Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract

Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract Harold S. Nelson, MD, Jennie Lahr, AB, Rosemary Rule, RN, MS, Allen Bock, MD, and Donald Leung, MD, PhD Denver, Colo. Background: Immediate hypersensitivity to peanuts is a frequent cause of anaphylactic reactions and deaths in children and adults. Currently, preventive treatment consists of avoidance, which is difficult because of the widespread and often disguised use of peanuts in the food industry. Methods: Twelve patients with immediate hypersensitivity to ingestion of peanuts were recruited. Half were treated with injections of peanut extract: a maintenance level of tolerance was first achieved by a rush protocol, then maintained with weekly injections for at least 1 year. The other six were untreated control subjects. All patients underwent double-blind, placebo-controlled, oral peanut challenges initially, after approximately 6 weeks, and after 1 year. Results: All treated patients achieved the maintenance dose of 0.5 ml of 1:100 wt/vol peanut extract by the rush injection protocol. All experienced increased tolerance to double-blind, placebo-controlled peanut challenge and decreased sensitivity on titrated skin prick testing with peanut extract, whereas the threshold to oral peanut challenge and cutaneous reactivity to peanut extract were unchanged in the untreated control subjects. Systemic reactions were common in the treated group both during rush immunotherapy and with maintenance injections. Only three patients remained tolerant of the full maintenance dose. The increased tolerance to oral peanut challenge was maintained in the three subjects who received full maintenance doses, but there was partial (n = 2) or complete (n = 1) loss of protection in the patients who required dose reduction because of systemic reactions. Conclusions: Injections of peanut extract increase the tolerance of patients with peanut allergy to oral ingestion of peanuts. Injections result in repeated systemic reactions in most patients, even during maintenance injections. For clinical application of this method of treatment, a modified peanut extract is needed. (J Allergy Clin Immunol 1997;99:744-51.) Key words: lmmunotherapy, food allergy, peanut allergy Immediate hypersensitivity to peanuts is a frequent cause of anaphylactic reactions 1 and deaths 2-4 in children and adults. The threat to the patient is compounded by the tendency for sensitivity to peanuts to persist 5 and for From National Jewish Medical and Research Center, Denver. Supported in part by National Institutes of Health grant RR-00051 and The National Jewish Medical and Research Center Clinical Investigation Committee. Received for publication Aug. 12, 1996; revised Dec. 17, 1996; accepted for publication Dec. 18, 1996. Reprint requests: Harold S. Nelson, MD, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Copyright 9 1997 by Mosby-Year Book, Inc. 0091-6749/97 $5.00 + 0 1/1/80338 744 Abbreviations used ASCU: Adult Special Care Unit DBPCPC: Double-blind, placebo-controlled peanut challenge NJMRC: National Jewish Medical and Research Center RIT: Rush immunotherapy SPT: Skin prick test peanut products to be used widely in the food industry. 3-s Therefore the peanut-sensitive patient may, despite efforts at avoidance, accidentally ingest peanut antigens in unexpected food products. We previously reported our experience in a shortterm double-blind, placebo-controlled study of immunotherapy for treatment of peanut sensitivity. 6 In that study three subjects received rush immunotherapy (RIT) by injection of peanut extract, followed by four weekly maintenance injections. Immunotherapy was shown to result in decreased skin prick test (SPT) reactions to peanut extract and decreased sensitivity to ingestion of peanuts in double-blind, placebo-controlled oral challenges. In this study we have evaluated a larger group of peanut-sensitive subjects for their response to RIT and have extended the duration of maintenance treatment. Six peanut-sensitive subjects were given RIT with up to four hourly injections of peanut extract on consecutive days, followed by at least 1 year of maintenance injections. Efficacy was assessed by results of serial titrated SPTs, by measurements of peanut-specific IgG and IgE antibodies, and by three double-blind, placebo-controlled oral challenges with peanuts conducted before RIT and after 1 month and at least I year of maintenance immunotherapy. At the same time, six patients with similar sensitivity to peanuts served as untreated control subjects, undergoing the same immunologic assessments and oral peanut challenges. METHODS Subjects Twelve adults with a history of immediate hypersensitivity reactions to peanuts were recruited for the study. Six of these subjects were treated with injections of peanut extract; the other six served as untreated control subjects. Allocation to

