medication or modification of the administration protocol. Shecontinued the treatment at home with 8 drops/day, but reporteda severe asthma attack 1 week later together with mouth itchinessimmediately after SLIT, lasting for several hours. She was in-structed to stop SLIT for 2 days and then to restart with progress-ive doses up to 4 drops. However, she had to discontinue SLITbecause of repeated asthma attacks time-related to the treatment.

The second patient we report is a 13-year-old boy diagnosed at10 years with allergic asthma and a seasonal and chronic rhinitis.The history was also positive for symptoms after contact with catsand horses. The skin prick test work-up was positive for grass andcereal pollens, dust mites, molds, and cat dander. He was startedon SCIT with 2 separate injections, the first with a mix of grass(80%) and rye (20%) pollens, and the second with a mix of Dpteronyssinus (50%) and Dermatophagoides farinae (50%; Phos-tal; Stallergenes). After the first injection, the patient reportedshortness of breath and was wheezing. He recovered immediatelyafter receiving a b2-agonist inhalation and an oral antihistamine.One week later, he was administered the same dose and rapidlycomplained about chest tightness. For the next 2 injections, the pa-tient was pretreated with an antihistamine but still developedshortness of breath and an immediate large local reaction at thesite of injection. The treatment was discontinued because of theseside effects. He was then started on SLIT with a mix of 80% grassand 20% rye pollens (Stalloral 300) and 10 weeks later with a mixof D pteronyssinus (50%) and D farinae (50%; Stalloral 300). Thetreatment was administered by an initial ultrarush protocol, fol-lowed by 8 drops on alternate days with each mix. After startingthe dust mite treatment, he complained of heavy nasal congestion,which finally resulted in stopping the dust mite preparation, with arapid relief of the symptoms. The grass mix SLIT was well toler-ated and stopped after grass pollen season as indicated. In late fall,the dust mite mix was started again by ultrarush with a good tol-erance, but with reoccurrence of heavy nasal congestion togetherwith increased symptoms of asthma. SLIT treatment was stoppedby the patient, followed by rapid symptom relief.

Both patients presented here had important side effects afterSCIT, justifying discontinuation of immunotherapy. Because ofthe excellent safety profile of SLIT in the literature and theabsence of reported systemic side effects,3 we felt that in thesehighly motivated patients, SLIT would be an efficient4 and safealternative to SCIT.5 However, both patients had respiratory—that is, systemic—side effects. In the first patient, they evenprogressed from large local reactions with SCIT to respiratoryreactions with SLIT, thus increasing in severity.

With this report on 2 patients started on SLIT because ofsignificant side effects of SCIT, we would like to attract theclinician’s attention to potential systemic side effects with SLITdespite the good safety profile generally reported for this proce-dure.6,7 Special caution should be exerted in patients with a pre-vious history of side effects on immunotherapy, because SLITdoes not represent a totally safe immunotherapy procedure.

Marie M. Cochard, MD

Philippe A. Eigenmann, MD

From the Department of Pediatrics, University Hospitals of Geneva, Switzerland.

E-mail: Philippe.Eigenmann@hcuge.ch.

Disclosure of potential conflict of interest: P. A. Eigenmann has received speakers’ fees

from ALK-Abello, AllergoPharma, and Phadia; has received research support from the

Swiss National Research Foundation and the Yde Foundation; and has provided expert

testimony for the European Food Safety Agency (EFSA) regarding food allergy and

the European Commission. M. M. Cochard has declared that she has no conflict of

interest.

REFERENCES

1. Wilson DR, Lima MT, Durham SR. Sublingual immunotherapy for allergic rhinitis:

systematic review and meta-analysis. Allergy 2005;60:4-12.

2. Stelmach I, Kaczmarek-Wozniak J, Majak P, Olszowiec-Chlebna M, Jerzynska J.

Efficacy and safety of high-doses sublingual immunotherapy in ultra-rush scheme

in children allergic to grass pollen. Clin Exp Allergy 2009;39:401-8.

3. Passalacqua G, Guerra L, Compalati E, Canonica GW. The safety of allergen spe-

cific sublingual immunotherapy. Curr Drug Saf 2007;2:117-23.

4. Di RV, Marcucci F, Puccinelli P, Parmiani S, Frati F, Sensi L, et al. Long-lasting ef-

fect of sublingual immunotherapy in children with asthma due to house dust mite: a

10-year prospective study. Clin Exp Allergy 2003;33:206-10.

5. Bufe A, Ziegler-Kirbach E, Stoeckmann E, Heidemann P, Gehlhar K, Holland-Letz

T, et al. Efficacy of sublingual swallow immunotherapy in children with severe grass

pollen allergic symptoms: a double-blind placebo-controlled study. Allergy 2004;59:

498-504.

