PPL

MDM

7.5

552

for test

of duplicate wheats in millimeters Numbers in parentheses indicate

DlSCUS!SlON

- -,.. I

yi-ds

141

patient’s basophils did not release to PPL, MDM, or anti-IgE, thereby precluding further histamine release studies.

tests*

I04

I530

not sufficient

Skin

102

‘0 I

diameters <5 mm.

_._-

IL1

I2/5/80 12/I l/W 12/23/H) l/l5/8I

BP0

-__--

IgE

nglml)

(nglmll

-I

12/3/80 i2/4/80

BPO-IgE

studies

for standard antigen concentration. dilution of standard reagent.

uniess

otberwtsc

systemic reactions to putative penicillin contamination in food products, and occupational exposure to penicillin could not be avoided in her profession as a nurse anesthetist. These considerations provided the major motivation for the patient to submit to the risks of attempted desensitization. Desensitization to penicillin has been successfully performed using intravenous.‘” intradermal,“‘. Ii and oral”. 6 routes. We prefer to begin desensitization intradermally in an extremity because this method provides visualization of skin reactivity and allows fol tourniquet application to retard absorption if a significant systemic reaction were to occur. The desensitization procedure in this patient produced a series of graded and limited allergic reactions that did not result in hemodynamic changes. On several occasions a dose that had previously provoked an allergic response was repeated without observable reaction, suggesting that clinical tolerance to penicillin was being achieved incrementally. Premeditation priur to desensitization was not employed, since there is littie evidence that it is helpful. Furthermore, antecedent

VOLUME 71 NUMBER 3

Desensitization

Skin MDM Penilloate

tests*

constituents Penicillin

Penicilloate

5

5

5 (I : 100,000)

neg

neg

6.5

neg

neg

8.2

neg

neg

8.2

neis

neis

neg

neg

neg

net2

neg

neg

neg

neg

neg

w

drug therapy may mask mild allergic reactions, which otherwise may indicate the need to modify the intended treatment schedule. Unlike most cases of short-term penicillin desensitization, there was a need in this case to maintain long-term clinical tolerance. Continuous oral administration was the chosen method. Some precedents for this can be found in the literature. Ganier and LiebermanI reported a case of x-linked agammaglobulinemia in a patient with a history of allergic reaction to penicillin and positive major and minor determinant skin tests, who was desensitized and then maintained on oral ampicillin for at least 6 mo. 0 ‘Donovan and Klorfajn” desensitized a patient to penicillin and maintained him on oral penicillin for several weeks. Graybill et a1.13reported desensitization of a patient by intradermal and intravenous penicillin and then switching to oral phyenoxymethylpenicillin and later dicloxicillin, without allergic sequellae. O’Drisc011~ desensitized nurses allergic to penicillin orally and maintained them on oral penicillin. Brown et a1.18 recently described the case of an 11-yr-old boy with cystic fibrosis and penicillin allergy, who was desensitized to ticarcillin and then maintained on oral phenoxymethylpenicillin. Certain

to penicillin

299

parallels can be noted with the case reported here. The patient’s skin tests were negative for a period of time after desensitization but then reverted to positive while on oral therapy. Unlike the case reported in this article, their patient remained skin-test negative to both the major and minor determinants after a second desensitization. Interestingly, increasing the dose of oral penicillin seemed to increase the threshold for adverse reactions to ticarcillin. Exceeding this threshold was most dramatically illustrated by the occurrence of allergic symptoms when the therapeutic blood level of ticarcillin was increased by probenecid administration. In our case, increasing the dose of phenoxymethylpenicillin from 250 mg b.i.d. to 250 mg t.i.d. was apparently successful in reducing the frequency of intermittent urticarial lesions. This suggests the possibility that the degree of clinical tolerance, and perhaps the extent of cellular desensitization as well, is dose dependent. Such a “dynamic equilibrium” state for cellular desensitization to penicillin was recently postulated by Sullivan” to account for the observed attenuation of largely minor determinant skin-test responses after bolus intravenous penicillin doses in a previously desensitized patient. Despite long-term clinical tolerance of oral penicillin, the skin test to the penicilloyl determinant remains strikingly positive in our patient. This may be possible because the intradermal concentration of PPL administered during skin testing is probably greater than that achieved in vivo by daily oral administration. This observation provides another indication that although a degree of clinical tolerance has been achieved, complete cellular desensitization to penicillin has not resulted. A therapeutic course of higherdose penicillin would therefore need to be given with caution to our patient. Skin testing with both major and minor penicillin determinants confirmed the diagnosis of penicillin hypersensitivity in our patient. Serum penicilloyl IgE by RAST and basophil histamine release were initially nondiagnostic. Although skin testing and RAST results are generally concordant, the latter is less sensitive, as illustrated by this case. A potentially serious error would have resulted in this case if the diagnosis of penicillin allergy had been based solely on the results of penicilloyl RAST testing. At present RAST testing for minor determinant antigens has not been developed. The immunologic indices followed in this patient provide several interesting observations. Skin testing to both PPL and MDM was initially positive and became completely negative during the desensitization process. Three weeks after desensitization, the PPL