J ALLERGY CLIN IMMUNOL Nelson et al. 745 VOLUME 99, NUMBER 6, PART 1 TABLE I. Projected RIT schedule Time Dose Day (AM) Concentration (ml) 1 8 1:10,000 wt/vol, 0.05 9 0.10 10 0.20 11 0.40 2 8 1:1,000 wt/vol, 0.05 9 0.10 10 0.15 11 0.20 3 8 0.30 9 0.40 10 0.50 11 1:100 wt/vol. 0.07 4 8 0.10 9 0.15 10 0.20 11 0.30 5 8 0.40 10 0.50 The schedule was modified if systemic reactions occurred; no further injections were given that day, and the initial dose on the following day was that which had resulted in the systemic reaction. active treatment was not random, but rather reflected the subjects' choice. This protocol was approved by the Institutional Review Board at National Jewish Medical and Research Center (NJMRC), and all subjects gave their written consent before entry into this study. Peanut preparations Peanut extract was prepared from equal parts of defatted Spanish, Virginia, and red skin peanuts extracted at 1:10 wt/vol by Bayer Allergy Products (Spokane, Wash.). Peanuts used for oral challenges were from the same lots of defatted peanuts. For oral challenge the defatted peanut mix was placed in capsules, and indistinguishable placebo capsules containing dextrose (USP) were prepared by the Pharmacy Service of the NJMRC. Skin testing Titrated SPTs were performed in duplicate with serial 10-fold dilutions of the stock peanut extract and of another allergen extract to which the subject was sensitive. Negative controls consisted of phenol-saline solution, and positive controls consisted of 1 mg/ml histamine base. Skin tests were performed by pricking through a drop with a solid bore needle. A wheal of 3 mm in diameter was considered a positive response. In the treated subjects, skin tests were performed before and on completion of RIT, after 1 month of weekly maintenance injections, and on completion of maintenance immunotherapy, which was of at least 1 year's duration. Control subjects underwent skin testing on enrollment and again after 6 weeks and 1 year. RIT RIT with peanut extract was administered, when tolerated, according to the schedule given in Table I. However, when systemic reactions occurred, the injections were terminated for the day, and the previous dose was repeated as the first injection at the next session. The starting dose was 0.05 ml of the most TABLE II. Schedule for double-blind, placebocontrolled, oral peanut challenges Dose No. Amount of defatted peanut 1 1 mg 2 5 mg 3 10 mg 4 20 mg 5 50 mg 6 100 mg 7 200 mg 8 500 mg 9 1 gm 10 2 gm 11 4 gm 12 8 gm Most subjects began with the 100 mg dose. However, those with a history of severe reactions began with the 1 mg dose. Doses were administered at 30-minute intervals until the attending physician determined that the patient was experiencing a reaction to the ingested peanuts or until all doses had been administered. On placebo days the same number of glucose-containing capsules was administered at the same intervals. One peanut is equivalent to 432 rag. dilute of the serial 10-fold dilutions of the stock extract, which produced a positive SPT response (wheal >- 3 mm in diameter). The final dose was 0.5 ml of a 1:100 wt/vol dilution of the stock extract. Injections were administered hourly beginning at 8:00 AM in the Adult Special Care Unit (ASCU) of NJMRC. The ASCU is designed to provide careful observation and monitoring for severely ill patients or patients undergoing potentially dangerous treatments or challenges. All injections were administered by a trained intensive care nurse. A physician trained in advanced cardiac life support was in attendance throughout the period of RIT, and a physician trained in advanced trauma life support was available on call in the hospital. Injections were discontinued for the day if a systemic reaction occurred. Subjects could leave the ASCU 1 hour after the last injection for the day or, if a systemic reaction occurred, when all signs of the reaction had subsided. Maintenance immunotherapy Maintenance injections of the final dose attained during RIT were administered weekly for 8 weeks, then an attempt was made to increase the interval by 1 week every 2 months up to once monthly. Maintenance injections were administered in the ASCU by the same nurse who administered RIT. The same requirements for remaining in the unit 1 hour after injections and until all symptoms had subsided after systemic reactions, which were used during RIT, also applied to maintenance injections. Double-blind, placebo-controlled peanut challenges (DBPCPCs) Both actively treated and control subjects underwent three DBPCPCs at the same intervals as the skin testing (i.e., at entry and after 1 month of maintenance injections, or for control subjects, 6 weeks after entry and at the end of participation in the study). Peanut and placebo challenges were performed on separate days within 1 week of each other. The schedule for peanut challenges is listed in Table II. Subjects with a history of anaphylactic peanut reactions (2 actively treated subjects and 1

