Further observations of stopping venom immunotherapy: Comparison of patients stopped because of a fall in serum venom-specific IgE to insignificant levels with patients stopped prematurely by self-choice Robert E. Reisman, MD, and Renee Lantner, MD Buffalo, N.Y. This .study extends our experience applying the criterion of a fall in serum venom-speciJic IgE (RASTJ to insignijkant levels as an indication to stop venom immunotherapy (VIT) and compares the follow-up results with the results of re-stings in patients who stopped VIT “prematurely” by self-choice. All patients in both groups had a history of venom anaphylaris, most with cardiovascular andlor respiratory symptoms and initial elevated serum venom-specific IgE; all patients received WT. The groups were closely matched for age, sex, nature of initial sting reaction, and insect identi’cation. k’n the group with low-level RAST titers, the duration of VIT was 6 months to 5 years (mean 2% years). Re-stings occurred from 1 month to 7 years (mean 2.2 years) after cessation of therapy. There were 75 re-stings in 41 patients with-four systemic reactions (10% per patient and 5% pe)r sting). All four reacting patients had tolerated several stings during cessation of VIT before the re-sting systemic reaction; two patients had subsequent stings with no reaction. In the group of patients who stopped VITfor other reasons, the duration of VIT was 5 months to 4 years (mean 1.8 years). Re-stings occurred from 4 months to 6 years (mean 2 .l years) afte(v stopping therapy. There were 74 re-stings in 38 patients with seven systemic reactions in four patients (9.5% per patient and 10.57~ per sting). Two of the reacting patients had tolerfited stings before the re-sting reaction. The results suggest that, whereas a fall in RAST titers might be an adequate criterion for stopping VIT, most patients probably tolerated re-stings because of either a beneficial effect of the relatively short duration of immunotherapy or the selflimiting nature of insect sting allergy. (J ALLERGY CLIN IMMUNOL 1989;83:1049-54 .) VIT is a highly effective treatment for patients who have had allergic reactions after insect stings. ” * One unresolved problem is the development of guidelines for the cessation of treatment: When is it safe to stop injections and a.ssure continued lack of reactions to subsequent insect stings? We have previously pro- posed that therapy could be stopped when serum venom-specific IgE, as measured by RAST, fell to insignificant levels.3 Other investigators have sug- gested that 5 years of therapy is sufficient, regardless of the status of antibody titers.4, ’ In this study, we have extended the data base of the patient group in From the Allergy Research Laboratory, Buffalo General Hospital, Department of Medicine, State University of New York at Buf- falo, Buffalo, N.Y. Received for publication April 5, 1988. Revised Aug. 8, 1988. Accepted for publication Aug. 11, 1988. Reprint requests: Robert E. Reisman, MD, Buffalo General Hos- pital, Department of Medicine, 100 High St., Buffalo, NY 14203. Abb.reviation used VIT: Venom immunotherapy which therapy was stopped because of a fall in IgE antibody titers and compared follow-up results with results of a patient group in which therapy was stopped by patient self-choice, without physician advice. MATERIAL AND METHODS Patient selection Patients were selected who met the following criteria: (1) history of insect sting anaphylaxis, (2) positive venom skin tests and elevated titers of serum venom-specific IgE; a positive venom skin test was defined as a wheal of at least 5 mm in diameter with surrounding erythema elicited by 0.02 cc of a venom concentration ~0.1 pgiml, with a negative diluent controL6 Serum venom-specific IgE was measured by RAST, as previously described.’ A net uptake of radioactivity >5% of a positive standard was considered 1049
Transcript
Further observations of stopping venom immunotherapy: Comparison of patients stopped because of a fall in serum venom-specific IgE to insignificant levels with patients stopped prematurely by self-choice
Robert E. Reisman, MD, and Renee Lantner, MD Buffalo, N.Y.
