Allergic reactions to insect stings and bites.

Abstract: Insect stings are an important cause of anaphylaxis. Anaphylaxis can also occur from insect bites but is less common. Insect venoms contain several well-characterized allergens that can trigger anaphylactic reactions. Effective methods to diagnose insect sting allergy and assess risk of future sting reactions have been developed. Management strategies using insect avoidance measures, self-injectable epinephrine, and allergen immunotherapy are very effective in reducing insect-allergic patients' risk of reaction from future stings. Diagnostic and management strategies for patients allergic to insect bites are less developed.

Key Words: anaphylaxis, insect reaction, insect venom

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Insect stings by members of the Hymenoptera family have caused human deaths since at least the time of the Ancient Egyptians and are currently responsible for at least 40 deaths from allergic reactions per year in the United States. The prevalence of insect sting allergy is estimated to be between 0.5 and 3%, and people who have previously experienced generalized allergic insect sting reactions are at increased risk for reactions from future stings. Effective management strategies using allergen immunotherapy can greatly reduce the risk of future anaphylactic reactions and their associated morbidity and mortality. (1-6)

Insect bites can also cause allergic reactions, but scientific knowledge about insect bite allergy is limited. Reactions have most commonly been reported after bites from mosquitoes and other flies and from Triatoma bugs. (7) Unfortunately, management strategies to reduce the risk of future insect bite reactions are less well developed and less effective than for insect sting allergy.

The three families of stinging insects in the order Hymenoptera are Vespidae, Apidae, and Formicidae. (5) Yellow jackets, wasps, and hornets all belong to the Vespidae family (vespids); honeybees and bumblebees belong to the Apidae family (apids); and stinging ants belong to the Formicidae family (formicids). In most areas of the United States, yellow jackets are the leading cause of allergic insect sting reactions; however, in many areas of the South, fire ants (Fig. 1) or wasps (Fig. 2) are the leading causes of these reactions. (1), (4), (5)

Yellow jackets are very aggressive insects that nest in the ground, hollow logs, wall tunnels, and caverns, where they can be easily disturbed. They are attracted to food, drinks, picnic areas, and garbage.

Hornets, which are close relatives of yellow jackets, form large paper nests in shrubs and trees and are also very aggressive. The two main species in the United States are the baldfaced (or white-faced) hornet and the yellow hornet. Hornets are also very aggressive, especially when near the nest.

Wasps form honeycomb paper nests under the eaves of houses and other buildings and in trees and shrubs. The insects can be seen on the surface of the nest.

Domestic honeybees are less aggressive and usually sting only when disturbed; however, persons who disturb their hives may suffer massive numbers of stings. Their hives, which are frequently located in hollow trees or logs or in buildings, are quite large and can contain thousands of bees. After stinging the victim, they usually leave the barbed stinger and attached venom sac imbedded in the victim's skin. Although some vespids occasionally leave stingers, this is a rare occurrence. The Africanized (or killer) honeybee is a much more aggressive hybrid honeybee that developed from interbreeding between African honeybees and domestic honeybees in South America. Over the last several decades they have advanced northward and entered the United States (Fig. 3). These insects are much more likely to attack in swarms than domestic honeybees. Their venom is very similar to domestic honeybee venom.

The imported fire ant probably entered the United States on cargo through the port of Mobile, AL, in the early portion of the 20th century. (5) Since that time, it has spread beyond the southeastern United States and now occupies more than 310 million acres (Fig. 3). Colonies have now been identified in California. It has largely overtaken or hybridized with the domestic fire ant in its habitat. Fire ant nests or mounds may contain more than 100,000 ants. These insects have made several adaptations that include multiple (polygyny) queen colonies, deeper colonies, and use of roads and buildings as heat sumps to enhance their ability to survive colder temperatures and promote their spread northward. The dominant species in the United States is Solenopsis invicta. The other species, Solenopsis richteri, is confined to a small area along the North-central portion of the Mississippi-Alabama border. Imported fire ants are very aggressive, especially if their nest is disturbed. They sting by grasping the victim's skin in their mandibles and pivoting around to deliver the stings, which can be multiple. In highly endemic areas, more than 50% of the population is stung each year. Some persons have received thousands of stings from massive attacks. Such massive attacks can occur on immobilized individuals in indoor settings. (5)