746 Nelson et al. J ALLERGY CLIN IMMUNOL JUNE 1997 TABLE III. RIT Systemic reactions Treatments Subject Injections to Cutaneous Cutaneous + Epinephrine Inhaled No. maintenance only pulmonary injections bronchodilator 1 63 5 29 39 7 2 30 7 2 3 0 3 36 3 2 3 0 4 23 3 6 5 4 5 35 9 5 7 1 6 21 2 2 2 1 Mean 34.7 4.8 7.7 9.8 2.2 Median 33 4.0 3.5 4.0 1.0 Indicated are number of injections to achieve maintenance, number of systemic reactions manifested by cutaneous symptoms such as urticaria, itching, or angioedema and those accompanied also or solely by lower respiratory signs or symptoms. In the last two columns are the number of treatments with injected epinephrine or inhaled albuterol by nebulizer or MDI given for treatment of the systemic reactions. control subject) began with the l mg dose, whereas those who reported less severe reactions (4 actively treated and 5 control subjects) began with the 100 mg dose. The placebo and the peanut-containing capsules were each administered according to the same schedule on separate days. Challenges were discontinued when the subject had clear-cut symptoms of a reaction (usually characterized by moderately severe abdominal pain). When the challenges were terminated, subjects were given 50 gm of activated charcoal (Actidose; Paddock Labs, Minneapolis, Minn.) to help terminate the reaction. Subjects remained under observation for 2 hours in the absence of a reaction. After reactions, they remained in the unit until all symptoms had subsided and for at least 8 hours afterward as a precaution against a recurrent late reaction. Peanut-specific humoral response Serum was obtained at the same times as the oral peanut challenges were performed. These three serum specimens were analyzed for peanut-specific IgE and IgG by using the Pharmacia CAP system FEIA (Pharmacia Inc., Diagnostics, Columbus, Ohio). For determination of specific IgE, peanut covalently coupled to ImmunoCAP was reacted with a patient's serum. After washing, ~-galactosidase-labeled rabbit anti-ige was added. After incubation and washing, 4-methylumbelliferyl-[3- D-galactoside was added. After the reaction was stopped, the fluorescence was measured, and the amount of specific IgE present in the serum specimen was computed from IgE standards run in parallel. The results were expressed as kilounits per liter. The method for analysis of peanut-specific IgG was similar, except that the [3-galactosidase-labeled anti-igg antibody was of mouse origin and the final fluorescence was compared with an IgO standard. The results were expressed as micrograms per liter. Statistical analysis Peanut-specific IgE and IgG, thresholds on oral peanut challenge, and sensitivity to peanut skin testing were compared between and within subjects by repeated-measures analysis of variance, which included terms for group, time, the group-bytime interaction, and a random effect for subjects within groups. Individual linear contrasts were performed on simple effects between and within groups if the group-by-time interaction was significant at the 0.05 level. IgE, IgG, and results of oral challenges were transformed by taking the log 10 before analysis, and summary statistics for these variables are the geometric mean and geometric standard error and the lower and upper 95% confidence limits about the geometric mean. Skin test results are summarized as the mean and standard error. In addition, skin test results for each antigen and follow-up time were reduced to a dichotomy, increase versus decrease or no change compared with baseline, and the percents increasing from baseline were compared between study groups by Fisher's exact test. All results are reported by using two-tailed tests of significance with actual p values. All statistical analyses were performed in JMP version 3.1.5 (SAS Institute, Cary, N.C.). RESULTS Patient demographics There were four male and two female subjects in each group. The ages of the active treatment patients ranged from 18 to 56 years, and the ages of the control subjects ranged from 33 to 46 years. Ten of the 12 participants were in their forth or fifth decade of life. All 12 subjects dated the onset of peanut allergy to infancy or early childhood. All members of the active treatment group had experienced cutaneous and pulmonary symptoms on ingestion of peanuts; and one had, in addition, experienced hypotension. One control subject had experienced cutaneous and gastrointestinal symptoms; four reported cutaneous and lower respiratory tract symptoms; and one reported urticaria, throat swelling, and hypotension. The control group had less often made emergency department visits for treatment of their peanut reactions than the active treatment group. Three subjects in the control group had made no visits to emergency departments, and three had gone once. Only one subject in the active treatment group reported no emergency department visits; one had made a single visit; and one each had made 33, 5, "5 to 10," and "about 15" emergency department visits. NIT The median number of injections required to reach maintenance immunotherapy was 33, and the median number of systemic reactions was 9 (Table III). One subject, however, required 63 injections to reach the