6. Agostinis F, Foglia C, Landi M, Cottini M, Lombardi C, Canonica GW, et al. The

safety of sublingual immunotherapy with one or multiple pollen allergens in chil-

dren. Allergy 2008;63:1637-9.

7. Nichani JR, de Carpentier J. Safety of sublingual grass pollen immunotherapy after

anaphylaxis. J Laryngol Otol 2008;23:1-2.

Available online June 1, 2009.

doi:10.1016/j.jaci.2009.04.040

J ALLERGY CLIN IMMUNOL

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LETTERS TO THE EDITOR 379

The safety of initiating Hymenoptera immuno-therapy at 1 mg of venom extract

To the Editor:Various venom immunotherapy (VIT) schemes have been

proposed since the introduction of purified Hymenoptera venomsin the late 1970s; they differ in several aspects, including theinitiating dose. The recommended starting dose is between0.001 and 0.1 mg or less for ‘‘highly sensitive’’ patients.1 Thepresent report evaluates the safety of administering 1 mg as theinitial dose in 2 different VIT protocols: ultrarush and modifiedrush.

Before undertaking this project, a brief pilot study involving 82adult volunteers (60 male and 22 female volunteers) had shown nocorrelation between the initial venom dose (from 0.0001 mg to1 mg) and the frequency or severity of observed systemic allergicreactions (SRs) caused by VIT.2

A total of 670 patients with venom allergy, aged 33.8 6 16.2years (median age, 32 years; range, 5-65 years) and with a historyof SRs, have been treated over a period of 14 years. Sixty-eightchildren (age range, 5-14 years) were included in the study. Theultrarush protocol was proposed to high-risk adults (professionalor amateur beekeepers, farmers and other outdoor workers) and topersons living in distant locations, such as small islands, whichlack in-hospital care.

The identification of the offending insect was based on thepatient’s history and in vivo (intradermal skin testing) and in vitro(CAP-FEIA; Phadia AB, Uppsala, Sweden) venom-specific IgEdeterminations. Lyophilized and freshly reconstituted venomswere used for skin testing and VIT (Pharmalgen [ALK-Abello,Madrid, Spain] and Alyostal [Stallergenes, Antony, France]). Torule out any placebo effect–related symptoms, 0.10 mL of diluentpreceded the first 1-mg venom dose (0.1 mL of the 10 mg/mLvenom concentration) in both protocols. Patients were closelymonitored for adverse reactions, which were classified in accor-dance to the recommendations of the American Academy ofAllergy, Asthma & Immunology (AAAAI) Committee onInsects.3

Three hundred sixty-eight (54.9%) of 670 patients were treatedwith bee venom, 242 (36.1%) were treated with vespid venom,and the remaining 60 (9%) were treated with both bee and vespid

J ALLERGY CLIN IMMUNOL

AUGUST 2009

380 LETTERS TO THE EDITOR

TABLE I. Immunotherapy protocols followed in the study and number of participating patients in each, according to venom

sensitization

Ultrarush

(inpatient treatment, 4-d hospitalization)

Modified rush

(outpatient treatment: Monday, Wednesday, and Friday)

Venom used: honeybee (n 5 48), vespid

(n 5 8), both (n 5 6)

Venom used: honeybee (n 5 320), vespid

(n 5 234), both (n 5 54)

Venom

concentration

Volume

(mL)

Dose

(mg)

Venom

concentration

Volume

(mL)

Dose

(mg)

Day 1 Placebo 0.10 0 Day 1 Placebo 0.10 0

10 mg/mL 0.10 1 10 mg/mL 0.10 1

0.30 3 0.30 3

0.60 6 0.60 6

100 mg/mL 0.10 10 100 mg/mL 0.10 10

0.20 20 Total dose 20

0.30 30 Day 3 100 mg/mL 0.10 10

0.40 40 0.20 20

0.50 50 0.30 30

Total dose 160 0.40 40

Day 2 100 mg/mL 0.60 60 Total dose 100

0.40 40

Total dose 100 Day 5 100 mg/mL 0.45 45

0.55 55

Day 4 100 mg/mL 1.00 100 Day 8 100 mg/mL 1.00

Total dose 100 Total dose 100

The time interval between doses was 30 or 60 minutes (if reactions occurred). After reaching the 100-mg maintenance dose, treatment continued with the same dose at increasing

intervals.

TABLE II. Systemic reactions caused by rush and ultrarush VIT

Venom

concentration

Dose

(in mg)

Injections

(no.)

Observed

reactions

(no.)