[FIGURE 1 OMITTED]

Other Hymenoptera insects have caused allergic sting reactions. Some of these include the bumblebee and sweat bee as well as several types of ants, including Myrmecia in Australia and Pogonomyrmex, or the harvester ant, in the United States. (6)

Hymenoptera Venoms

Flying Hymenoptera venoms are mainly aqueous solutions that contain peptides, proteins, and vasoactive amines including acetylcholine, norepinephrine, histamine, dopamine, and 5-hydroxytryptamine. (4), (8) These substances are responsible for venom toxicity, and several of the proteins and peptides are allergenic. Approximately 50 [micro]g protein is injected per sting.

The yellow hornet, white faced hornet, and yellow jacket allergens are very similar and cross-react extensively. The major allergen in each is antigen 5; other allergens include phospholipase A, hyaluronidase, and acid phosphatase. The venom of the wasp, which is less closely related to these insects, cross-reacts moderately with their venoms. The major allergen of honeybee venom is phospholipase [A.sub.2]; other allergens include melitin, hyaluronidase, apamin, and peptide 401. Honeybee and vespid venoms share only limited immunologic cross-reactivity. (1), (4)

[FIGURE 2 OMITTED]

Imported fire ant venom differs significantly from the venom of flying Hymenoptera. The volume injected is much smaller, ranging from 0.04 to 0.11 [micro]l, and 95% of its volume is composed of alkaloids; only 5% is an aqueous component. (5), (8) The alkaloid component contains piperidines, which have antimicrobial, cytotoxic, and hemolytic activities, and seems to be responsible for the sterile pustule from fire ant stings but does not cause allergic responses. The smaller aqueous phase contains the allergenic proteins. Protein content can be much higher in the summer and can vary from 10 to 100 ng per sting. Solenopsis invicta venom contains four allergenic proteins that have been identified. Sol i I, a 37-kDa protein, possesses phospholipase activity and cross-reacts weakly with vespid phospholipase. Sol i II, which is a 26-kDa protein, makes up approximately two-thirds of fire ant venom protein but does not have a corresponding protein in vespid venom. Sol i III, which is a 24-kDa protein, is related to antigen 5 but lacks cross-reactivity with antigen 5 from vespid venom. Sol i IV, a 13-kDa protein, has some identity with Sol i II but lacks cross-reactivity with any venom proteins. Solenopsis richteri venoms contain proteins corresponding to and extensively cross-reactive to Sol i I, II, and III but lack a protein similar to Sol i IV. (8)

[FIGURE 3 OMITTED]

Insect Sting Reactions

Insect sting reactions can be classified as usual (or normal), large local, anaphylactic, and toxic. The usual or normal reaction features an area of swelling, erythema, and pain around the sting site. These features are transient, resolving within a few hours. Fire ant stings are unique in that a pustule usually develops at the sting site within 24 hours.

Large local reactions are characterized by more extensive erythema and swelling surrounding the sting site and often continue to enlarge for 1 to 2 days before resolving slowly over several more days. Large local reactions frequently recur with future stings but are only a small risk factor (<10%) for anaphylaxis after future stings. (9)

Anaphylactic reactions, mediated through immunoglobulin (Ig) E and exhibiting the typical features of systemic allergic symptoms, are generally the most serious. Anaphylactic reactions probably occur in 0.5 to 1.5% of stings, but one estimate is as high as 3%. (1-3), (5), (6) Reaction severity can range from mild urticaria and SC angioedema to severe reactions with obstruction of the airway, hypotension, and shock. Patients who have previously experienced insect sting anaphylaxis are at increased risk for anaphylaxis from future stings; however, most fatalities occur with the first anaphylactic reaction. Although most fatalities occur in adults, children and adolescents experience more insect sting reactions. The presence of an atopic disease increases risk of stinging insect allergy only marginally.