J ALLERGY CLIN IMMUNOL Nelson et al. 747 VOLUME 99, NUMBER 6, PART 1 TABLE IV. Maintenance immunotherapy Systemic reactions Treatments Subject Injections to Cutaneous Cutaneous + Epinephrine Inhaled Dose Final No. maintenance only pulmonary injections bronchodilator (ml} concentration 1 43 0 30 30 11 0.1 1:1000 2 43 0 18 7 6 0.5 1:100 3 36 0 13 16 11 0.5 1:100 4 34 7 7 5 4 0.1 1:100 5 32 11 5 18 0 0.3 1:1000 6 21 0 3 0 0 0.5 1:100 Listed from left to right are number of maintenance injections that each subject received, number of systemic reactions manifested only by cutaneous symptoms such as itching, urticaria, or angioedema and number with lower respiratory signs or symptoms, with or without cutaneous manifestations, number of treatments with injected epinephrine or inhaled albuterol either by nebulizer or metered-dose inhaler, and finally the dose and concentration of peanut extract that the subject was receiving at the end of participation in the study. projected dose of 0.5 ml of 100 wt/vol peanut extract and experienced 34 systemic reactions. Most of the systemic reactions were treated with epinephrine. A few reactions were quite mild, and the subjects chose not to receive treatment; however, some included symptomatic bronchoconstriction, and subjects were treated with inhaled bronchodilators administered by metered-dose inhaler or nebulization. As an indication of the degree of severity of these reactions, it should be noted that no reaction was associated with a fall in blood pressure, none was accompanied by gastrointestinal symptoms or apparent laryngeal edema, and repeat treatment to reverse the reaction was required only eight times (5 of these in Subject 1). Only once were more than two treatments required. All six subjects received and tolerated the maximum projected dose of 0.5 ml of 1:100 wt/vol peanut extract, Maintenance immu notherapy The projected maintenance schedule called for weekly injections of the final RIT dose for 8 weeks, then gradual prolongation of the interval between injections to a maximum of 1 month. For most patients this schedule could not be followed (Table IV). In two patients (subjects 2 and 3) irregularity in attendance for maintenance immunotherapy resulted in the dose rising and falling, and the period over which maintenance injections were given was extended to 18 months (subject 3) and 24 months (subject 2). Three other subjects (subjects 1.4, and 5) were unable to tolerate as maintenance the maximum dose achieved during RIT because they had systemic reactions even though the injections were continued on a weekly schedule. This resulted in a gradual decrease in the dose these subjects received, and in two subjects it resulted in a final dose that was less than one tenth that achieved during RIT. Only one subject continued on the proposed schedule of monthly maintenance injections. Systemic reactions occurred during maintenance immunotherapy with the same or even greater frequency than they had during RIT. The subjects experienced a median of 13.5 reactions to 35 injections for a systemic reaction rate of 39% compared with 23% during RIT. Although these reactions were not accompanied by hypotension, gastrointestinal symptoms, or signs of laryngeal edema, they prevented increase of the interval between injections to the projected 4 weeks and transfer of the maintenance injection therapy to the outpatient clinic. In half of the individuals they prevented continued maintenance injections at the level that had been attained during the rush protocol. Systemic reactions were usually responsive to a single injection of epinephrine or a bronchodilator treatment; however, repeat epinephrine and/or inhaled 13-agonist treatment was required for 17 of the 103 systemic reactions. Oral challenge with peanut All placebo challenges proceeded through the full schedule of doses without occurrence of symptoms. suggesting an allergic reaction. Results of all peanut challenges were positive, with the reaction characterized by onset of cramping abdominal pain. As soon as the presence of an allergic reaction to peanut was recognized, activated charcoal was administered by mouth to reduce further absorption. A few patients experienced flushing or a few urticarial lesions. No subject experienced generalized urticaria, angioedema, bronchoconstriction, or hypotension. At the time of enrollment, the active treatment and control groups did not differ significantly in sensitivity to oral challenge with peanut (p - 0.89). All six of the subjects who received injections of peanut extract showed decreased sensitivity I month after the rush injections (p - 0.0002) (Fig. 1). Subsequently, three of these six subjects were unable to tolerate injections of the highest dose of peanut extract achieved during RIT and required reductions of 80% to over 90% in the injected dose. even though they returned to weekly injections. In two of these three subjects, there was partial loss of the increase in tolerance to peanut ingestion; whereas in the third patient, peanut sensitivity returned to the original level (Fig. 1). In the three patients who continued to tolerate the maximum rejected dose achieved during RIT. there was no decrease

