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Clinical and immunologic studies of rapid venom immunotherapy in Hymenoptera-sensitive patients
Clinical and immunologic studies of rapid venom immunotherapy in Hymenoptera-sensitive patients David I. Bernstein, MD,* Robert J. Mittman, MD,* Steven L. Kagen, MD,** Leslie Korbee, BS,* Mary Enrione, BS,* and I. Leonard Bernstein, MD* Cincinnuti,
Ohio.
und Appleton.
Wis.
A ?- to .5-hour regimen of rapid venom immunotherapy (RVIT) was administered to 33 patients u’ith antrphylactic sensitivity to Hymenoptera venom in a hospital setting in which fu,‘l emergencv resuscitation equipment ~‘a.7 a~~ailahle. The RVIT was adminivtered as 10 in,:~reasing dose3 @each treatment venom ever.! IO to 1.5 minute.\ to achieve a,final dose or: dq\ I of 58.55 pg per venom. Patients returneci,fijr booster venom injections I$ 60 p<;s or’ da>, 3. 70 ~8 on day 7. 80 pg on day 21. and IO0 p,q on da> 35 clf‘ter RVIT. Serial antigen-induced leukocyte histamine release studie.> were peJ&med on da1 I in IO patients bcfure and after RVIT, as well as 3E months after initiation of RUT. 91’33 patients, 32 achieved a cumulative venom dose on da! I of’ at least SO pg. and the entire group rec,eived a mean dose of 95.46 pg. Local reactions during RVIT oxurred in 18 (557~) patients. Four patients (12%) cT.uperienced mild systemic reactions durin g or after completion of RVIT. Subsequent booster venom doses administered to 29 patients were \vell tolerated. 4 decrease in venom-inductId leukocyte-histamine release ftiom baseline MUS detected in three (30%) piltierrts immediately after RVIT and in seven (70%) patients months aj‘ter ac,hieving maintenanc~c~ d,~xr.s Cutaneorrs sensitivity decreased by at least one lox,,, concentration in eight (327~) of -7.5 pgtierrts. Twentv-two natural re-stirq events occurred in I? (50%) of 24 patients vurve!ed qfter successfulcompletion oj’ RVIT, of whom ,se\zen itient$ed the insect as one ,for vt3hic.h thq had been treated. No systemic reactions bvere reported. Re.su(ts of this study indicate that A VIT is a sqfe, alternative method of venom administration fhr patients who are at immediart r-irk for re-sting anaphylactic episodes. (.I ALLERGY CLIN I,MML:VOL 1989:84:9.5/-4. j
It has been estimated that approximately 0.4% of the population experience anaphylactic reactions after Hymenoptera-venom stings.’ Anaphylactic reactions caused by Hymenoptera stings may result in at least 40 deaths annually in the United States.’ The introduction of venom IT for treatment of Hymenopterasensitive parients has reduced the risk of anaphylactic SRs after subsequent re-stings.3 In clinical practice. venom IT is administerecl by increasing subcutaneous injections of venom doses during a 6- to 14-week
From the *Division of Immunology, Department of Medicine. University of Cincinnati Medical Center, Cincinnati. Ohio. and **St. Eiizaheth Hospital, Appleton, Wk. Received for publication Nov 14. 1988. Revised June 28, 1989. Accepted for publication July 5, 1989. Reprint requer;ts: David I. Bernstein, MD. University of Cincinnati Medical Gnter. 231 Bethesda Ave., M.L: 563. Cincinnati, OH 45261. l/1/15494
Abbreviations
IT: HB: W: MV: RVIT: LHR: SR: LR:
used
immunotherapy Honeybee Wasp Mixed vespid Rapid venom immunotherapy Leukocyte histamine release Systemic reaction Local reaction
period until a monthly venom maintenance dose of 100 kg per venom is achieved. Such slow or modified rush venom IT regimens are considered safe and have been used for treating most Hymenoptera-sensitive patients .‘. 5 When specific IT with venom was initially studied. a regimen involving rapid administration of large doses of venom during 2 to 3 days was abandoned, in part because of a high frequency of SRs associated 951
952 Bernstein et al.
J. ALLERGY
I. RVIT schedule of venom dosages for a single treatment venom administered on day 1 at IO- to 15-minute intervals and venom doses subsequently administered on days 3, 7, 21, and 35 TABLE
Time
Dose h.4
Day 0.05 0.10 0.20 0.40 0.80 2.00 5.00 10.00 20.00 gl.oJ 58.55* 3 7 21 35
60 70 80 100
*Total dose (day 1) per venom
with treatment.6Nevertheless,in certain highly sensitive patients, there are specific situations in which an acceleratedform of venom IT may be preferable to slower conventional regimens. For example, RVIT may be indicated for those patients who experience severeSRsduring the warmer months of the year and may be at significant risk for subsequentre-sting reactions during the 8- to 1Zweek period required for diagnostic evaluation and attainment of maintenance doses of venom. A combined experience in 33 Hymenoptera-sensitivepatients with a 2- to 5-hour scheduleof RVIT is describedin this article. Our data indicate that RVIT is a safe alternative method for administration of venom injections to individuals with anaphylactic sensitivity to Hymenoptera allergens. MATERIAL AND METHODS Study group All 33 patientsreceivingRVIT met the eligibility guidelines for venom treatment established by the American Academy of Allergy and Immunology Committee on Insects.’ These guidelines include a prior history of an immediate allergic SR after an Hymenoptera sting and demonstrable intracutaneous reactivity to a concentration of 1 pg/ml or less of venom. As an alternative to RVIT, all patients were offered the standard protocol of modified rush IT. After the potential risks and experimental nature of this method were carefully explained, patients who chose to participate signed an informed-consent statement. A com-
CLIN. IMMUNOL. DECEMBER 1989
plete medical history was performed to exclude underlying cardiac or respiratory disease. Patients with significant cardiopulmonary disease and patients receiving concomitant pblocker drugs were excluded. Before initiation of RVIT, baseline screening studies were performed that included an electrocardiogram, complete blood count, and serum electrolytes. Prospective patients who exhibited clinically significant abnormalities on any of these tests were excluded.
Treatment
protocol
RVIT was administered by physicians at the Asthma and Allergy Treatment Center of the Deaconess Hospital in Cincinnati, Ohio, and St. Elizabeth Hospital in Appleton, Wis. Initially, patients were treated as hospital inpatients, but it soon became evident that RVIT could be performed safely in an ambulatory hospital setting. During RVIT, vital signs and blood pressure were carefully monitored. All patients had indwelling intravenous lines in place during the procedure, and full emergency resuscitation equipment was readily available. The hospital resuscitation team was notified on days when RVIT was administered. The RVIT treatment protocol is presented in Table I, and the venom schedule used on day 1 for a single venom is outlined. For a single venom, 10 increasing subcutaneous doses were administered every 10 to 15 minutes during 2 hours. The starting dose was 0.05 p,g of venom, and subsequent doses were increased every 10 minutes until a cumulative dose of 58.55 +g per venom was achieved on day 1. If multiple venoms were required, venoms were administered concurrently on day 1. Multiple venoms were advanced according to the same schedule for a single venom with each injection separated by an interval of 10 minutes. Thus, to achieve the final target dose on day 1 for two venoms, approximately 200 minutes were required, and for two venoms, approximately 300 minutes were needed. For 10 (nine of whom were treated in Cincinnati, Ohio) patients who received MV, the total dose on day 1 was 58.55 p,g, and by day 35, a dose of 100 kg was administered. In these patients the MV dosage was subsequently increased on a biweekly basis until a final 300 pg target dose was achieved. There were four patients at the second study site (Appleton, Wis.) who were administered a total dose of MV that ranged between 165 and 178.5 (*g on day 1 and who also achieved a maximal dose of 300 p.g of MV on day 35. If an immediate LR (defined by a wheal > 1 cm) was observed, the same venom dose was repeated before increasing to the next larger dose. If the maximal venom dose was achieved on day 1, patients received follow-up injection doses of each treatment venom of 60 pg on day 3, 70 p,g on day 7, 80 pg on day 21, and 100 p.g on day 35. Thus, it followed that a total dose equivalent to 118.55 pg per venom was administered within the first 3 days of treatment. After day 35, patients were administered maintenance doses of 100 p,g per venom at monthly intervals.