Toxic reactions, which are caused by physiologic effects of large amounts of venom from multiple stings, can mimic anaphylaxis. Several of the venom constituents have physiologic effects that are the same as or similar to the mediators of allergic reactions. Reactions that mimic systemic allergic reaction but lack detectable venom-specific IgE have also been reported. (10), (11)

Other complications of insect stings include serum sickness reactions, neuritis, myasthenia gravis, cerebral infarction, Guillain-Barre syndrome, encephalitis, Henoch-Schonlein purpura, Reye-like syndrome, myocardial infarction, and cardiac arrhythmia.

Diagnosis and Management of Insect Sting Reactions

Local Reactions

The diagnosis of local reactions is usually evident from clinical history and physical findings. The usual or normal reaction does not require treatment, but analgesics or cold compresses can be used if needed. (1) If a stinger is in place, it should be removed, preferably by scraping, because squeezing the venom sac within the first few seconds after a sting could inject additional venom. Infection from insect stings is a rare complication in immunocompetent hosts, and antibiotics are not indicated in the absence of infection. If the sting is from a fire ant, the pustule should be left intact. Large local reactions are usually of little consequence and usually are managed like normal reactions; however, on occasion they can be severe, with extensive swelling and localized hives. Although no studies have confirmed efficacy, many physicians have found potent topical or oral corticosteroids to reduce severity of these reactions. Because patients with large local reactions have a slightly increased risk of anaphylaxis from future stings, it is optional but usually not necessary to prescribe self-injectable epinephrine for these patients. Immunotherapy was found to be ineffective in preventing future large local reactions in one study, but a recent case report described effective use of immunotherapy to prevent severe debilitating local sting reactions in one patient. (9), (12) Immunotherapy is not indicated in the vast majority of patients with large local reactions but might be considered in the most severe circumstances based on this report.

Anaphylactic Reactions from Flying Hymenoptera Stings

The clinical diagnosis of acute anaphylaxis from an insect sting is usually straightforward and is based on a history and/or physical evidence of a sting and the typical features of an acute systemic allergic reaction. (1), (4) The diagnosis is confirmed by demonstrating venom-specific IgE antibodies by either skin testing or in vitro testing, usually at least 3 to 4 weeks after the acute reaction to reduce the likelihood of a false-negative result. These tests not only confirm the diagnosis but also identify appropriate venoms for immunotherapy. The management of acute insect sting anaphylaxis is no different from anaphylaxis from other causes. Preventive management strategies are designed to reduce a patient's risk of future reactions and their associated morbidity and mortality, and include avoidance measures to reduce a patient's chances of being stung, provision of emergency treatment, and evaluation of the patient as a potential candidate for immunotherapy. Many insect-allergic patients do not receive optimal preventive management, and immunotherapy in particular is underused. The development of preventive strategies is based on the natural history of insect sting allergy, confirmation of the diagnosis, and use of venom immunotherapy to affect the natural course of the disease. (1), (3), (4)

Natural History

Hunt et al (3) found that an insect-allergic adult faces an approximately 60% risk of an anaphylactic reaction after a subsequent sting. Since the publication of that report, several other studies of field stings and deliberate challenges have demonstrated that insect-allergic patients have a risk for future reaction of approximately 30 to 60% from the next sting and an approximately 60% cumulative risk for reactions from future stings. (1-4) Factors such as patient age and severity of the previous reaction also affect future risk. (1), (2), (13) For example, children who have isolated urticaria and/or SC angioedema only rarely have more severe reactions after future stings. (13) Adults with isolated cutaneous reactions also frequently have reactions no worse than the previous ones, but are at greater risk of more severe reactions than children. (4) Conversely, patients who have had severe reactions, such as those who developed hypotension with loss of consciousness from previous reactions, are likely to have severe reactions from future stings. (1), (2)

Sensitization occurs commonly after insect stings, with venom-specific IgE being detected in up to 25% of stung individuals. Such asymptomatic sensitization is usually transient. Golden et al, (2) however, found that patients with elevated venom IgE antibodies but no history of an anaphylactic sting reaction face a risk for anaphylaxis from a future sting of approximately 17%. Insect-allergic patients lose venom sensitivity at a rate of approximately 12%/yr. (2)