300

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J. ALLERGY CLIN. MWNOL. MARCH 1983

et al.

skin test reverted from negative to positive and has remained so to date. By 5 wk the penicilloate minor determinant skin test again became positive but reverted to negative between 3 to 6 mo. All minor determinant skin tests remain negative as of late 1982. The conversion of positive penicillin skin tests to negative during drug desensitization is well documenteds6* 13-13* lR, lg Presumably this reflects lowdose desensitization of tissue mast cells. The return of skin-test reactivity at 3 wk after desensitization could reflect partial recovery of cellular desensitization and/or the intense penicillin-specific immune response that was underway at that time, as evidenced by serologic results. Pencilloyl-specific IgE and IgG antibodies both peaked on postdesensitization day 20. Furthermore, total serum IgE increased by more than 1500 rig/ml between day 8 and day 20. Since only 180 rig/ml of this rise can be accounted for by penicilloyl IgE, the remainder may represent an intense IgE response to minor penicillin determinants. Most of this rise in total IgE had dissipated by day 195, at which time the MDM skin test became negative. It is difficult to explain why the PPL skin test did not revert to negative in parallel with the MDM. On the contrary, an interesting paradox can be seen in Table II. After the peak of the penicilloyl IgE immune response on day 20, there is a rough inverse correlation between circulating penicilloyl IgE antibody and PPL skin reactivity. Skin sensitivity to PPL increased dramatically and then remained more or less stable in the face of progressively declining penicilloyl IgE in serum. This pattern suggests the possibility that mast cell sensitivity to immunologic challenge was continuing to increase over at least the first 60 days after desensitization. If this interpretation is correct, it indicates that skin mast cell reactivity returns gradually over a period of many weeks after the desensitization process. Unfortunately, since this patient did not have another positive immediate-type skin test prior to desensitization, whether the desensitization and return of skin mast cell reactivity was immunologically specific or global in nature could not be delineated. In this regard, SullivanZo recently reported three cases of penicillin desensitization in which skin-test conversion occurred for p-lactam antigens, while other skin-test responses were only minimally diminished, suggesting a form of allergen-specific mast cell desensitization. The pattern of IgG penicilloyl antibody and IgE (total and specific) are in agreement with results in the literature. Kraft et al.*l followed RAST titers to benzylpenicilloyl and total IgE in patients after acute reactions to penicillin. Most patients demonstrated a peak response within 30 days followed by a decline.

In summary, this case illustrates the successfui desensitization of an exquisitely penicillin-sensitive individual. Through 18 mo of observation the patient has remained clinically tolerant to penicillin. No adverse consequences of prolonged antibiotic therapy have been observed in this patient, although gastrointestinal intolerance, superinfection, and the emergence of penicillin resistant bacteria are all possible complications of long-term penicillin therapy. Whether longterm oral penicillin therapy will ultimately achieve permanent desensitization is unknown. The therapeutic regimen employed in this case is not advocated for all skin test-positive, penicillin-allergic individuals. Desensitization to penicillin is not an innocuous procedure; its complications have been recently reviewed3 and include serious potentially lifethreatening allergic reactions. The vast majority of such patients can be managed with alternative drugs? with the occasional use of desensitization for lifethreatening infections. For the rare individual whose sensitivity is so marked that avoidance of symptoms by environmental control cannot be achieved. the above procedure for long-term desensitization maj prove useful.