Immunologic
studies
Skin testing to relevant venoms (Hollister-Stier Laboratories, Spokane, Wash.) was performed in 25 patients by the end point intracutaneous titration method with increasing
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84 6. PART 1
tenfold concentrationsranging from lo-” to 10” pg/ ml. In thesepatients, skin testing was performedboth immediately before and after completion of RVIT. Serial LHR studies in responseto a specific venom used for RVIT were performed in 10 treated patients according to the methods of May et al.’ 0n the day of RVIT, LHR to venoms was performed twice, before RVIT and after the full dose of treatment venom (58.55 kg per venom) had been achieved. A third and final LHR study was repeated on peripheral b.ood of these subjects after they had been receiving maintenance doses of venom for a mean duration of 3% months. In all experiments, LHR was measured in response to tenfold increasing venom concentrations ranging from 10 ’ to IO’ pg/ml. To assess the variability of LHR studies in our laboratory, serial studies of LHR were reproduced 3 hours apart with peripheral leukocytes from untreated Hymenoptera-sensitive patients in response to varying dilutions of venom.The meandifference in percentLHR between IO identical studies performed 3 hours apart was
4.4 ?C2.8. Thus, a change in LHR that was 2 SDSgreater than the meanor a 3 10%changewas consideredsignificant. RESULTS Thirty-three patients with documented anaphylactic sensitivity to Hymenoptera received RVIT between June of 1984 .md April of 1988. This group was comprised of 24 male and nine female subjects with a mean age of 3,8years. Symptoms that occurred during prior anaphylactic episodes after live stings are listed in Table II. There were 11 patients in whom the most severe reporh:d symptoms were urticaria and angioedema. Eight other patients reported stridor or wheezing as the most severe anaphylactic symptom encountered during previous sting reactions. Hypotension and/or syncope were the most severe symptoms in 14 patients. The duration of time between the most recent sting reaction and initiation of RVIT ranged between 1 week and 15 years (x = 17.9 months). There were 16 (48%) patients who were treated within 1 month of their most recent sting SR. RVIT was administered safely to all 33 patients with no serious anaphylactic reactions occurring during treatment. A summary of the individual treatment venoms and their respective doses, as well as the total cumulative venom doses administered on day 1. is listed in Table III. Treated patients were evenly divided between patients who received only one and patients who were administered more than one venom. The total cumulative venom dose administered on day 1 of RVIT ranged between 28.55 and 238 p,g (x = 95.46 kg). All but one patient achieved a cumulative venom dose on day I of >50 kg. The latter individual (No. 17) who received a total dose of only 28.55 of HB venom experienced repeated LRs and subjective complaints of palmar itching after venom injections. Recurrent complaints of palmar itching af-
immunotherapy
953
ter subsequent injections prevented this patient from achieving a full monthly maintenance dose of 100 pg. It is noteworthy that four patients (Nos. 25. 26. 27, and 29) achieved a cumulative venom dose in excess of 200 pg. These larger total doses were attributable to the fact that the MV reagent was administered to the latter four patients at a concentration of 300 pgiml so that a total dose of at least 176 ~g of MV was achieved on day 1. Because the remainder of MVtreated patients were administered a venom concentration of 100 p,g/ml, their total cumulative doses on day 1 were relatively less, ranging between 56.0 and 175.9 l.lg. As presented in Table III, LRs during RVIT were common. Eighteen (55%) of 33 patients experienced significant immediate LRs as defined by wheal diameters >l cm. Two of these subjects also experienced urticarial SRs during RVIT. In no case were LRs severe enough to prevent eventual progression to the final target venom dose. However, when a large LR was observed, the previous dose was repeated at the discretion of the investigator before advancing to the next larger venom dose. There were 14 (42%) patients in whom neither LRs or SRs were encountered during RVIT. Four (12%) mild SRs, consisting of three immediate and one delayed response were observed during or after RVIT. As presented in Table III. three of four of these reactions were manifested by mild urticaria and angioedema. No manifestations of respiratory complaints or vascular collapse were documented during RVIT. One patient (No. 6) developed hives localized to the cervical area after a total cumulative dose of 50.6 p.g of HB venom had been administered and was treated with 50 mg of intramuscular diphenhydramine. A second patient (No. IS) experienced systemic angioedema and hives after administration of a cumulative dose of 119.1 pg of HB and MV venoms, which were treated successfully with a single subcutaneous injection of epinephrine. A third patient (No. 28) experienced diffuse urticaria beginning 24 hours after a cumulative dose of 110 p.g of W and MV venoms had been administered, which responded to ora diphenhydramine. As noted above, another patient (No. 17) complained of palmar itching after achieving a cumulative dose of 28.55 p*gof HB venom on day 1. In this patient, there was no objective sign of an allergic SR. However. it was assumed that this complaint could have represented an early prodromal anaphylactic symptom, and this response was therefore classified as a mild SR. It is noteworthy that all three individuals who experienced immediate systemic symptoms during RVIT were receiving HB venom.
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TABLE II. Results of initial diagnostic evaluation including age, symptoms during anaphylactic reactions, and time elapsed (months) since most recent reaction Patient No. 1
Prior reactions*
Age
Ml 17
U, D
2
24
U
3 4
32 34
U, H H, W
5 6 7 8 9 10 11 12 13 14 15
57 46 41 35 29 37 29 44 40 49 38
H, U A, U, U, U, U, U, U U, A
16 17 18 19 20 21 22 23 24 25
41 63 38 36 40 52 66 27 7 27
U H, H, U U, U, U, U H H,
26
38
A
27
41
A, U, H, D, W
28
16
U, A
29 30 31 32 33
26 61 40 28 56
U, A, I-L D H H H, S H, S, ST
S U, ST D A A A, ST D A, D
S S, A D A, H D
S, U
ID threshold
(pg/ml)
HB (0. l), YJ (0. l), YH (O.Ol), WFH (O.Ol), W (0.01) W (O.l), YJ (O.l), YH (O.l), WFH (0.1) YJ (O.Ol), YH (l), WFH (0. l), W (1) YJ (O.Ol), YH (O.Ol), WFH (O.Ol), w (0.01) YJ (0.1) HB (0.1) YJ (0.01) HB (0.01)
WFH Cl), YJ (l), YH (l), W (1) YJ (0.1) YJ (0.01). WFH (0. l), YH (0.1)
YJ (l), YJ (I), WFH (1) W (1) w (0.01) YJ (0.1) HB (O.OOl), YH (O.Ol), WFH (0. l), YJ (0.1) w (0.01) HB (0.001) YJ (0.1) w (0.1) YJ (0.01) YJ (0.001) YJ (0.001) YJ (0.1) YJ (O.l), WFH (0. I), YH (0.1) WFH (O.Ol), YJ (0. l), YH (O.l), w (0.1) YJ (O.Ol), YH (O.Ol), WFH (O.Ol), w (0.1) YJ (O.Ol), WFH (O.Ol), YH (O.Ol), W (0.01) W (O.Ol), YJ (O.Ol), WFH (0. l), YH (0.1) YJ (O.l), YH (l), WFH (l), W (1) YJ (0.1)
W (11, YJ (1) YJ (O.Ol), W (0.1) YJ (0.01)
CLIN. IMMUNOL. DECEMBER 1989
prior
Time since last sting (months)
1 18 12 7 1 1 1 6 6 1
24 120 1 1 120 180 1 1 1.5 1 1 1 8 2.5 3 1 4 12 1 5 48 1 1
ID, Intradermal; U, u&aria; D, dyspnea; W, wheezing; ST, stridor; H, hypotension; S, syncope; A, angieedema; YH, yellow hornet; WFH, white-faced hornet; YJ, yellow jacket. *Anaphylactic
symptoms.