This .study extends our experience applying the criterion of a fall in serum venom-speciJic IgE (RASTJ to insignijkant levels as an indication to stop venom immunotherapy (VIT) and compares the follow-up results with the results of re-stings in patients who stopped VIT “prematurely” by self-choice. All patients in both groups had a history of venom anaphylaris,
most with cardiovascular andlor respiratory symptoms and initial elevated serum
venom-specific IgE; all patients received WT. The groups were closely matched for age, sex, nature of initial sting reaction, and insect identi’cation. k’n the group with low-level RAST titers, the duration of VIT was 6 months to 5 years (mean 2% years). Re-stings occurred from 1 month to 7 years (mean 2.2 years) after cessation of therapy. There were 75 re-stings in 41 patients with-four systemic reactions (10% per patient and 5% pe)r sting). All four reacting patients had tolerated several stings during cessation of VIT before the re-sting systemic reaction; two patients had subsequent stings with no reaction. In the group of patients who stopped VITfor other reasons, the duration of VIT was 5 months to 4 years (mean 1.8 years). Re-stings occurred from 4 months to 6 years (mean 2 .l years) afte(v stopping therapy. There were 74 re-stings in 38 patients with seven systemic reactions in four patients (9.5% per patient and 10.57~ per sting). Two of the reacting patients had tolerfited stings before the re-sting reaction. The results suggest that, whereas a fall in RAST titers might be an adequate criterion for stopping VIT, most patients probably tolerated re-stings because of either a beneficial effect of the relatively short duration of immunotherapy or the selflimiting nature of insect sting allergy. (J ALLERGY CLIN IMMUNOL 1989;83:1049-54 .)
VIT is a highly effective treatment for patients who have had allergic reactions after insect stings. ” * One unresolved problem is the development of guidelines for the cessation of treatment: When is it safe to stop injections and a.ssure continued lack of reactions to subsequent insect stings? We have previously pro- posed that therapy could be stopped when serum venom-specific IgE, as measured by RAST, fell to insignificant levels.3 Other investigators have sug- gested that 5 years of therapy is sufficient, regardless of the status of antibody titers.4, ’ In this study, we have extended the data base of the patient group in
From the Allergy Research Laboratory, Buffalo General Hospital, Department of Medicine, State University of New York at Buf- falo, Buffalo, N.Y.
Received for publication April 5, 1988. Revised Aug. 8, 1988. Accepted for publication Aug. 11, 1988. Reprint requests: Robert E. Reisman, MD, Buffalo General Hos-
pital, Department of Medicine, 100 High St., Buffalo, NY 14203.
Abb.reviation used VIT: Venom immunotherapy
which therapy was stopped because of a fall in IgE antibody titers and compared follow-up results with results of a patient group in which therapy was stopped by patient self-choice, without physician advice.
MATERIAL AND METHODS Patient selection
Patients were selected who met the following criteria: (1) history of insect sting anaphylaxis, (2) positive venom skin tests and elevated titers of serum venom-specific IgE; a positive venom skin test was defined as a wheal of at least 5 mm in diameter with surrounding erythema elicited by 0.02 cc of a venom concentration ~0.1 pgiml, with a negative diluent controL6 Serum venom-specific IgE was measured by RAST, as previously described.’ A net uptake of radioactivity >5% of a positive standard was considered
1049
1050 Reisman and ILantner J. ALLERGY CLIN. IMMUNOL. JUNE 1999
significant. Serum samples obtained before and during VIT were usually available for analysis with the follow-up sam- ples, and (3) VIT initiated and stopped because of either a fall in sernm venom-specific IgE to insignificant levels (physician recommendation) or patient self-choice.
Follow-up data Follow-up information concerning the history of field re-
stings and reactions was obtained from the patients who had stopped VIT by telephone communication, written com- munication, and personal interview. Whenever it was pos- sible, serum was obtained for analysis of venom-specific IgE titers.
RESULTS VIT has been initiated in approximately 400 pa-
tients. Information was available from 110 patients who had stopped VIT by self-choice and 84 patients who had stopped VIT because of a fall in serum venom-specific IgE. In the latter group with low-level RAST titers, 41 patients reported a total of 75 re- stings. There were four systemic reactions in four patients. There were 74 re-stings in the 38 patients who stopped VIT by self-choice. Seven reactions oc- curred in four patients. The re-sting reaction rates were 5.3% per sting and 9.8% per patient in the group with low-level RAST titers, and 9.5% per sting and 10.5% per patient in the self-choice group. These data are presented in Table I.
The clinical data comparing the 41 patients in the group with low-level RAST titers and 38 patients in the patient self-choice group are presented in Table II. The groups are extremely well matched. The age, sex ratios, and nature of the auaphylactic symptoms leading to initiation of VIT are almost identical. The incidence of cardiovascular and respiratory symp- toms, particularly, is similar. There were four patients in the self-choice group and five patients in the group with low-level RAST titers who were younger than
16 years and had had generalized urticaria as the only symptom of anaphylaxis. Most patients in each group received either honeybee or yellow jacket VIT.