Injections caus-

ing

reaction (%)

10 mg/mL 1 mg 730 0 0

3-6 mg 1,460 25 1.7

100 mg/mL 10-50 mg 3,650 84 2.3

>50 mg 2,190 110 5

Total 8,030 219 2.7

Reactors to

bee venom

Reactors to

vespid venom

Dose Mild Moderate Severe Mild Moderate Severe

3-6 mg 8 3 – 5 – –

>6-50 mg 39 11 3 6 0 –

>50 mg 41 23 8 7 1 –

Patients* 71 31 9 18 1 0

Total� 83/428 (19.3%) 18/302 (5.9%)

Mean RR 13.8%

Mild, Cutaneous involvement with or without other mild symptoms treated with H1-

antagonist (any route) with or without epinephrine (100 mg administered

subcutaneously) administered at the site of venom injection or tourniquet or ice

(for retardation of absorption); Moderate, cutaneous plus symptoms from other

organs responding to epinephrine (300 mg administered subcutaneously) with or

without an H1-antagonist administered intravenously, corticosteroids administered

intravenously, or b2-agonists; Severe, any of the above plus cardiovascular

symptoms or respiratory obstruction with or without severe abdominal symptoms

requiring repeatedly administered doses of epinephrine (300 mg administered

subcutaneously), fluids, H1- and H2-antagonists, corticosteroids (all administered

intravenously), and b2-agonists; Life-threatening, hypotension (unresponsive to

epinephrine administered subcutaneously) with or without respiratory obstruction

requiring incubation and/or hospitalization and/or intensive care unit stay; RR,

mean reaction rate for the entire population of patients with Hymenoptera allergy.

*Total number of patients reacting in each grade of reaction (some individuals

reacted to >1 concentration).

�Total number and percentage of patients who reacted to each venom.

venoms. In the case of patients with multiple allergies, venomswere administered through separate injections in opposite arms,within an hour’s interval. Sixty-two (9.3%) adults were hospital-ized and subjected to the ultrarush protocol; the rest were treatedas outpatients with a modified rush immunotherapy scheme. The2 VIT schemes are shown in Table I.

A total of 730 initial 1-mg venom doses were administered;they were preceded by 670 placebo injections to excludevasovagal reactions. During the updosing phase of both regimens,8030 injections were delivered; 2190 of 8030 were from the10 mg/mL venom concentration, and only 25 (17 mild and 8moderate) SRs were observed, none of them occurring within30 minutes from the initial 1-mg dose. No reactions were causedby the placebo diluent injections. A total of 219 SRs, mostly mildin severity, were observed in 95 patients during the entireupdosing course. The great majority of reactions were causedby bee venom injections at the 100-mg concentration. All severereactions, none of which were life-threatening, occurred in 9patients with honeybee allergy; close to 75% of these occurred atthe 100-mg concentration (Table II). The observed adversereactions per number of injections and the number of reactorsaccording to dose/concentration administered and type of venomare also shown in Table II.

SRs during VIT have been reported to occur in 5% to 15% ofpatients with vespid allergy and 20% to 40% of honeybee venom–treated patients, mainly during the first weeks of treatment,regardless of the VIT scheme used.1 The exact risk factors forsystemic reactions to VIT have not been well established. Themajority of published reports suggest that immunotherapy withhoneybee venom results in more reactions than with Vespidaevenoms. It is not clear whether the cause of this phenomenon isdue to the different enzymatic content of Apidae venom.4,5 Therapid dose increments and the high cumulative daily doses in

Does access to care equal asthma control inschool-age children?

To the Editor:In 2005, 6.5 million children under 18 years were documented

as having asthma.1 Access to care is thought to be key to asthmacontrol. The ‘‘medical home’’ is a concept that started for childrenwith special needs but now has been extended to all individuals.2

Those with a medical home have fewer hospitalizations and emer-gency department visits.3 Likewise, in both adults and children,hospitalization rates and emergency care use have been shownto be higher in those with public or no insurance.4-8

This study sought to examine the relationship between access tocare and asthma control for children within the Denver PublicSchool Asthma Program, an outreach program in 19 (14 elementaryand 5 middle) schools in the Northeast/Northwest sections ofDenver. Of these students, 728 were identified as having asthma andwere invited to participate. Approval was received from theNational Jewish Health Institutional Review Board, and consentplus assent were obtained from all participants and caregivers. Thechildren’s demographic information and various measures ofasthma control were compared according to the presence or absenceof medical insurance or a medical provider by using the t test forcontinuous variables and the x2 test for categorical data. In addition,for insurance or medical provider status, comparisons were ana-lyzed according to the type of medical insurance (ie, public vs pri-vate) and the type of provider (ie, primary care vs specialty).

Demographic characteristics for the 155 students enrolledincluded a mean 6 SD age of 9.2 6 2.6 years, with 58% male,25% black, and 51% Hispanic. The majority qualified for reducedlunch (79%), had health insurance (90%, of which 54% werepublic plans; Fig 1, A), and had a physician caring for their asthma(92%; Fig 1, B).