Twenty-nine patients who received a venom dose of at least 50 pg on day 1 of RVIT without experiencing SRs during or after treatment returned on days 3 and 7 for administration of venom doses of 60 and 70 kg, respectively. Both of these doses on days 3 and 7 were selected because they exceeded doses of venom equivalent to one live sting. All 29 patients
tolerated both injections on days 3 and 7 after RVIT, as well as subsequent injections of 80 and 100 pg administered on days 21 and 35, respectively. The four patients (Nos. 6,15,17, and 28) who experienced SRs during or after RVIT did not receive these followup scheduled challenge doses of venom. Their subsequent injection schedule was modified so that venom
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TABLE III. Summary
immunotherapv
of results of RVIT on day 1 including types and doses (micrograms) venom(s) administered, total cumulative dose of venom (micrograms), reactions during changes in ID threshold concentration after WIT -~IPatient No.
Venoms
Reactions during RVIT
Total cumulative dose
1 2 3 4 5 6 I 8 9 10 11 12 13 14 1.5 16 17
I-IB (58.6) W (58.6) MV (58.7) ‘A’ (58.8) MV (58.6) ‘W (58.6) MV (58.6) W (58.6) MV (58.6) YJ HB YJ HB W (38.6) MV (23.5) YJ MV MV (58.6) W (58.6) W (58.6) YJ HB (60.55) MV (58.55) W HB
175.9 117.4 117.2 117.2 58.6 50.6 58.6 54.7 62.1 58.7 58.7 117.2 58.6 52.0 119.1 58.95 28.55
18 19 20 21 22 23 24 25 26 21 28
YJ W YJ YJ YJ YJ MV W (58.55) MV (175.65) W (55) MV (165) W (59.5) MV (178.5) W (50) MV ((60)
58.55 58.55 59.35 55.8 5x.5 58.5 56.0 234.21 220.0 238.0 110.0
29 30 31 32 33
W (58.55) MV (175.65) YJ YJ (58.55) W (58.55) YJ (55.55) W (58.55) YJ (58.55)
234.2 51.7 117.1
LR LR LR
955
of WIT, and -
Change in ID threshold* 0
LR, hives LR LR LR
LR LR, hives LR LR, palmar itching
f I (W. WFH, YH, YJj (1 0 +I 0 +2
+2 (W, WFHj 0 0 0 0 +1 ND t-1 0
LR LR LR
0 0 0 fl
-
0 0
LR LR LR LR Late onset hives
ND ND ND ND ND
-
ND ND + 1 (YJ, W) 0
117.1
-
58.55 x = 95.46 kg
18 LR, 4 SR
ID, Intradermai; YJ, yellow jacket; WFH, white-faced hornet: -, no local reaction; ND, skin testing not performed. *Changes in en(Jpoint intracutaneous threshold concentration expressed as increase ( + ), decrease ( - 1, or no change (0) in log,!, concentration required to elicit a wheal of 4 mm greater than the wheal elicited by saline control.
doses were advanced slowly on a weekly basis, as deemed appropriate by the treating physician. Immunologic
studies
In 25 patients, intradermal threshold titration testing was performed before and after RVIT on day 1 with tenfold increasing concentrations of specific treatment venoms. As presented in Table III, only eight (32%) of these individuals exhibited a 21 log,, decrease in
intradermal sensitivity after completion of RVIT. In the remaining patients, no changes in intracutaneous reactivity were observed. Serial LHR studies were performed in 10 subjects, as described in the MATERIAL AND METHODS section. Results of these studies are illustrated in Fig. 1. Of the 10 patients, one was tested to HB, two to W, two to MV, and five to yellow jacket venom. Three patients exhibited decreases of at least 10% histamine
956
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et al.
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CLIN. IMMUNOL. DECEMBER 1999
100 , 90 80 70 60 50 40 30 20 10 -
Baseline (Day 1)
Post 1.7: (Day 1)
Maintenance
mean-3.6
mo.
FIG. 1. Serial studies of LHR in response
to Hymenoptera venom (1 pgiml) performed in 10 patients before and after RVIT (day 1) and repeated mean of 3% months later. One patient was tested to HB, two to W, five to yellow jacket, and ~0 to MV venoms.
releaseto venom (1 pg/ml) comparedto baselineafter completion of venomtreatmenton day 1. Five subjects exhibited an increase of 210% in percent LHR to venom after RVIT, and there was no change from baseline in two other patients. When the sameLHR studieswere repeatedafter patientshad beenreceiving maintenancevenom injections for a mean duration of 3% months, a definite decreasefrom baseline in percent LHR to the samevenom was observed in seven (70%) of 10 patients studied. After completion of RVIT on day 1, there was no association between changesobserved in percent LHR and changesin intradermal sensitivity to venom antigens. Natural
re-sting
reactions
Questionnaires and telephone surveys were performed in 24 patients who successfullycompletedthe RVIT scheduleregarding the outcomesof natural restings after RVIT. The number of re-sting episodes and duration of time elapsedsince day 1 of RVIT were obtained and are listed in Table IV There were 12 (50%) of 24 patients surveyed who reported natural re-sting episodes.Among this group there was a total of 22 Hymenoptera r-e-stings.The duration of time elapsedbetween day 1 of RVIT and the first re-sting episode ranged from 3 days to 12 months. Three of thesepatients (Nos. 4, 29, and 30) identified the offending insects as different from insects for which they were receiving treatment. As demonstrated, sevenof 12 patients were able to identify the stinging insect as identical to one of the insects for which they had received treatment. Of the latter seven patients,
there were two patients who were stung within 2 months, one of whom was restung 3 days after day 1 of RVIT. No SRs were reported by any patients who experienced natural re-stings, nor was emergency treatmentof thesere-sting episodesrequired. It should also be notedthat one patient (No. 6) who experienced an urticarial SR during day 1 of RVIT after achieving an HB venom dose of 50.6 pg was not advancedbut maintained at GO pg on days 3, 7, and 21. This patient happenedto receive 20 accidental HB stings within 2 months after day 1 and did not have a reaction. DISCUSSION
Venom IT is highly effective for preventing recurrent anaphylaxis after insect stings in patients with proven Hymenoptera sensitivity. Because of its superior efficacy, venom has largely supplanted whole body extracts as the primary immunologic therapy for Hymenoptera-sensitivepatients.9In general, it is recognizedthat the primary goal of venomIT is to achieve a target maintenancedose of 50 to 100 kg of venom that is associatedwith a high probability of protection from subsequentre-sting reactions.lo Most regimens currently used in clinical practice use increasing doses of venom administered during periods of 6 to 14 weeks before a final maintenance dose can be achieved.4,’ For this reason, there have beenprevious attemptsto acceleratethe initial phases of venom treatment. In 1979, a protocol of rush IT was attempted in which relatively large doses of venom ranging from 69 to 5657 pg were administered
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84 6, PART 1
IV. Summary
Patient No.
of natural
re-sting
Time elapsedt Imo)
episodes
reported
Insect identified
by 24 patients
immunotherapy
after completion
Treatment venom(s)
of RVlT* No. of re-sting episodes
1
-.
