Paul M. Maurialb, M.D., Susan H. Bards, M.D., John W. Gaorgitis, M.D.,* and Robert E. Raisman, M.D. Buffalo, N. Y.

In ongoing sfudirs of’ the nuturul history of’stinging-insec,t allergy, /32 purients lcith large locwl reactions hatIe hec>tl wcrluated OWI 8 y,-; 79 prrtimr.\ rc~tumed jbr reevaluatiort Based on RAST analysis with honeybee und vespid venoms. patient.s wow divided into RAST--poaitiw und RAST-negative groups. Sisg-.six patients were RAST --negati\,e with positive !wom skin tests in iBc/c. Seventy-jive restings in this group led lo no systemic, reactions and 74 large local reactions. Af ji,llowup RASTs remuined negczticr, c/rid rhe inc~idencc of positive skin tests was wwhanged. Sixty-seven patients had detec,tahlc .serum venom-specific IgE co\‘t,ring a wide range III antibody titers, itldistinguishuble from patients with systemic reactions. Twentyfour of 67 patientA received wnom immunotherapy (VIT). RAST titers rlec~reuscd similoriy in the VIT and untreated gr0up.s. There were IS restings resulting in 40 recurrent iurge local reactions oc~curring in equal incidence in treuted and untreated patients. One .swtemic r-euction occurred in an untreated patient. in rrGwinp I 18 patients \,xith sting trnaph~luxsis. a previous large local reaction ocwrred in jive. These results .tuggest that after r-epeut stings. patirntJ \j$h large local reaction> tend to hove subsequent large locul rrtrctions, regurdlass of the presence of venom-specific IgE or immunotherapy. There is smuil risk of anuphyluris. Determinution oj .serum venom-specijc IgE by RAST or skin tests does not uid in treattnent or in predicting prognosis. Thus skin test,s ure not necessu~ in putients who have had large (ocnl reuctions, and wfio~n immunotherupy is not indicated. i J iZLLERGY Ci.lfG IMMUNOL 74.494-8. 1984 .)

Large local reactions after Hymenoptera stings are quite common, often resulting in considerable mor- bidity because of pain and swelling. In the absence of associated systemic symptoms, therapy for such local reactions is confined to symptomatic treatment, and prophylactic immunotherapy is not recommended.

There have been conflicting opinions regarding the importance of large local reactions as an indicator of the development of subsequent systemic sensitivity. Earlier reports in the literature have suggested that after large local reactions, between 10% and 4OYo of

I-ram the Allergy Research Laboratory, Buffalo General Hospital. State University of New York at Buffalo, Buffalo, N. Y.

Supported in part by National Institutes of Health-National Institute of’ Allergy and Infectious Diseases grant 5 ROl AI 14501.

Presented in part at the Thirty-ninth Annual Meeting of the AmerG can Academy of Allergy and Immunology, March 1983.

Received for publication Aug. 4. 19X3. Accepted for publication March 13, 1984. Reprint requests: Robert E. Reisman. M.D.. 50 High St., Buffalo.

NY 14203. “Henry and Bertha Buswell Research Fellow, SUNY/Buffalo

School of Medicine.

4!34

individuals may have systemic reactions after the next sting experience. ‘. ’ In our initial studies of this prob- lem, patients were evaluated shortly after a large local sting reaction.‘! Approximately half of the patients were found to have serum venom-specific IgE. In this article, we report the follow-up resting experience of individuals who have had large local reactions. A small group of these patients received specific venom immunotherapy. These observations suggest that pa- tients with large local reactions from insect stings, when they are restung, are likely to have recurrent large local reactions with small risk of systemic ana- phylaxis, regardless of the presence of venom-specific 1gE or venom immunotherapy.

MATERIAL AND METHODS Patients

Between 1976 and 1982, 133 patients were observed at the Allergy Research Division of the SUNY/Buffalo for evaluation of large local reactions to an insect sting. A large local reaction is defined as a reaction with swelling and erythema, contiguous with the sting site, peaking at 48 to 72 hr and often lasting as long as 1 wk. For this study, patients with any systemic symptoms, such as u&aria and respira-

VOLUME 74 NUMBER 4, PART 1

Natural history of large local reactions 495

tory distress and/or hypotension, were excluded. At the initial evaluation, a detailed history was obtained, including specifics of the size, duration and site of the reaction, iden- tification of the culprit insect if possible, previous sting experience, and concomitant allergic problems. Serum was obtained for analysis of venom-specific IgE, and intrader- ma1 testing was carried out with the various insect venoms.