FIG 1. A, 90% (139/155) of children had health care coverage, 54% public

plans such as Colorado Health Services (CHS), Child Health Plan Plus

(CHP), or Colorado Indigent Care Program (CICP). B, 94% (145/155) identi-

fied having a medical care provider that cared for their child’s asthma.

89% (129/145) of those students with providers were managed by primary

care providers (although not all parents knew if this was a pediatrician or

family physician; undetermined, not know specialty; missing, not filled

out; physician assistant/nurse practitioner, PA/NP).

J ALLERGY CLIN IMMUNOL

VOLUME 124, NUMBER 2

LETTERS TO THE EDITOR 381

the ultrarush protocols have also been considered risk factors,especially in patients with bee venom allergy.1 Female sex, adult-hood, and a history of a previous severe allergic reaction to Hyme-noptera stings are additional risk factors, yet the most importantrisk factors, not only for reactions but also for VIT failures, areunderlying mastocytosis, increased baseline serum tryptaselevels, and ‘‘mast cell activation disorders.’’6,7

In our study the relative incidence was 13.8% (19.3% inhoneybee venom–treated patients and 5.9% in vespid venom–treated patients). In the AAAAI study involving 1226 patientswho reached the maintenance dose, SRs during updosingoccurred with a lower frequency (9.7%)3; the higher incidencenoted in the present study might relate to the exclusive applicationof rush regimens and the high percentage of patients with beevenom allergy in our patient population (54.9% vs 31.9% of theAAAAI study3). The latter is consistent with the fact that ourcountry maintains the highest concentration of beehives persquare meter of land. Other studies involving smaller numbersof patients receiving ultrarush immunotherapy have reported anincidence of SRs in the range of 7% to 12.8%.8

The use of an initial dose of 1 mg in both the modified rush andultrarush protocols was shown to be safe. This is supported by ourSR rate being similar or lower in magnitude than those reportedby other investigators, even though most of our patients weretreated with bee venom, including our pediatric group, which wasalmost exclusively bee venom sensitive. Perhaps when starting ata higher venom dose, one bypasses the low, IgE-stimulatingdoses9 while saving time, money, and discomfort for the patients.

In conclusion, initiating VIT at the 1-mg dose can be appliedsafely in rush protocols.

Areti Roumana, MD

Constantinos Pitsios, MD, PhD

Stamatios Vartholomaios, MDEvangelia Kompoti, MD

Kalliopi Kontou-Fili, MD, PhD

From the Department of Allergology & Clinical Immunology, Laikon General Hospital,

Athens, Greece. E-mail: kontoufk@otenet.gr.

Disclosure of potential conflict of interest: The authors have declared that they have no

conflict of interest.

REFERENCES

1. M€uller U, Golden DBK, Lockey RF, Shin B. Immunotherapy for Hymenoptera

venom Hypersensitivity. Clin Allergy Immunol 2008;21:377-92.

2. Kontou-Fili K, Papaioannou D, Palaiologos G. Hymenoptera immunotherapy: lack

of correlation between the initial venom concentration and severity of observed

reactions. Schweiz Med 1991;121(suppl):S63.

3. Lockey RF, Turkeltaub PC, Olive ES, Hubbard JM, Baird-Warren IA, Bukantz SC.

The Hymenoptera venom study III: safety of venom immunotherapy. J Allergy Clin

Immunol 1990;86:775-80.

4. Birnbaum J, Ramadour M, Magnan A, Vervloet D. Hymenoptera ultra-rush venom

immunotherapy (210 min): a safety study and risk factors. Clin Exp Allergy 2003;

33:58-64.

5. Mosbech H, M€uller U. Side-effects of insect venom immunotherapy: results from an

EAACI multicenter study. Allergy 2000;55:775-80.

6. Kontou-Fili K. High omalizumab dose controls recurrent reactions to venom immu-

notherapy in indolent systemic mastocytosis. Allergy 2008;63:376-8.

7. M€uller UR, Haeberli G. The problem of anaphylaxis and mastocytosis. Curr Allergy

Asthma Rep 2009;9:64-70.

8. Schiavino D, Nucera E, Pollastrini E, De Pasquale T, Buonomo A, Bartolozzi F,

et al. Specific ultrarush desensitization in Hymenoptera venom-allergic patients.

Ann Allergy Clin Immunol 2004;92:409-13.

9. Maia LCS, Vaz NM, Vaz EM. Effect of soluble antigen on IgE responses in the

mouse. Int Arch Allergy Appl Immunol 1974;46:339-46.

Available online June 29, 2009.

doi:10.1016/j.jaci.2009.05.026