I’
3 4
10
5 7 8 9 II 12 13 14 16 18 19 20 21 22 23 26 29 30 31 32 33 Total
12 6 --6
I! 1 ._ i) 1
2 9% 3 weeks 11 10 5 4 3 days
HB
w, MV
YJ HB -
HB. YJ HB w -._ YJ YJ YJ W. MV W, MV YJ W, YJ W. YJ
w -Unknown YJ YJ Unknown HB HB YJ -YJ
957
i
:I f) iI :I 0 2 0 0 0 I 1 2 1 I 2 I 0 I 22
YJ, yellow jacket. *No SRs were reported. ‘ITime elapsedbetween day 1 of RVIT and first re-sting episode
during 2 to 3 days.6 The latter trial was associated with a high rate of allergic SRs, perhaps attributable to relatively large venom doses administered. When patients returned 1 month later for live-sting challenges, there was a high rate of SRs. This apparent lack of efficacy may have been related to the fact that no booster venom injections were administered during the interim period between initial rush treatment and sting challenge. Subsequently, Thumheer et al.” demonstrated that a venom dose of 100 p.g could be achieved by using a rush treatment schedule administered during 10 consecutive days. In this study there was also a similar high rate (38%) of SRS during treatment. In 1984, Nataf et a1.12reported a rush venom protocol in which a target dose of 100 pg of venom could be administered to 52 patients on day 4 after a 3-day rush treatment regimen. In this study, only one mild urticarial reaction was encountered during the initial 3 days of treatment. In addition, SRs did not occur after subsequent injections of 100 pg
administered on days 6, 9, 16, or 30. Van der Zwan et a1.13reported a 6-hour rush IT schedule with wasp venom in 11 Hymenoptera-sensitive patients. In these cases, 216 p,g of W venom was administered in 6 hours without SRs. Follow-up subcutaneous doses of 100 kg administered 7, 14, and 28 days later were also well tolerated. The results of our study indicated that RVIT can be accomplished safely with single or multiple venoms in most patients with anaphylactic sensitivity to Hymenoptera. The prevalence of LRs encountered in most of our patients (55%) was no different than the prevalence reported with other forms of slow or modified rush venom IT.4,5 The proportion of patients who experienced SRs was also comparable to that which has been documented in studies of slow or modified rush venom IT.4 SRs that did occur during RVIT were not of a serious nature and responded readily to treatment. Because two of three of the subjects with immediate SRs were receiving only HB venom and the
958
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et al.
other subjectsreceivedboth HB and MV, it is possible that HB venom may be associatedwith a greater risk than other venoms for development of SRs during RVIT. The efficacy of this RVIT regimen was evaluated by performing a careful survey of natural re-sting events after treatment. Our survey revealed that no anaphylactic reactions were reported after 22 natural sting episodes. However, only sevenpatients in this survey who received a total of 15 stings could identify the stinging insect as identical to one for which they were receiving treatment. Included in the latter group of sevenpatients were two patients who were stung within 2 months of initiation of RVIT and who did not suffer SRs. Live sting challenges were not performed in this study to evaluate the protective effect of RVIT, particularly within the initial weeksof treatment. However, other investigators have addressed this question. In 11 patients treated by RVIT to W venom, all tolerated W-sting challenges at least 1 month after commencingtreatment.” Urbanek et al. I4 performed rush IT in 11 patients with anaphylactic sensitivity to HB during 7 days. Live sting challenges administeredat approximately 1 week after beginning treatment were tolerated without SRs. Thus, it is apparent from the work of theseother investigators that this form of RVIT may be effective for achieving protection from live venom stings within the first 1 to 2 weeksaswell asmonths after initiation of treatment. However, further studies of this nature are required and in larger numbers of Hymenoptera-sensitivepatients before the immediate protective effect of RVIT can be ascertained. Patients treated with the RVIT protocol did not achieve a 100 pg dose of venom until week 5. A previous study with a different treatment protocol demonstratedthat only 79% of Hymenoptera-sensitive patientsreceiving a 50 p.gmaintenancedoseof venom were protectedfrom live sting challenges.I5However, it should be emphasizedthat nearly all our patients receiveda total cumulative doseof approximately 188 pg per venom within the first 7 days of therapy. To addressthis concern, we have since modified the protocol presentedin Table I so that patients now receive weekly (instead of biweekly) venom injections after day 7 until they achievea targetdoseof 100 pg. Thus, the entire protocol can be completed by day 21. Immunologic studies were performed during RVIT to explain the efficacy of RVIT. Desensitization as determined by a decreasein cutaneousreactivity to the specific treatment venoms was achieved in only one third of treated patients. Similarly, only 30% of thesepatients exhibited a decreasein basophil releas-
J. ALLERGY
CLIN. IMMUNOL. DECEMBER 1989
ability in response to venom after treatment with RVIT. The finding of no change in antigen-induced histamine release in two thirds of our patients is in agreementwith a recent study that demonstratedthat no significant decreasein LHR releasability to antigen occurs during rapid desensitization to penicillin. I6 There was no correlation betweenchangesin basophil sensitivity and cutaneous reactivity to venom after completion of RVIT. These disparate results could reflect intrinsic differences between circulating basophils and cutaneousmast cells. However, most of our patients eventually demonstrateddecreasedhistamine release to venom months after they had received maintenancevenom IT. Further investigations are required to define the exact mechanismof tolerance to natural stings and sting challenges achieved by RVIT. In summary, this regimen of RVIT possessesacceptablesafetyfor treating Hymenoptera-sensitivepatients. It may be particularly indicated for those patients who are at immediate risk of being restung. Specifically, this treatmentis particularly indicated for patients who experience severeSRs during the peak of the summerseasonso that maintenancelevel doses can be attained rapidly within days after the initial sting episode. REFERENCES 1. Settipane GA, Boyd GK. Prevalence of bee sting allergy in 4,992 Boy Scouts. Acta Allergol 1970;25:286-91. 2. Barnard JH. Studies of 400 Hymenoptera sting deaths in the United States. J ALLERGYCLINIMMUNOL1973;52:259-64. 3. Lichtenstein LM, Valentine MD, Sobotka AK. A case for venom treatment in anaphylactic sensitivity to Hymenoptera sting. N Engl J Med 1974;290:1223-7. 4. Golden DBK, Valentine MD, Kagey-Sobotka A, Lichtenstein LM. Regimens of Hymenoptera venom immunotherapy. Ann Intern Med 1980;92:620-4. 5. Clayton WF, Reisman RE, Mueller U, et al. Modified rapid venom desensitization. Clin Allergy 1983;13: 123-9. 6. Yunginger JW, Paul1 BR, Jones RT, Santrach PJ. Rush venom immunotherapy program for honeybee-sting sensitivity. J ALLERGYCLINIMMUNOL1979;63:340-7. 7. Golden DBK, Schwartz HJ. Guidelines for venom immunotherapy. J ALLERGYCLINIMMUNOL1986;JJ:J2J-8. 8. May DC, Lyman M, Albert0 R, Cheng J. Procedures for immunochemical study of histamine release from leukocytes with small volumes of blood. J ALLERGY1970;46:12-20. 9. Hunt KJ, Valentine MD, Sobotka AK, et al. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978;299:157-61. 10. Reisman RE. Insect allergy. IN: Middleton E Jr, Reed CE, Ellis EF, et al. eds. Allergy: principles and practice, vol II. 3rd ed. St. Louis: CV Mosby, 1988:1345-64. 11. Thumheer U, Stoller R, Lanner A, Hoigne R. Venom immunotherapy in Hymenoptera-sting allergy. Clin Allergy 1983;38:465-75.
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12. Nataf P. Guinnepain MT, Herman D. Rush venom immunotherapy: a 3-day programme for Hymenoptera allergy. Clin Allergy 1984;14:269-75. 13. Van der Zwan JC, Flinterman J, Jankowski IG, et al. Hyposensitisation to wasp venom in six hours. Br Med J 1983; 287: 1329-3 1. 14. Urbanek R. Karitzky D, Forster J. Die Hyposensibilisierungsbehandiung mit reinem bienengift. Dtsch Med Wschr 1978: 103:1656-60
Rapid venom
immunotherapy
959
15. Golden DBK, Kagey-Sobotka A, Valentine MD. et ~1. Dose dependence of Hymenoptera venom immunotherapy. J ALLERGYCLIN IMMUNOL 1981;67:370-4. 16. Pienkowski MM, Kazmier WI. Adkinson NF Jr. Basophil histamine release remains unaffected by clinical desensitization to penicillin. J ALLERGYCLIE: ISIMLWOI. 1988X: 17! -8.