The duration of VIT was similar in the two groups. The average duration of VIT for patients in whom therapy was stopped because of a fall in serum venom-specific IgE was 2% years, compared to 1.8 years in the patients who stopped by self-choice.
The average interval between stopping VIT and the first re-sting was slightly more than 2 years in each group (Table II). The identification of the insect caus- ing the re-sting also was comparable. Most patients were able to identify the re-sting insect as the same insect that had caused the initial reaction.
To summarize, the clinical data suggest no differ- ence between the two groups with regard to the ob- served factors that may influence venom sensitivity.
The details of those patients who had systemic re- actions are presented in Table III. There were four patients in whom VIT had been stopped because of a fall in serum venom-specific IgE who eventually had systemic reactions after re-stings. All four patients had tolerated insect stings after cessation of VIT before the sting that eventually caused the systemic reaction. One patient (W. G.) tolerated multiple honeybee stings after the systemic reaction with no difficulty.
There were four patients who had stopped VIT by self-choice who had systemic reactions after re-stings. One patient (S. S.) had four subsequent reactions after yellow jacket stings. Two patients (E. F. and J. W.) had tolerated insect stings with no difficulty before the subsequent systemic reaction. The fourth patient (R. R.) had a systemic reaction from a honeybee sting 3 years after VIT was stopped.
When the data from both groups were combined, there were eight patients who had re-sting reactions after VIT was stopped. VIT had been administered for 1% years to one patient, 2 years to six patients, and 3 years to one patient. Re-sting reactions occurred in one of 27 patients who had received VIT for 1 L/2 years or fewer, and in one of 26 patients who had received VIT for more than 2 years.
After cessation of VIT, serum was obtained from 23 patients in the group with low-level RAST titers and 14 patients in the self-choice group. In the patients in whom VIT was stopped because of a fall in serum venom-specific IgE, antibody titers demonstrated no change or decreased in 15; one of these patients had had a re-sting systemic reaction. In eight patients, the antibody titers increased. Three of these patients had had a re-sting reaction and one had had a local reaction (Table IV).
In the patients who had stopped VIT by self-choice,
2 NR 5 SR 1% SR 2 SR 3 SR 3 SR 2 NR 5 SR 6 NR 3 SR
HE, Honeybee; YJ, yellow jacket; W, wasp; H, hornet; BB, bum- blebee; NR. no reaction; SR, systemic reaction.
there were six patients in whom antibody titers did not change. None of these patients had reacted to the re-sting. In eight patients, there was an increase in antibody titers; three of these patients had re-sting systemic reactions and two had local rections. These data do suggest that patients who have stopped VIT prematurely are likely to have an anamnestic response in antibody titers after re-stings.
DISCUSSION
The initial purpo:se of this study was to extend the observations concerning the fall in serum venom- specific IgE to insignificant levels as a criterion for stopping VIT. Our initial data have been reported pre- viously.3 At present, VIT has been stopped in 84 pa- tients on the basis of this criterion. There have been 75 re-stings in 41 Ipatients with four systemic reac-
J. ALLERGY CLIN. IMMIJNOL. JUNE 1999
TABLE IV. Effect of re-sting on serum venom-specific IgE
VIT stopped: Fall in serum venom-specific IgE (23 pts)
Change in RAST titer
Interval of re-sting to RAST analysis
Same or decrease Increase
<6 mo 10 (1 SR) 7 (3 SR) 6 1x10-l yr 4 1 (I LR)
>I yr 1
VIT stopped: Patient self-choice (14pts)
Change in RAST titer
Interval of re-sting to RAST analysis
Same or decrease Increase
<6 mo 3 7 (2 SR) (2 W
6 mo-I yr 1 >l yr 2 I (I SR)
Pfs, Patients; LR, local reaction; SR, systemic reaction.
tions. In the initial study, there had been 55 re-stings in 25 patients with three systemic reactions. Thus, ‘one additional reactor has been added. There is no apparent reason for these differences in incidence in reaction in the earlier study group (three of 25) versus one of 16 in the more recently studied patients. The results continue to support the use of this criterion for stopping VIT. It is of interest to note that all four patients had tolerated several stings before the re-sting that eventually led to a reaction. In addition, one of the patients has had several stings after the re-sting with no difficulty.