748 Nelson et al. J ALLERGY CLIN IMMUNOL JUNE 1997 "-'o~ 8000 I I l II r l l '9,~ 4o0o t [[ [ [lll It [ ='~176176 I ill llj LIII III!1 L= r" I- 1 2 3 4 5 6 Active Treatment 9 Reduced Maintenance Dose Baseline [] 1 Month [].0002" 12 Months [],007* *Compared To Baseline 2500 A E o 0 if) e- l- 2000 1500 1000 500 0 1 3 4 Controls 5 6 Baseline [] 1Month [] NS* 12 Months [] N S* *Compared To Baseline FIG. 1. Double-blind oral peanut challenges. Graphs compare threshold doses of dried peanuts that produced symptoms in double-blind, placebo-controlled challenges. Upper graph shows results in subjects who received active treatment. For each patient threshold dose at baseline, dose after 1 month of maintenance, and dose after 12 months of maintenance are presented. Diamonds over the final column indicate those subjects (n = 3) who were unable to tolerate the full maintenance dose of peanut extract, Lower graph presents data from the control group in s similar format. in tolerance to oral ingestion of peanut during the course of the year or more of participation in the study (Fig. 1), and they remained less sensitive on skin testing with peanut extract. At the end of 1 year of maintenance injections, the active treatment group remained less reactive to oral peanut challenge than at baseline (p = 0.007). In the control group there was no consistent or significant change in the sensitivity to orally ingested peanut: one subject became slightly less sensitive, and three became slightly more sensitive. Cutaneous reactivity Skin test reactivity to peanut did not differ between active treatment and control groups at baseline (Fig. 2). RIT with peanut extract resulted in a reduction of skin reactivity to peanut extract in all patients (Fig. 2). One month after RIT, the degree of reduction in the endpoint sensitivity varied from I to 3 log-ten dilutions (p = 0.0009). During the ensuing 11 or more months of maintenance immunotherapy, there was a partial return to the original level of skin sensitivity to peanut extract

J ALLERGY CLIN IMMUNOL Nelson et al. 749 VOLUME 99, NUMBER 6, PART 1 Active Patients Baseline 1 Month 12 Months 0-1 -2 9149 9-3 9 9 9-4 9 9-5 9 A baseline.0009 NS 9 patients with reduced maintenance dose Control Patients 0-1 -2 9-3 -4 9149149-5 9149 A baseline NS NS FIG, 2. Results of titrated SPTs with peanut extract. Reactivity is expressed as dilution of peanut extract that produced the same size reaction at each time interval for the same subject (1 month indicates 1 month after completion of RIT for active patients but 6 weeks after baseline for control subjects). In most instances the threshold wheal size was 3 mm mean diameter. Dilutions are expressed as the negative log (1:10 wt/vol designated as -1 and 1:100 wt/vol designated -2, etc.). Level of significance for the change from baseline is given at the bottom of each column, his, Not significant. in four of the six patients, and the final skin sensitivity for the treated group at 1 year did not differ significantly from baseline (Fig. 2). In three of the four subjects who had a return toward baseline skin reactivity to peanut, this was accompanied by and probably resulted from a reduction in the injected dose of peanut extract because of the occurrence of repeated systemic reactions to the injections. There was no overall change in cutaneous sensitivity to peanut extract in the control subjects (Fig. 2). The subjects who received immunotherapy with peanut extract did not experience any overall change in their sensitivity to the other allergen extracts (cat, grass, timothy, ragweed, or Kochia) for which they did not receive immunotherapy. Five of six control subjects became less sensitive to the unrelated allergen, but this was not significantly different from the active treatment group. Peanut-specific IgE and IgG Serum specimens were available from all subjects before the initial peanut challenge (baseline) and at the end of participation in the study (final). Specimens were available for five actively treated subjects from 1 month after completion of RIT and for six control subjects at corresponding times, 6 weeks after their initial oral peanut challenge (midpoint). The levels of peanutspecific IgG did not change significantly in the control group over time. Geometric means with 95% confidence intervals for the three testing intervals