Ohio.
und Appleton.
Wis.
A ?- to .5-hour regimen of rapid venom immunotherapy (RVIT) was administered to 33 patients u’ith antrphylactic sensitivity to Hymenoptera venom in a hospital setting in which fu,‘l emergencv resuscitation equipment ~‘a.7 a~~ailahle. The RVIT was adminivtered as 10 in,:~reasing dose3 @each treatment venom ever.! IO to 1.5 minute.\ to achieve a,final dose or: dq\ I of 58.55 pg per venom. Patients returneci,fijr booster venom injections I$ 60 p<;s or’ da>, 3. 70 ~8 on day 7. 80 pg on day 21. and IO0 p,q on da> 35 clf‘ter RVIT. Serial antigen-induced leukocyte histamine release studie.> were peJ&med on da1 I in IO patients bcfure and after RVIT, as well as 3E months after initiation of RUT. 91’33 patients, 32 achieved a cumulative venom dose on da! I of’ at least SO pg. and the entire group rec,eived a mean dose of 95.46 pg. Local reactions during RVIT oxurred in 18 (557~) patients. Four patients (12%) cT.uperienced mild systemic reactions durin g or after completion of RVIT. Subsequent booster venom doses administered to 29 patients were \vell tolerated. 4 decrease in venom-inductId leukocyte-histamine release ftiom baseline MUS detected in three (30%) piltierrts immediately after RVIT and in seven (70%) patients months aj‘ter ac,hieving maintenanc~c~ d,~xr.s Cutaneorrs sensitivity decreased by at least one lox,,, concentration in eight (327~) of -7.5 pgtierrts. Twentv-two natural re-stirq events occurred in I? (50%) of 24 patients vurve!ed qfter successfulcompletion oj’ RVIT, of whom ,se\zen itient$ed the insect as one ,for vt3hic.h thq had been treated. No systemic reactions bvere reported. Re.su(ts of this study indicate that A VIT is a sqfe, alternative method of venom administration fhr patients who are at immediart r-irk for re-sting anaphylactic episodes. (.I ALLERGY CLIN I,MML:VOL 1989:84:9.5/-4. j
It has been estimated that approximately 0.4% of the population experience anaphylactic reactions after Hymenoptera-venom stings.’ Anaphylactic reactions caused by Hymenoptera stings may result in at least 40 deaths annually in the United States.’ The introduction of venom IT for treatment of Hymenopterasensitive parients has reduced the risk of anaphylactic SRs after subsequent re-stings.3 In clinical practice. venom IT is administerecl by increasing subcutaneous injections of venom doses during a 6- to 14-week
From the *Division of Immunology, Department of Medicine. University of Cincinnati Medical Center, Cincinnati. Ohio. and **St. Eiizaheth Hospital, Appleton, Wk. Received for publication Nov 14. 1988. Revised June 28, 1989. Accepted for publication July 5, 1989. Reprint requer;ts: David I. Bernstein, MD. University of Cincinnati Medical Gnter. 231 Bethesda Ave., M.L: 563. Cincinnati, OH 45261. l/1/15494
Abbreviations
IT: HB: W: MV: RVIT: LHR: SR: LR:
used
immunotherapy Honeybee Wasp Mixed vespid Rapid venom immunotherapy Leukocyte histamine release Systemic reaction Local reaction
period until a monthly venom maintenance dose of 100 kg per venom is achieved. Such slow or modified rush venom IT regimens are considered safe and have been used for treating most Hymenoptera-sensitive patients .‘. 5 When specific IT with venom was initially studied. a regimen involving rapid administration of large doses of venom during 2 to 3 days was abandoned, in part because of a high frequency of SRs associated 951
952 Bernstein et al.
J. ALLERGY
I. RVIT schedule of venom dosages for a single treatment venom administered on day 1 at IO- to 15-minute intervals and venom doses subsequently administered on days 3, 7, 21, and 35 TABLE
Time
Dose h.4
Day 0.05 0.10 0.20 0.40 0.80 2.00 5.00 10.00 20.00 gl.oJ 58.55* 3 7 21 35
60 70 80 100
*Total dose (day 1) per venom
with treatment.6Nevertheless,in certain highly sensitive patients, there are specific situations in which an acceleratedform of venom IT may be preferable to slower conventional regimens. For example, RVIT may be indicated for those patients who experience severeSRsduring the warmer months of the year and may be at significant risk for subsequentre-sting reactions during the 8- to 1Zweek period required for diagnostic evaluation and attainment of maintenance doses of venom. A combined experience in 33 Hymenoptera-sensitivepatients with a 2- to 5-hour scheduleof RVIT is describedin this article. Our data indicate that RVIT is a safe alternative method for administration of venom injections to individuals with anaphylactic sensitivity to Hymenoptera allergens. MATERIAL AND METHODS Study group All 33 patientsreceivingRVIT met the eligibility guidelines for venom treatment established by the American Academy of Allergy and Immunology Committee on Insects.’ These guidelines include a prior history of an immediate allergic SR after an Hymenoptera sting and demonstrable intracutaneous reactivity to a concentration of 1 pg/ml or less of venom. As an alternative to RVIT, all patients were offered the standard protocol of modified rush IT. After the potential risks and experimental nature of this method were carefully explained, patients who chose to participate signed an informed-consent statement. A com-
CLIN. IMMUNOL. DECEMBER 1989
plete medical history was performed to exclude underlying cardiac or respiratory disease. Patients with significant cardiopulmonary disease and patients receiving concomitant pblocker drugs were excluded. Before initiation of RVIT, baseline screening studies were performed that included an electrocardiogram, complete blood count, and serum electrolytes. Prospective patients who exhibited clinically significant abnormalities on any of these tests were excluded.
Treatment
protocol
RVIT was administered by physicians at the Asthma and Allergy Treatment Center of the Deaconess Hospital in Cincinnati, Ohio, and St. Elizabeth Hospital in Appleton, Wis. Initially, patients were treated as hospital inpatients, but it soon became evident that RVIT could be performed safely in an ambulatory hospital setting. During RVIT, vital signs and blood pressure were carefully monitored. All patients had indwelling intravenous lines in place during the procedure, and full emergency resuscitation equipment was readily available. The hospital resuscitation team was notified on days when RVIT was administered. The RVIT treatment protocol is presented in Table I, and the venom schedule used on day 1 for a single venom is outlined. For a single venom, 10 increasing subcutaneous doses were administered every 10 to 15 minutes during 2 hours. The starting dose was 0.05 p,g of venom, and subsequent doses were increased every 10 minutes until a cumulative dose of 58.55 +g per venom was achieved on day 1. If multiple venoms were required, venoms were administered concurrently on day 1. Multiple venoms were advanced according to the same schedule for a single venom with each injection separated by an interval of 10 minutes. Thus, to achieve the final target dose on day 1 for two venoms, approximately 200 minutes were required, and for two venoms, approximately 300 minutes were needed. For 10 (nine of whom were treated in Cincinnati, Ohio) patients who received MV, the total dose on day 1 was 58.55 p,g, and by day 35, a dose of 100 kg was administered. In these patients the MV dosage was subsequently increased on a biweekly basis until a final 300 pg target dose was achieved. There were four patients at the second study site (Appleton, Wis.) who were administered a total dose of MV that ranged between 165 and 178.5 (*g on day 1 and who also achieved a maximal dose of 300 p.g of MV on day 35. If an immediate LR (defined by a wheal > 1 cm) was observed, the same venom dose was repeated before increasing to the next larger dose. If the maximal venom dose was achieved on day 1, patients received follow-up injection doses of each treatment venom of 60 pg on day 3, 70 p,g on day 7, 80 pg on day 21, and 100 p.g on day 35. Thus, it followed that a total dose equivalent to 118.55 pg per venom was administered within the first 3 days of treatment. After day 35, patients were administered maintenance doses of 100 p,g per venom at monthly intervals.