To evaluate critically this postulate for stopping VIT, it is necessary to examine the re-sting reaction rate in other groups of patients. Those patients re- ceiving adequate doses of VIT are almost completely protected against further re-sting reactions.‘. 2 In pa- tients who do not receive VIT, the re-sting reaction rates have varied between 12% to 60%.*, *. 9 Our own data suggest that the longer patients avoid venom ex- posure (re-sting) after a systemic reaction, the less likely they are to have another reaction if they are re- stung.’ The evaluation of the efficacy of VIT and the criterion for stopping VIT must be considered in light of the natural history of the disease process. Recently, Golden et al.4 and Schuberth et al.’ have suggested that 5 years of VIT is sufficient, regardless of the status of the IgE antibody titer. Intentional re-stings up to 3 years after cessation of therapy have been well tolerated with no reaction.
VOLUME 83 NUMBER 6
Stopping of venom therapy 1053
In attempting tlo evaluate these different standards for stopping therapy (fall in serum-antibody levels or duration of immunotherapy), the group of patients who had stopped immunotherapy by self-choice was compared to those patients in whom therapy was stopped because of a fall in IgE antibody titers. One hundred ten patients were identified who had stopped VIT by self-choice. There were 74 re-stings in 38 patients, with seven reactions occurring in four pa- tients . This represents a reaction rate of 9.5% per sting and 10.5% per patient. These data indicate that the systemic reaction rates are very similar in those pa- tients in whom VIT was stopped because of a fall in serum venom-specific IgE and in those who had stopped by self-choice. Retrospective analysis dem- onstrated that the: clinical feature of the two groups were similar. The age, sex ratios, initial anaphylactic symptoms, type of VIT, duration of VIT, identification of the insect causing the re-sting, and the interval between stopping VIT and the first re-sting, were al- most identical in the two groups.
Unfortunately, the serum venom-specific IgE titer of those patients who had stopped VIT prematurely was not available for comparison with the group in whom VIT had been stopped because of the low titer. In all patients who had stopped prematurely, serum venom-specific l.gE had previously been elevated.
The average interval between stopping immuno- therapy and the lirst re-sting was slightly more than 2 years in each group. In our initial studies of those patients who had not received VIT, there was a 50% incidence in reactions if the re-sting occurred within the average time interval of 4’/2 years. After the in- terval was extended to an average 7.3 years, the re- action rate fell dramatically to about 12%.9 Thus, it would appear that patients who have received VIT for at least 2 years h.ave a marked reduction in the like- lihood of having a re-sting reaction. Further analysis of the relationship and duration of VIT to subsequent re-sting reactions after cessation of VIT did not con- tribute significant conclusions. Six of the eight pa- tients with re-sting reactions received VIT for 2 years, one patient, fewer than 2 years (1 l/2 years); and one patient, for more than 2 years (3 years). The re-sting reaction rates in those patients receiving VIT fewer than 2 years (one of 27) and more than 2 years (one of 26) were almost identical.
Schuberth et al.” have demonstrated that stinging- insect allergy is a remarkably benign process in chil- dren who have had dermal reactions as the only man- ifestation of anaphylaxis. Subsequent re-stings in these untreated children have resulted in a very small number of’ reactions. In this study, there were only four patients in the self-choice group and five patients in the group with low-level RAST titers in this cate-
gory. The patient groups reported in this article and the group without VIT that had been studied included children, adults, and patients with cardiovascular and respiratory symptoms, as well as generalized hives. The low reaction rates in the patients in this study cannot be attributed to the relatively benign nature of the disease process in the subgroup of children with dermal reactions only.
In our initial study of the natural history of stinging- insect allergy and its modification by VIT, the re-sting reaction rate was reported as 20% in patients who had stopped VIT by self-choice. The lowering of that fig- ure in the present study is due to the inclusion of additional patients and the reclassification of eight patients who had previously been considered treatment failures. After thorough data review and personal pa- tient contact, these changes in classification were made for the following reasons: None of the patients had typical anaphylaxis from a re-sting after cessation of VIT. Two patients were stung while they were receiving maintenance yellow jacket-venom therapy, with complaints of “feeling faint,” and “facial flush- ing.” One patient had a systemic reaction after ces- sation of whole body extract therapy. Two patients who had short courses of VIT and did not reach full mainten.ance doses had questionable re-sting reac- tions, one with nausea and the other of “feeling faint.” Two patients had only local reactions after re-stings, and one patient had hives that occurred 2 months after the re-sting.