Follow-up information was obtained from 4 to 100 mo (mean 36) after the initial evaluation (Table I). At that time a detailed history of resting experience was obtained in the same manner as was done initially. Skin tests were re- peated, and serum was obtained for analysis of serum venom-speciftc IgE. For comparison RAST analysis with sequential serum specimens was done at the same time. In RAST-negative patients, resting data were considered both prospectively and retrospectively from the time of the initial visit.

To ascertam the frequency with which large local reac- tions precede systemic allergic reactions from insect stings in our own experience, the histories of 118 patients with sting anaphylaxis were reviewed.

Immunologic evaluation

Skin fesfs. Honeybee, yellow jacket, and hornet venoms were collected locally by electrical stimulation,” and Polistes venom-sac extract was obtained commercially. Intradermal tests were done with venom concentrations ranging from 0.0001 pg to 1 pg/ml. Reactions of 2+ or more at 0.01 &ml or less were considered to be sig- nificant. In our experience 25% of nonallergic individuals have demonstrated positive reactions to venom concentra- tions of 1 .O pg/ml and 5% to 10% of nonallergic individu- als react to 0.1 kg/ml.

RAST. RAST was performed as previously described with some modifications.” Specific IgE antibodies to hon- eybee, bald-faced hornet, yellow jacket, and wasp venoms were measured. Ten micrograms of each dialyzed vespid venom protein and 100 Fg of honeybee venom protein were coupled per disc. In preliminary experiments these concen- trations of venom produced maximal binding of racliola- beled antisera. Results were expressed in percent of net binding of a serum pool from ragweed-sensitive patients to ragweed discs. A net binding to the discs of >5% was regarded as significant. The binding of the ragweed standard varied between 11.5% and 12.8% of the total activity added. The background activity, when normal human serum (NHS) was assayed, was 0.7% for the ragweed discs and varied between 0.8% and 1.4% of the total activity added for the venom discs. Average percent of binding was calcu- lated from the following formula:

Avg percent of binding = avg cpm patient serum - avg cpm NHS x 1oo

total specific cpm added

RESULTS

Patients were divided into two groups on the basis of the presence of serum venom-specific IgE by

TABLE 1. Characteristics of 133 patients with large local reactions

RAST-positive RAST-negative

No. of patient 67 66

Age 34 (8 to 78)* 36 (2 to 80)* Atopic 26% 29% Time between last 3.6 (<I to 12)* 5.4 (<I to 48)*

large local reaction and evaluation (mo)

Follow-up (mo) 36 (4 to lOO)* 29 (9 to 61)*

Patients were divided on the basis of the presence of serum venom- specific 1gE.

*Mean range in parentheses.

RAST analysis at their initial evaluation. Sixty-seven patients had serum venom-specific IgE reacting with one or more insect venoms (RAST positive) and 66 patients had undetectable serum venom-specific IgE (RAST negative). The two groups were comparable with regard to age, sex, and presence of atopy (Table I). There were no differences in size and duration of the sting reaction or site of the sting. The initial evaluation was done at a similar time interval after the most recent large local reaction (mean 4.5 mo). Follow-up evaluation in 79 patients was obtained at a comparable period of time. Extensive efforts were made to contact the remaining patients but were un- successful.

Data for the RAST-negative group were analyzed both prospectively and retrospectively. In this group of 66 patients, 49 insect stings had occurred in 28 subjects before the sting leading to their initial evalu- ation. In this retrospective analysis, all of these prior stings had caused large local reactions. Therefore, the total number of restings in this group consisted of 28 leading to evaluation and 21 previous stings.

Thirty-three patients were observed for follow-up 9 to 61 mo after their initial visit (mean 29 mo). Twenty-six subsequent restings occurred in 10 pa- tients resulting in 2.5 large local reactions. The RAST remained negative in all 10 of the patients restung observed prospectively. There was no change in the percentage of patients with positive skin tests. In total then, there were 74 large local reactions and no sys- temic reactions in these patients with resting episodes.

In the RAST-positive group, follow-up informa- tion including repeat skin tests and RAST was avail- able in all 24 patients who had received venom im- munotherapy and in 22 of the 43 patients who had not received therapy. The follow-up interval ranged from 4 to 100 mo with an average of 36 mo. Restings in

496 Mauriello et al J ALLERGY CLIN. IMMUNOL. OCTOBER 1984

TABLE il. Follow-up resting data --

Resting data

P8tf8nt group Initial no. of NO. of patients No. of resting5 Large bcal Systemic

patiits eveluet8d (no. of patients) reactions reactions

RAST-negative Retrospective data Prospective data

RAST-positive Immunotherapy No therapy

Total

66 hh 49 (28) 49 ( 100%) 33 26 ( 10) 2s (96%) 0

h7 14 24 31 (14) 23 (74%) 0

43 22 24 (IX) -I 17 (70%) I -133 130 (70) 114 (88%) I

this RAST-positive group were considered only pm- spectively. There were 55 restings resulting in 40 large local and one systemic reaction. Venom immu- notherapy did not influence the frequency of large local reactions (Table II). The one systemic reaction was accompanied by a large local reaction and oc- curred in a patient who had not received venom im- munotherapy .