Immunologic
studies
Skin testing to relevant venoms (Hollister-Stier Laboratories, Spokane, Wash.) was performed in 25 patients by the end point intracutaneous titration method with increasing
VOLUME NUMBER
Rapid venom
84 6. PART 1
tenfold concentrationsranging from lo-” to 10” pg/ ml. In thesepatients, skin testing was performedboth immediately before and after completion of RVIT. Serial LHR studies in responseto a specific venom used for RVIT were performed in 10 treated patients according to the methods of May et al.’ 0n the day of RVIT, LHR to venoms was performed twice, before RVIT and after the full dose of treatment venom (58.55 kg per venom) had been achieved. A third and final LHR study was repeated on peripheral b.ood of these subjects after they had been receiving maintenance doses of venom for a mean duration of 3% months. In all experiments, LHR was measured in response to tenfold increasing venom concentrations ranging from 10 ’ to IO’ pg/ml. To assess the variability of LHR studies in our laboratory, serial studies of LHR were reproduced 3 hours apart with peripheral leukocytes from untreated Hymenoptera-sensitive patients in response to varying dilutions of venom.The meandifference in percentLHR between IO identical studies performed 3 hours apart was
4.4 ?C2.8. Thus, a change in LHR that was 2 SDSgreater than the meanor a 3 10%changewas consideredsignificant. RESULTS Thirty-three patients with documented anaphylactic sensitivity to Hymenoptera received RVIT between June of 1984 .md April of 1988. This group was comprised of 24 male and nine female subjects with a mean age of 3,8years. Symptoms that occurred during prior anaphylactic episodes after live stings are listed in Table II. There were 11 patients in whom the most severe reporh:d symptoms were urticaria and angioedema. Eight other patients reported stridor or wheezing as the most severe anaphylactic symptom encountered during previous sting reactions. Hypotension and/or syncope were the most severe symptoms in 14 patients. The duration of time between the most recent sting reaction and initiation of RVIT ranged between 1 week and 15 years (x = 17.9 months). There were 16 (48%) patients who were treated within 1 month of their most recent sting SR. RVIT was administered safely to all 33 patients with no serious anaphylactic reactions occurring during treatment. A summary of the individual treatment venoms and their respective doses, as well as the total cumulative venom doses administered on day 1. is listed in Table III. Treated patients were evenly divided between patients who received only one and patients who were administered more than one venom. The total cumulative venom dose administered on day 1 of RVIT ranged between 28.55 and 238 p,g (x = 95.46 kg). All but one patient achieved a cumulative venom dose on day I of >50 kg. The latter individual (No. 17) who received a total dose of only 28.55 of HB venom experienced repeated LRs and subjective complaints of palmar itching after venom injections. Recurrent complaints of palmar itching af-
immunotherapy
953
ter subsequent injections prevented this patient from achieving a full monthly maintenance dose of 100 pg. It is noteworthy that four patients (Nos. 25. 26. 27, and 29) achieved a cumulative venom dose in excess of 200 pg. These larger total doses were attributable to the fact that the MV reagent was administered to the latter four patients at a concentration of 300 pgiml so that a total dose of at least 176 ~g of MV was achieved on day 1. Because the remainder of MVtreated patients were administered a venom concentration of 100 p,g/ml, their total cumulative doses on day 1 were relatively less, ranging between 56.0 and 175.9 l.lg. As presented in Table III, LRs during RVIT were common. Eighteen (55%) of 33 patients experienced significant immediate LRs as defined by wheal diameters >l cm. Two of these subjects also experienced urticarial SRs during RVIT. In no case were LRs severe enough to prevent eventual progression to the final target venom dose. However, when a large LR was observed, the previous dose was repeated at the discretion of the investigator before advancing to the next larger venom dose. There were 14 (42%) patients in whom neither LRs or SRs were encountered during RVIT. Four (12%) mild SRs, consisting of three immediate and one delayed response were observed during or after RVIT. As presented in Table III. three of four of these reactions were manifested by mild urticaria and angioedema. No manifestations of respiratory complaints or vascular collapse were documented during RVIT. One patient (No. 6) developed hives localized to the cervical area after a total cumulative dose of 50.6 p.g of HB venom had been administered and was treated with 50 mg of intramuscular diphenhydramine. A second patient (No. IS) experienced systemic angioedema and hives after administration of a cumulative dose of 119.1 pg of HB and MV venoms, which were treated successfully with a single subcutaneous injection of epinephrine. A third patient (No. 28) experienced diffuse urticaria beginning 24 hours after a cumulative dose of 110 p.g of W and MV venoms had been administered, which responded to ora diphenhydramine. As noted above, another patient (No. 17) complained of palmar itching after achieving a cumulative dose of 28.55 p*gof HB venom on day 1. In this patient, there was no objective sign of an allergic SR. However. it was assumed that this complaint could have represented an early prodromal anaphylactic symptom, and this response was therefore classified as a mild SR. It is noteworthy that all three individuals who experienced immediate systemic symptoms during RVIT were receiving HB venom.
994
Bernstein et al.
J. ALLERGY
TABLE II. Results of initial diagnostic evaluation including age, symptoms during anaphylactic reactions, and time elapsed (months) since most recent reaction Patient No. 1
Prior reactions*
Age
Ml 17
U, D
2
24
U
3 4
32 34
U, H H, W
5 6 7 8 9 10 11 12 13 14 15
57 46 41 35 29 37 29 44 40 49 38
H, U A, U, U, U, U, U, U U, A
16 17 18 19 20 21 22 23 24 25
41 63 38 36 40 52 66 27 7 27
U H, H, U U, U, U, U H H,
26
38
A
27
41
A, U, H, D, W
28
16
U, A
29 30 31 32 33
26 61 40 28 56
U, A, I-L D H H H, S H, S, ST
S U, ST D A A A, ST D A, D
S S, A D A, H D
S, U
ID threshold
(pg/ml)
HB (0. l), YJ (0. l), YH (O.Ol), WFH (O.Ol), W (0.01) W (O.l), YJ (O.l), YH (O.l), WFH (0.1) YJ (O.Ol), YH (l), WFH (0. l), W (1) YJ (O.Ol), YH (O.Ol), WFH (O.Ol), w (0.01) YJ (0.1) HB (0.1) YJ (0.01) HB (0.01)
WFH Cl), YJ (l), YH (l), W (1) YJ (0.1) YJ (0.01). WFH (0. l), YH (0.1)
YJ (l), YJ (I), WFH (1) W (1) w (0.01) YJ (0.1) HB (O.OOl), YH (O.Ol), WFH (0. l), YJ (0.1) w (0.01) HB (0.001) YJ (0.1) w (0.1) YJ (0.01) YJ (0.001) YJ (0.001) YJ (0.1) YJ (O.l), WFH (0. I), YH (0.1) WFH (O.Ol), YJ (0. l), YH (O.l), w (0.1) YJ (O.Ol), YH (O.Ol), WFH (O.Ol), w (0.1) YJ (O.Ol), WFH (O.Ol), YH (O.Ol), W (0.01) W (O.Ol), YJ (O.Ol), WFH (0. l), YH (0.1) YJ (O.l), YH (l), WFH (l), W (1) YJ (0.1)
W (11, YJ (1) YJ (O.Ol), W (0.1) YJ (0.01)
CLIN. IMMUNOL. DECEMBER 1989
prior
Time since last sting (months)
1 18 12 7 1 1 1 6 6 1
24 120 1 1 120 180 1 1 1.5 1 1 1 8 2.5 3 1 4 12 1 5 48 1 1
ID, Intradermal; U, u&aria; D, dyspnea; W, wheezing; ST, stridor; H, hypotension; S, syncope; A, angieedema; YH, yellow hornet; WFH, white-faced hornet; YJ, yellow jacket. *Anaphylactic
symptoms.