were: 9.9 (4.8,20.3), 9.6 (4.9,18.9), and 9.5 (4.1,21.9) I~g/L. In the active treatment group, on the other hand, the geometric mean increased almost eightfold (p < 0.0001) and remained almost fivefold above baseline at the end of 1 year (p < 0.0001). Geometric means and 95% confidence intervals were: 16.3 (8.6,31.1), 125.0 (62.4,250.6), and 75.2 (43.0,131.6) ixg/l. Serum peanut-specific IgE did not change significantly over time in either group. Geometric means and 95% confidence intervals for the control group were: 9.48 (1.1,81.1), 8.23 (1.0,67.8), and 8.43 (1.1,65.8) ku/l. In the active treatment group the levels at the corresponding times were: 28.9 (11.4,73.5), 44.89 (21.1,95.3), and 23.9 (9.4,60.9) ku/l. DISCUSSION Peanuts are a common cause of anaphylactic reactions to ingestion of food. In a review of 266 children and adults evaluated for anaphylaxis in university-affiliated private allergy-immunology practices over a period of 50 months, 89 anaphylactic reactions were believed to be caused by ingestion of food, and peanuts were responsible for 20 cases (exceeded only by 26 cases caused by various crustaceans), l Furthermore, peanuts are the most common cause of fatal anaphylactic reactions to foods.3, 4 Inadvertent ingestion of peanuts was responsible for three of six fatal anaphylactic reactions in children 3 and four of seven fatal reactions, which occurred in children and adults. 4 All of the individuals experiencing fatal reactions to peanuts were aware of their sensitivity because of previous reactions. Nevertheless, they inadvertently ingested peanuts in food preparations

750 Nelson et al. J ALLERGY CLIN IMMUNOL JUNE 1997 such as cupcakes, cookies, sandwiches, candy, cake, and even chili. Peanut exposure is common in infancy and early childhood. 7 It has been estimated that up to 10% of atopic patients may be allergic to peanuts. 7 Furthermore, once sensitized, individuals tend to remain sensitized indefinitely. 5 A long-term follow-up study of 32 children with challenge-proven peanut sensitivity revealed that 24 had accidentally ingested peanut 2 to 12 years afterward, and all had experienced recurrent reactions, s The recommended treatment for individuals with known anaphylactic sensitivity to peanuts is avoidance and use of injected epinephrine as soon as they become aware of an inadvertent ingestion. However, as noted above, avoidance of accidental ingestion is difficult when eating away from home, and many persons with known peanut sensitivity do not routinely carry epinephrine with them. 3, 4 Therefore an improved treatment is needed for anaphylactic sensitivity to peanuts and other foods. We have previously reported that injection of peanut extract reduces skin test reactivity to peanut and increases the tolerance to peanut ingested in double-blind oral challenges. 6 In this controlled study we have confirmed the previous findings in a larger number of subjects. We have also followed up these patients for periods of at last 1 year to determine the long-term efficacy of peanut immunotherapy. We found that, unlike immunotherapy with pollen extracts, maintenance immunotherapy with peanut extract was accompanied by as high a rate of systemic reactions as was the rush protocol. For this reason we were unable to maintain half the subjects at the dosage of peanut extract that we had achieved during RIT. With this reduction in maintenance dose, there was also partial or complete loss of the increased tolerance to oral peanut challenge, which had been achieved during RIT. However, the treated group as a whole tolerated significantly higher doses of peanut at the end of the year of maintenance injections as compared with their baseline and an untreated control group who did not receive RIT. The average dose of peanut required to produce a reaction increased from 2092 mg to 6810 mg in the treated group. The most sensitive subject in the treated group (who had a history of 33 emergency department visits after inadvertent peanut ingestion) initially reacted to 16 mg or one twenty-seventh of a peanut. After RIT, his threshold increased to 7888 mg, or 18.3 peanuts. By the end of the study, despite a reduction in maintenance dose of peanut extract because of systemic reactions, his threshold to oral peanut challenge was still increased at 385 mg of peanut allergen. The clinical significance of this increased tolerance is uncertain; however, several months after the completion of his participation in the study, he again experienced an inadvertent peanut ingestion, which he recognized and treated with epinephrine, and proceeded to a hospital emergency department. Symptoms subsided, and no further treatment was required. It is impossible to know whether this reaction was less severe because of his year of injection therapy. No other patient experienced unintentional peanut exposure during or shortly after participation in the study. In our previous study we treated three