In total, there were 130 restings resulting in 114 large local and one systemic reaction. Although the identity of the resting insect could not always be made with certainty, most patients believed the culprit to be the same as that causing the initial reaction.

Of the 66 patients without serum antibodies at ini- tial evaluation, 58% had positive skin tests to one or more venoms (0.01 to 0.0001 pgimi). All patients who had demonstrable serum antibodies had positive skin tests. Thus 80% of the total patients had a posi- tive skin test with one of the venoms. Among the patients who had demonstrable venom-specific IgE, half reacted to yellow jacket venom and half to hon- eybee venom. Titers ranged from 10% to 150% of a positive standard (Fig. 1). Fourteen patients had dual yellow jacket-and bee-venom sensitivity.

Patients reacting with vespid venoms all reacted with yellow jacket venom, usually with the highest RAST titer. Reactions with hornet and wasp venoms were less intense and less frequent.

At the time of follow-up, patients with initially positive RASTs had a decrease in IgE antibody titers, which was independent of venom immunotherapy. In 23 untreated patients, RASTs decreased in 20, reach- ing insignificant levels in 13 (~5% STD). In the 24 patients treated with venom immunotherapy, IgE antibody titers decreased in 12, five of which fell to insignificant levels (Fig. 2).

Of 1 IX patients evaluated for systemic allergic reactions to stinging insects, five patients had a his- tory of a previous large local reaction.

DISCUSSEON

The results of this study indicate that patients who have had large local reactions after insect stings con- tinue to have similar reactions with subsequent stings. Over an 8-year period, 133 patients with large local reactions were evaluated. Follow-up information was obtained in 79 of these patients at an average time of 3 yr after their local reactions. With the use of prospec- tive and retrospective information, there were 130 re- stings, most causing repeat large local reactions. Only one of the patients had a subsequent systemic reac- tion. In the 54 patients in whom follow-up informa- tion was not available, it may be presumed that a subsequent systemic reaction would most likely have led to a repeat consultation. In this study the incidence of a systemic reaction, after a large local reaction, was very low (li 130% to 0.77%). As some of the repeat stings might have been from other stinging in- sects to which the patient was not sensitive, the actual incidence may be slightly higher.

Other studies of patients with large local sting reactions have found a somewhat higher incidence of subsequent systemic reactions. Graft et a1.6 found two systemic reactions after 64 restings in 32 children. Albrecht et al.’ reported 59 systemic reactions after 177 resting episodes, a reaction rate of 33%. Only a small portion of these were life-threatening, and these authors concluded that there was a 5% chance of a severe reaction after a large local reaction.

In our initial studies, patients were separated into RAST-positive and RAST-negative groups to eval- uate the role of venom-specific IgE in possibly pre- dicting those patients at risk for a generalized reac- tion.” In this present study that extends the number of patients, the incidence of serum venom-specific IgE was about the same, approximately 50%. Venom skin tests were positive in a substantial number of RAST- negative patients, and, in total, skin tests were posi- tive in 80% of the patients. This is the same incidence

VOLUME 74 NUMBER 4, PART 1

Natural history of large local reactions 497

E *O t am

m -e L E 0.0 3; 60. 0 8 0.0. j5j

0.0 40. 0.0.

oz 0.0. 0.0 0.0

20- .*.. 10 ------t,‘,,

i 0

00 00

0.0 0.0. 0.0.

0.00.. l oooooo

0.00.. 0.0..

------------.--

0’ J Honeybee Yellow Jacket

FIG. 1. Titers of serum honeybee and yellow jacket venom-specific IgE in the 67 RAST-positive patients at the time of the initial evaluation. Fourteen patients had antibodies reacting with both venoms. RAST titers are expressed in percent of a positive standard.

of positive skin tests found in two other studies of patients with large local reactions.“. i

The presence of serum venom-specific IgE did not influence the outcome of restings. The one systemic reaction did occur in a RAST-positive patient, but almost all of these patients continued to have large local reactions.

Ten RAST-negative subjects had one or more interval stings without the subsequent development of venom-specific IgE. These data suggest that individ- uals who did not produce venom-specific IgE after a large local sting reaction are unlikely to do so after subsequent restings. For this reason retrospective sting experience in RAST-negative subjects was in- cluded in the data analysis.