Twenty-nine patients who received a venom dose of at least 50 pg on day 1 of RVIT without experiencing SRs during or after treatment returned on days 3 and 7 for administration of venom doses of 60 and 70 kg, respectively. Both of these doses on days 3 and 7 were selected because they exceeded doses of venom equivalent to one live sting. All 29 patients
tolerated both injections on days 3 and 7 after RVIT, as well as subsequent injections of 80 and 100 pg administered on days 21 and 35, respectively. The four patients (Nos. 6,15,17, and 28) who experienced SRs during or after RVIT did not receive these followup scheduled challenge doses of venom. Their subsequent injection schedule was modified so that venom
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84 6, PART 1
TABLE III. Summary
immunotherapv
of results of RVIT on day 1 including types and doses (micrograms) venom(s) administered, total cumulative dose of venom (micrograms), reactions during changes in ID threshold concentration after WIT -~IPatient No.
Venoms
Reactions during RVIT
Total cumulative dose
1 2 3 4 5 6 I 8 9 10 11 12 13 14 1.5 16 17
I-IB (58.6) W (58.6) MV (58.7) ‘A’ (58.8) MV (58.6) ‘W (58.6) MV (58.6) W (58.6) MV (58.6) YJ HB YJ HB W (38.6) MV (23.5) YJ MV MV (58.6) W (58.6) W (58.6) YJ HB (60.55) MV (58.55) W HB
175.9 117.4 117.2 117.2 58.6 50.6 58.6 54.7 62.1 58.7 58.7 117.2 58.6 52.0 119.1 58.95 28.55
18 19 20 21 22 23 24 25 26 21 28
YJ W YJ YJ YJ YJ MV W (58.55) MV (175.65) W (55) MV (165) W (59.5) MV (178.5) W (50) MV ((60)
58.55 58.55 59.35 55.8 5x.5 58.5 56.0 234.21 220.0 238.0 110.0
29 30 31 32 33
W (58.55) MV (175.65) YJ YJ (58.55) W (58.55) YJ (55.55) W (58.55) YJ (58.55)
234.2 51.7 117.1
LR LR LR
955
of WIT, and -
Change in ID threshold* 0
LR, hives LR LR LR
LR LR, hives LR LR, palmar itching
f I (W. WFH, YH, YJj (1 0 +I 0 +2
+2 (W, WFHj 0 0 0 0 +1 ND t-1 0
LR LR LR
0 0 0 fl
-
0 0
LR LR LR LR Late onset hives
ND ND ND ND ND
-
ND ND + 1 (YJ, W) 0
117.1
-
58.55 x = 95.46 kg
18 LR, 4 SR
ID, Intradermai; YJ, yellow jacket; WFH, white-faced hornet: -, no local reaction; ND, skin testing not performed. *Changes in en(Jpoint intracutaneous threshold concentration expressed as increase ( + ), decrease ( - 1, or no change (0) in log,!, concentration required to elicit a wheal of 4 mm greater than the wheal elicited by saline control.
doses were advanced slowly on a weekly basis, as deemed appropriate by the treating physician. Immunologic
studies
In 25 patients, intradermal threshold titration testing was performed before and after RVIT on day 1 with tenfold increasing concentrations of specific treatment venoms. As presented in Table III, only eight (32%) of these individuals exhibited a 21 log,, decrease in
intradermal sensitivity after completion of RVIT. In the remaining patients, no changes in intracutaneous reactivity were observed. Serial LHR studies were performed in 10 subjects, as described in the MATERIAL AND METHODS section. Results of these studies are illustrated in Fig. 1. Of the 10 patients, one was tested to HB, two to W, two to MV, and five to yellow jacket venom. Three patients exhibited decreases of at least 10% histamine
956
Bernstein
et al.
J. ALLERGY
CLIN. IMMUNOL. DECEMBER 1999
100 , 90 80 70 60 50 40 30 20 10 -
Baseline (Day 1)
Post 1.7: (Day 1)
Maintenance
mean-3.6
mo.
FIG. 1. Serial studies of LHR in response
to Hymenoptera venom (1 pgiml) performed in 10 patients before and after RVIT (day 1) and repeated mean of 3% months later. One patient was tested to HB, two to W, five to yellow jacket, and ~0 to MV venoms.
releaseto venom (1 pg/ml) comparedto baselineafter completion of venomtreatmenton day 1. Five subjects exhibited an increase of 210% in percent LHR to venom after RVIT, and there was no change from baseline in two other patients. When the sameLHR studieswere repeatedafter patientshad beenreceiving maintenancevenom injections for a mean duration of 3% months, a definite decreasefrom baseline in percent LHR to the samevenom was observed in seven (70%) of 10 patients studied. After completion of RVIT on day 1, there was no association between changesobserved in percent LHR and changesin intradermal sensitivity to venom antigens. Natural
re-sting
reactions
Questionnaires and telephone surveys were performed in 24 patients who successfullycompletedthe RVIT scheduleregarding the outcomesof natural restings after RVIT. The number of re-sting episodes and duration of time elapsedsince day 1 of RVIT were obtained and are listed in Table IV There were 12 (50%) of 24 patients surveyed who reported natural re-sting episodes.Among this group there was a total of 22 Hymenoptera r-e-stings.The duration of time elapsedbetween day 1 of RVIT and the first re-sting episode ranged from 3 days to 12 months. Three of thesepatients (Nos. 4, 29, and 30) identified the offending insects as different from insects for which they were receiving treatment. As demonstrated, sevenof 12 patients were able to identify the stinging insect as identical to one of the insects for which they had received treatment. Of the latter seven patients,
there were two patients who were stung within 2 months, one of whom was restung 3 days after day 1 of RVIT. No SRs were reported by any patients who experienced natural re-stings, nor was emergency treatmentof thesere-sting episodesrequired. It should also be notedthat one patient (No. 6) who experienced an urticarial SR during day 1 of RVIT after achieving an HB venom dose of 50.6 pg was not advancedbut maintained at GO pg on days 3, 7, and 21. This patient happenedto receive 20 accidental HB stings within 2 months after day 1 and did not have a reaction. DISCUSSION
Venom IT is highly effective for preventing recurrent anaphylaxis after insect stings in patients with proven Hymenoptera sensitivity. Because of its superior efficacy, venom has largely supplanted whole body extracts as the primary immunologic therapy for Hymenoptera-sensitivepatients.9In general, it is recognizedthat the primary goal of venomIT is to achieve a target maintenancedose of 50 to 100 kg of venom that is associatedwith a high probability of protection from subsequentre-sting reactions.lo Most regimens currently used in clinical practice use increasing doses of venom administered during periods of 6 to 14 weeks before a final maintenance dose can be achieved.4,’ For this reason, there have beenprevious attemptsto acceleratethe initial phases of venom treatment. In 1979, a protocol of rush IT was attempted in which relatively large doses of venom ranging from 69 to 5657 pg were administered
VOLUME NUMBER
TABLE
Rapid venom
84 6, PART 1
IV. Summary
Patient No.
of natural
re-sting
Time elapsedt Imo)
episodes
reported
Insect identified
by 24 patients
immunotherapy
after completion
Treatment venom(s)
of RVlT* No. of re-sting episodes
1
-.