REFERENCES I

2

3

3

s

h. I. 8.

4.

10.

Brown BC. Price EV. Moore MB Jr: P~nicilloyl-pr,lylysclre a!, an intradermal test of penicillin sensttivity. JAMA 189~599. 1964. Green GR. Rosenblum A: Repon of the penicilllll stud) group-American Academy of Allergy. J AI.LER<;~ CI.IN I~~~WNOL 48:331, 1971, deWeck AL: Drug reactions, irr Samter M, editor: Immunological diseases, ed. 3. Boston. 1978, Little. Brown and Co., p. 432. Cluff L, Caldwell J: Reactions to drugs, 111Maxwcit M. Wintrobe TR et al, editors: Harrison’s principles of internal medicine, ed. 7. New York, 1974, McGraw-Hill Book Co , Inc.. p. 381. Sullivan T, Yecies L. Shatz G, Parker C, Wedner H: Desensitization of patients allergic to penicillin using oraiiy administered p-lactam antibiotics. J ALLERGY CI.IN IMMLWOL 69275. 1982. O’Driscoll BJ: Desensitization of nurses allergic to pemcillin. Br Med J 2:473. 1955. Pedersen-Bjergaard J: Specific hyposensitization ot patients with penicillin allergy. Acta Allergoi 24:333. 1969. Schellenberg RR, Adkinson NF Jr: Measurement ot aholutc amounts of antigen-specific human IgE by a radioaliergosorbent test (RAST) elution technique. J Immunol49:428, 1975, Adkinson NF Jr. Lichtenstein LM: Techniques of asses&g the immune response to drugs, in Bundgaard H, Juul P. Kofod H, editors: Drug design and adverse reactions. Proceedings of the Alfred Benzon Symposium X. New York, 1977. Academic Press, Inc., pp. 123-140. Adkinson NF Jr: Measurement of total serum immumaglobulin E and allergen-specific immunoglobulin E antibody, in Rose

VOLUME 71 NUMBER 3

1 I.

12. 13.

14.

15.

NR, Friedman H, editors: Manual of clinical immunology, ed. 2. Washington, D.C., 1980, American Society for Microbiology, pp. 794-807. Lichtenstein LM, Osler AG: Studies on the mechanisms of hypersensitivity phenomena. IX. Histamine release from human leukocytes by ragweed pollen antigen. J Exp Med 120:507, 1964. Levine BB, Zolov DM: Prediction of penicillin allergy by immunological tests. J ALLERGY 43:231, 1969. Ciraybill JR, Sande MA, Reinarz JA et al: Controlled penicillin anaphylaxis leading to desensitization. South Med J 67:62, 1974. Gillman SA, Korotzer JL, Haddad ZH: Penicillin desensitization: correlation of clinical and immunological events using an in vitro model. Clin Allergy 2:63, 1972. Reisman RE, Rose NR, Witebsky E, Arbesman CE: Penicillin allergy and desensitization. J ALLERGY 33:178, 1962.

Desensitization

to penicillin

301

16. Ganier M, Lieberman P: Infantile agammaglobulinemia and immediate hypersensitivity to penicillin G. JAMA 237: 1852, 1977. 17. O’Donovan WJ, Klorfajn I: Sensitivity to penicillin. Lancet 2:444, 1946. 18. Brown LA, Goldberg ND, Shearer WT: Long-term ticarcillin desensitization by the continuous oral administration of penicillin. J ALLERGY CLIN IMMUNOL 6951, 1982. 19. Fellner MJ, Van Hecke E, Rozan M, Baer RL: Mechanisms of clinical desensitization in urticarial hypersensitivity to penicillin. J ALLERGY 45:55, 1970. 20. Sullivan TJ: Antigen-specific desensitization of patients allergic to penicillin. J ALLERGY CLIN ~MMUNOL69:500, 1982. 21. Kraft D, Roth A, Mischer P et al: Specific and total serum IgE measurements in the diagnosis of penicillin allergy. A long term follow-up study. Clin Allergy 721, 1977.