Golden et al.” also reported the results of re-stings in patients who had stopped VIT prematurely. In their study there were 36 field re-stings in 29 patients with seven reactions in six patients (reaction rate of 22% per patient and 19% per sting). Four of the patients had received maintenance VIT for a relatively short time.
It is possible that patients in whom VIT has been stopped may reacquire venom sensitivity after toler- ated re-stings. This may be particularly true if there is an increased titer in serum venom-specific IgE or increased skin test reactivity. These patients should be warned of that possibility, and it would be prudent to recommend the availability of emergency medi- cation.
To summarize, the re-sting reaction rates were sim- ilar and low in the two groups of patients in whom VIT was stopped, in one group because of a fall in serum venom-specific IgE and in the other group from self-choice. Retrospective analysis demonstrated marked similarity of the clinical features of insect- sting allergy in the patients in each group, including duration of VIT. These observations and results sug- gest that, while a fall in RAST titers to insignificant levels might be a criterion for stopping VIT, most
1054 Reisman and Lantner J. ALLERGY CLIN. IMMUNOL. JUNE 1989
patients might have: tolerated re-stings either because of a beneficial effect of the relatively short duration of VIT (2 years) or the self-limiting nature of insect- sting allergy. Our statistics in untreated patients sug- gest a higher re-sting rate (50%) would be expected in the 2-year period after an initial reaction. Thus, these observations Itend to support the concept that 2 years of VIT might be an adequate duration of VIT for most patients, approaching the concept of 5 years of VIT suggested and currently being analyzed by Golden et a1.4 and Schuberth et al5 Defining criteria other than a fall in venom-specific IgE, which might be used for a more appropriate selection of patients in whom therapy could be stopped after 2 years, re- mains unresolved.
2. Reisman RE, Dvorin DJ, Randolph CC, Georgitis JW. Stinging insect allergy: Natural history and modification with venom immunotherapy. J ALLERGY CLIN I~.~~IUNOL 1985;75:735.
3. Randolph CC, Reisman RE. Evaluation of decline in serum venom-specific IgE as a criterion for stopping venom im- munotherapy. J ALLERGY CLIN IMMUNOL 1986;77:823.
4. Golden DBK, Addison Bl, Blake K, Kagey-Sobotka A, Val- entine MD, Lichtenstein LM. Discontinuing venom immu- notherapy (VIT): immunologic and clinical criteria [Abstract]. J ALLERGY CLIN IMMUNOL 1987;79:126.
5. Schubetth KC, Kwitetovich KA, Kagey-Sobotka A, Lichten- stein LM, Valentine MD. Discontinuing immunotherapy in skin test positive children [Abstract]. J ALLERGY CLIN IMMUNOL 1987;79:126.
6. Georgitrs JW, Reisman RE. Venom skin tests in insect-allergic and insect-nonallergic populations. J ALLERGY CLIN IMMUNOL 1985;76:803.
7. Light WC, Reisman RE, Rosario NA, Arbesman CE. Com- parison of the allergenic properties of bee venom and whole bee body extract. Clin Allergy 1976;6:293.
8. Hunt ICI, Valentine MD, Sobotka AK, Benton AW, Amodio FJ, Lichtenstein LM. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978;399:157.
9. Savliwala MN, Reisman RE. Studies of the natural history of stinging-insect allergy: long-term follow-up of patients without immunotherapy. J ALLERGY CLIN IMMUNOL 1987;80:741.
10. Schuberth KC, Valentine MD, Kagey-Sobotka A, Szklo M, Kwiterovich KA, Valentine MD. An epidemiologic study of insect allergy in children. 1. Characteristics of the disease. J Pediatr 1982;100:546.
11. Golden DBK, Johnson K, Addison Bl, Valentine MD, Kagey- Sobotka A, Lichtenstein LM. Clinical and immunologic ob- servations in patients who stop immunotherapy. J ALLERGY CLIN IMMUNOL 1986;77:435.