I’
3 4
10
5 7 8 9 II 12 13 14 16 18 19 20 21 22 23 26 29 30 31 32 33 Total
12 6 --6
I! 1 ._ i) 1
2 9% 3 weeks 11 10 5 4 3 days
HB
w, MV
YJ HB -
HB. YJ HB w -._ YJ YJ YJ W. MV W, MV YJ W, YJ W. YJ
w -Unknown YJ YJ Unknown HB HB YJ -YJ
957
i
:I f) iI :I 0 2 0 0 0 I 1 2 1 I 2 I 0 I 22
YJ, yellow jacket. *No SRs were reported. ‘ITime elapsedbetween day 1 of RVIT and first re-sting episode
during 2 to 3 days.6 The latter trial was associated with a high rate of allergic SRs, perhaps attributable to relatively large venom doses administered. When patients returned 1 month later for live-sting challenges, there was a high rate of SRs. This apparent lack of efficacy may have been related to the fact that no booster venom injections were administered during the interim period between initial rush treatment and sting challenge. Subsequently, Thumheer et al.” demonstrated that a venom dose of 100 p.g could be achieved by using a rush treatment schedule administered during 10 consecutive days. In this study there was also a similar high rate (38%) of SRS during treatment. In 1984, Nataf et a1.12reported a rush venom protocol in which a target dose of 100 pg of venom could be administered to 52 patients on day 4 after a 3-day rush treatment regimen. In this study, only one mild urticarial reaction was encountered during the initial 3 days of treatment. In addition, SRs did not occur after subsequent injections of 100 pg
administered on days 6, 9, 16, or 30. Van der Zwan et a1.13reported a 6-hour rush IT schedule with wasp venom in 11 Hymenoptera-sensitive patients. In these cases, 216 p,g of W venom was administered in 6 hours without SRs. Follow-up subcutaneous doses of 100 kg administered 7, 14, and 28 days later were also well tolerated. The results of our study indicated that RVIT can be accomplished safely with single or multiple venoms in most patients with anaphylactic sensitivity to Hymenoptera. The prevalence of LRs encountered in most of our patients (55%) was no different than the prevalence reported with other forms of slow or modified rush venom IT.4,5 The proportion of patients who experienced SRs was also comparable to that which has been documented in studies of slow or modified rush venom IT.4 SRs that did occur during RVIT were not of a serious nature and responded readily to treatment. Because two of three of the subjects with immediate SRs were receiving only HB venom and the
958
Bernstein
et al.
other subjectsreceivedboth HB and MV, it is possible that HB venom may be associatedwith a greater risk than other venoms for development of SRs during RVIT. The efficacy of this RVIT regimen was evaluated by performing a careful survey of natural re-sting events after treatment. Our survey revealed that no anaphylactic reactions were reported after 22 natural sting episodes. However, only sevenpatients in this survey who received a total of 15 stings could identify the stinging insect as identical to one for which they were receiving treatment. Included in the latter group of sevenpatients were two patients who were stung within 2 months of initiation of RVIT and who did not suffer SRs. Live sting challenges were not performed in this study to evaluate the protective effect of RVIT, particularly within the initial weeksof treatment. However, other investigators have addressed this question. In 11 patients treated by RVIT to W venom, all tolerated W-sting challenges at least 1 month after commencingtreatment.” Urbanek et al. I4 performed rush IT in 11 patients with anaphylactic sensitivity to HB during 7 days. Live sting challenges administeredat approximately 1 week after beginning treatment were tolerated without SRs. Thus, it is apparent from the work of theseother investigators that this form of RVIT may be effective for achieving protection from live venom stings within the first 1 to 2 weeksaswell asmonths after initiation of treatment. However, further studies of this nature are required and in larger numbers of Hymenoptera-sensitivepatients before the immediate protective effect of RVIT can be ascertained. Patients treated with the RVIT protocol did not achieve a 100 pg dose of venom until week 5. A previous study with a different treatment protocol demonstratedthat only 79% of Hymenoptera-sensitive patientsreceiving a 50 p.gmaintenancedoseof venom were protectedfrom live sting challenges.I5However, it should be emphasizedthat nearly all our patients receiveda total cumulative doseof approximately 188 pg per venom within the first 7 days of therapy. To addressthis concern, we have since modified the protocol presentedin Table I so that patients now receive weekly (instead of biweekly) venom injections after day 7 until they achievea targetdoseof 100 pg. Thus, the entire protocol can be completed by day 21. Immunologic studies were performed during RVIT to explain the efficacy of RVIT. Desensitization as determined by a decreasein cutaneousreactivity to the specific treatment venoms was achieved in only one third of treated patients. Similarly, only 30% of thesepatients exhibited a decreasein basophil releas-
J. ALLERGY
CLIN. IMMUNOL. DECEMBER 1989
ability in response to venom after treatment with RVIT. The finding of no change in antigen-induced histamine release in two thirds of our patients is in agreementwith a recent study that demonstratedthat no significant decreasein LHR releasability to antigen occurs during rapid desensitization to penicillin. I6 There was no correlation betweenchangesin basophil sensitivity and cutaneous reactivity to venom after completion of RVIT. These disparate results could reflect intrinsic differences between circulating basophils and cutaneousmast cells. However, most of our patients eventually demonstrateddecreasedhistamine release to venom months after they had received maintenancevenom IT. Further investigations are required to define the exact mechanismof tolerance to natural stings and sting challenges achieved by RVIT. In summary, this regimen of RVIT possessesacceptablesafetyfor treating Hymenoptera-sensitivepatients. It may be particularly indicated for those patients who are at immediate risk of being restung. Specifically, this treatmentis particularly indicated for patients who experience severeSRs during the peak of the summerseasonso that maintenancelevel doses can be attained rapidly within days after the initial sting episode. REFERENCES 1. Settipane GA, Boyd GK. Prevalence of bee sting allergy in 4,992 Boy Scouts. Acta Allergol 1970;25:286-91. 2. Barnard JH. Studies of 400 Hymenoptera sting deaths in the United States. J ALLERGYCLINIMMUNOL1973;52:259-64. 3. Lichtenstein LM, Valentine MD, Sobotka AK. A case for venom treatment in anaphylactic sensitivity to Hymenoptera sting. N Engl J Med 1974;290:1223-7. 4. Golden DBK, Valentine MD, Kagey-Sobotka A, Lichtenstein LM. Regimens of Hymenoptera venom immunotherapy. Ann Intern Med 1980;92:620-4. 5. Clayton WF, Reisman RE, Mueller U, et al. Modified rapid venom desensitization. Clin Allergy 1983;13: 123-9. 6. Yunginger JW, Paul1 BR, Jones RT, Santrach PJ. Rush venom immunotherapy program for honeybee-sting sensitivity. J ALLERGYCLINIMMUNOL1979;63:340-7. 7. Golden DBK, Schwartz HJ. Guidelines for venom immunotherapy. J ALLERGYCLINIMMUNOL1986;JJ:J2J-8. 8. May DC, Lyman M, Albert0 R, Cheng J. Procedures for immunochemical study of histamine release from leukocytes with small volumes of blood. J ALLERGY1970;46:12-20. 9. Hunt KJ, Valentine MD, Sobotka AK, et al. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978;299:157-61. 10. Reisman RE. Insect allergy. IN: Middleton E Jr, Reed CE, Ellis EF, et al. eds. Allergy: principles and practice, vol II. 3rd ed. St. Louis: CV Mosby, 1988:1345-64. 11. Thumheer U, Stoller R, Lanner A, Hoigne R. Venom immunotherapy in Hymenoptera-sting allergy. Clin Allergy 1983;38:465-75.
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12. Nataf P. Guinnepain MT, Herman D. Rush venom immunotherapy: a 3-day programme for Hymenoptera allergy. Clin Allergy 1984;14:269-75. 13. Van der Zwan JC, Flinterman J, Jankowski IG, et al. Hyposensitisation to wasp venom in six hours. Br Med J 1983; 287: 1329-3 1. 14. Urbanek R. Karitzky D, Forster J. Die Hyposensibilisierungsbehandiung mit reinem bienengift. Dtsch Med Wschr 1978: 103:1656-60
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15. Golden DBK, Kagey-Sobotka A, Valentine MD. et ~1. Dose dependence of Hymenoptera venom immunotherapy. J ALLERGYCLIN IMMUNOL 1981;67:370-4. 16. Pienkowski MM, Kazmier WI. Adkinson NF Jr. Basophil histamine release remains unaffected by clinical desensitization to penicillin. J ALLERGYCLIE: ISIMLWOI. 1988X: 17! -8.