peanut-sensitive subjects, using a protocol similar to that used in this study. RIT was followed by four weekly maintenance injections of peanut extract. The efficacy parameters were the same: reduction in sensitivity to peanuts as determined by results of titrated SPTs and DBPCPCs. In that study we observed a 2 log decrease in cutaneous sensitivity to peanut extract in two patients and a 5 log-ten reduction in one. On DBPCPC the threshold dose for one subject increased from 1 gm to 8 gin, whereas for the other two subjects there was a marked reduction in symptoms occurring after ingestion of the 8 gm dose. No significant changes occurred in SPT threshold in three placebo-treated subjects, nor was there a change in the reaction to ingested peanuts in the one subject who had a repeat oral challenge. This study confirms and extends these preliminary observations. RIT with peanut extract significantly reduced sensitivity to peanuts assessed by titrated SPTs and DBPCPCs. In subjects who were able to tolerate this same dose of peanut extract by maintenance injection, the reduced sensitivity to peanut by oral challenge was maintained. In three subjects, in whom the dose of injected peanut extract was reduced because of the occurrence of repeated systemic reactions, reduced sensitivity to oral peanut challenge was partially maintained in two, although not to the same degree as it was at i month after RIT. Thus five of six subjects and the group as a whole had increased tolerance to ingested peanuts at the end of 1 year of maintenance injections. This can be contrasted to the results in the untreated control group who, after 1 year, demonstrated no overall change in peanut sensitivity. Indeed, in the control group one subject was less sensitive, and two showed unchanged sensitivity, but three showed increased sensitivity to peanuts. It is of interest that the SPT responses to peanuts, initially significantly reduced, were not significantly different from baseline by the end of a year of maintenance treatment. Serum peanut-specific IgG, on the other hand, more closely mirrored the results of oral challenges, being significantly increased after 1 month of maintenance injections and less, but still significantly elevated, after 1 year of treatment. In conclusion, we have clearly demonstrated that injection of peanut extract significantly increases the tolerance of anaphylactically sensitive subjects to the ingestion of peanut proteins. The degree of change that is induced by the course of RIT with peanut extract is clinically relevant. Unfortunately, in half the subjects, particularly those who were most sensitive, this dose of injected extract and degree of induced tolerance could not be maintained because of repeated systemic reactions to the injections. This high rate of systemic reactions makes this form of treatment with the currently available peanut extracts unacceptable. What is required for peanut immunotherapy to become a clinically applicable treatment is a modified peanut extract that will

J ALLERGY CLIN IMMUNOL Nelson et al. 751 VOLUME 99, NUMBER 6, PART 1 produce the desired immunologic response without the high incidence of systemic reactions. Nevertheless, this study demonstrates, for the first time in a controlled protocol, that long-term maintenance immunotherapy may be effective in the treatment of patients with peanut allergy and provides hope that advances in treatment of this potentially life-threatening illness can be made. We thank David Ik16, PhD, for performing the statistical analyses. REFERENCES 1. Kemp SF, Lockey RF, Wolf BL, Lieberman P. Anaphylaxis. A review of 266 cases. Arch Intern Med 1995;155:1749-54. 2, Settipane GA. Anaphylactic deaths in asthmatic patients. Allergy Proc 1989;10:271-4. 3. Yunginger JW, Sweeney KG, Sturner WQ, Glannandrea LA, Teigland JD, Bray M, et al. Fatal food-induced anaphylaxis. JAMA 1988;260:1450-2. 4. Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med 1992;327:380-4. 5. Bock SA, Atkins FM. The natural history of peanut allergy. J Allergy Clin Immunol 1989;83:900-4. 6. Oppenheimer J J, Nelson HS, Bock SA, Christensen F, Leung DYM. Treatment of peanut allergy with rush immunotherapy. J Allergy Clin Immunol 1992;90:256-62. 7. Sachs MI, Yunginger JW. Food-induced anaphylaxis. Immunol Allergy Clin North Am 1991;11:743-55. Bound volumes available to subscribers Bound volumes of The Journal of Allergy and Clinical Immunology are available to subscribers (only) for the 1997 issues from the Publisher, at a cost of $88.50 for domestic, $116.10 for Canadian, and $108.50 for international subscribers for Vol. 99 (January-June) and Vol. 100 (July-December). Shipping charges are included. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby-Year Book, Inc., Subscription Services, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318; phone 1 (800) 453-4351 or (314) 453-4351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.