Twenty-four patients had received venom therapy according to our own dosing regimen.8 Therapy was initiated several years ago when risk factors in pa- tients with local reactions with subsequent restings were not known. These patients all had had large local reactions and had had elevated titers of venom- specific IgE. The results of this current analysis sug- gest that venom immunotherapy did not affect the frequency or severity of subsequent large local reac- tions. However, there are bther observations that sug- gest that venom immunotherapy could be helpful to patients with large local reactions. Beekeepers often develop large local reactions early in the spring when

60 No Treatment

_I 50 60

Immunotherapy

0 htial 10 Evoluotion

FIG. 2. Fall in titers of serum venom-specific IgE in 22 patients receiving venom immunotherapy and in 19 pa- tients not receiving immunotherapy.

they are first exposed to bee stings. With increasing stings, large local reactions decrease in size.g Second, j.n patients receiving specific venom immunotherapy, large local reactions often occur in doses of 10 to 30 pg. As dosing is increased toward maintenance, these reactions tend to disappear.‘O

The relationship of large local and subsequent sys- temic reactions also was addressed by revnewing the histories of 118 patients observed consecutively for evaluation of insect-sting anaphylaxis. All had previ- <ous sting exposure with only five patients having had a large local reaction. This incidence of large local reactions preceding systemic reactions is lower than that reported in earlier studies’. ’ and, most recently, by Albrecht et al.7 In this latter study of 277 patients with systemic reactions, 59 reported a previous large local reaction (about 22%).

Several mechanisms for the development of large local reactions have been postulated. Although IgE antibodies have been incriminated, our data suggest

other mechanisms may be operable. As noted, about half of our patients did not have detectable serum venom-specific IgE, and at least 20% had no antibody detected by skin tests or RAST. Case et al.” measured

438 Maurielio et al. J. ALLERGY CLIN. IMMUNOL. OCTOBER 1984

venom-induced lymphocyte-stimulation responses in patients who had large local reactions. Five of six patients had increased lymphocyte stimulation when these patients were compared to patients who had had systemic reactions and to noninsect-allergic indi- viduals. These data suggest that cellular processes may be an important part of the etiology of large local reactions. Venom also has many pharmacologic com- ponents capable of mediator local inflammation. These include vasoactive amines, acid phosphatase, hyaluronidase, and phospholipase. Individual re- sponses to the pharmacologic action of these compo- nents may be responsible for tissue inflammation in large local reactions.

These data suggest several conclusions. Patients with large local reactions have a tendency to have recurrent large local reactions when they are restung, with small risk of systemic anaphylaxis. Determina- tion of serum venom-specific IgE by RAST or skin tests does not aid in treatment or in predicting prog- nosis. Thus skin tests are not necessary in patients who have had large local reactions, and venom im- munotherapy is not indicated.

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Intern Med 125665. 1980

2. Insect Allergy Committee Report. Milwaukee, 1972, Ameri- can Academy of Allergy (unpublished)

3. Green AW, Reisman RE, Arbesman CE: Clinical and immu- nologic studies of patients with large local reactions following insect stings. J ALLERGY CLIN IMMUNOL 66: 186, 1980

4. E&ridge EM, Elliott WB, Elliott AH, Eskridge PB, Doerr JC, Schneller N, Reisman RE: Adaptation of the electrical stimu- lation procedure for the collection of vespid venoms. Toxicon 19:893, 1981

5. Light WC, Reisman RE, Rosario NA, Arbesman CE: Com- parison of allergenic properties of bee venom and whole bee body extract. Clin Allergy 6:293, 1976

6. Graft DE, Schuberth KC, Kagey-Sobotka A, Kwiterovich KA. Lichtenstein LM, Valentine MD: Large local reactions follow- ing Hymenoptera stings in children. J ALLERGY CLIN IMMU-

NOL 69:124, 1983 fabst) 7. Albrecht I, Eichler G, Miiller U, Hoigne R: On the significance

of severe local reactions to Hymenoptera stings. Clin Allergy lo:675 1980

8. Clayton WF, Reisman RE. Miiller U. Arbesman CE: Modified rapid venom desensitization. Clin Allergy 13: 123, 1983

9. Light WC, Reisman RE, Wypych JI, Arbesman CE: Clinical and immunological studies of beekeepers. Clin Allergy 5:389. 1975

10. Golden DBK, Valentine MD, Kagey-Sobotka A, Lichtenstein LM: Regimens of Hymenoptera venom immunotherapy. Ann Intern Med 92:620, 1980

1 1. Case RL, Altman LC. Van Arsdel PP Jr: Role of cell-mediated immunity in Hymenoptera allergy. J ALLERGY CLIN IMMLWOI. 68:399. 1981