Diagnosis

Skin testing is the usual initial testing modality, because of better sensitivity, rather than radioallergosorbent test (RAST) or other in vitro assays. Commercial venoms for skin testing and immunotherapy exist for yellow jacket, white faced hornet, yellow hornet, wasp, and honeybee that are standardized by hyaluronidase content in the United States. Initial skin-prick tests are usually performed with venom concentrations of 1 [micro]g/ml each, and if negative, intradermal skin tests are generally placed. Intradermal skin testing uses a volume of 0.02 ml of each venom, starting with a concentration of 0.0001 to 0.01 [micro]g/ml and increasing the concentration in 10-fold steps until a positive reaction develops or a maximum concentration of 1.0 [micro]g/ml is reached. False-positive results can occur at this concentration, however, and higher concentrations consistently produce irritant responses. (1), (4) Although skin testing has usually demonstrated greater sensitivity than RAST, Hamilton et al recently described several skin test-negative patients who were shown to have venom-specific IgE using very sensitive RAST assay. (11), (12) The levels in some cases are below the range of detection of many commercial assays. Some of these patients have experienced reactions from subsequent stings.

Immunotherapy

Venom immunotherapy has over the past 25 years been shown to be extremely effective in reducing the risk of future sting reactions (Table 1). (1), (3), (4) Several studies have established that the risk of future sting reactions can be reduced to well below 5% and that the sting reactions of patients undergoing immunotherapy are usually milder than those experienced by the patients before beginning immunotherapy. The general criteria for selection of patients who should receive venom immunotherapy include a history of an anaphylactic reaction and presence of venom-specific IgE antibodies (Table 2). (1-4), (14) However, certain insect-allergic patients do not require immunotherapy. As mentioned earlier, children who have mild anaphylactic reactions with only isolated urticaria and/or SC angioedema are at minimal risk for major problems. (13) Therefore, immunotherapy is not generally prescribed for these children but is an acceptable option at parental request. (1) Like other insect-allergic patients, injectable epinephrine should be available for these patients.

To better define which patients should receive immunotherapy, several investigators, predominately from Europe, have conducted trials using observed sting challenges to identify patients at risk. (1) Sting challenges, however, present several problems including the risk of severe, uncontrollable anaphylaxis, (3) and negative sting challenges do not entirely eliminate the risk of a future sting reaction. The usual method of selection of patients for immunotherapy in the United States depends on the history and demonstration of venom-specific IgE antibodies but does not involve a sting challenge. (1)

Adults with a history of isolated cutaneous reactions also appear to be at a lower risk of more severe reactions in the future than those patients who have previously experienced more severe reactions. (4) However, their prognosis may not be as good as that of children with similar reactions. Currently, specialty practice parameters recommend venom immunotherapy for these adults, although some controversy exists over its need for all of these patients. (1)

Selection of particular venoms to include in the immunotherapy vaccine is controversial. Some investigators recommend that all venoms with positive test results be included in the immunotherapy vaccine, whereas others recommend that if the insect is clearly identified and if the venoms causing positive tests display prominent immunologic cross-reactivity, the immunotherapy vaccine need only contain the venom of that culprit insect. (1), (4), (14), (15)

Immunotherapy doses are usually given weekly beginning with 0.05 to 0.10 [micro]g by SC injection and then increased sequentially to a maintenance dosage of 100 [micro]g. Successful use of a 50-[micro]g maintenance dose has been reported. (4) Successful rush immunotherapy schedules have been developed. The maintenance dosage interval is generally increased subsequently. (1), (3), (4), (14)

The major risk of immunotherapy is anaphylaxis. Local reactions featuring swelling, pain, and erythema are common, but rarely cause significant problems. Systemic reactions have been reported to occur in 3 to 12% of patients, which is similar to the rate seen with inhalant immunotherapy. (1), (4), (6) Other complications are rare.

Criteria for discontinuing immunotherapy are evolving. One criterion that has been used is conversion to a negative skin test. However, most patients continue to have positive skin tests after several years of immunotherapy. Extensive follow-up studies of patients after discontinuation of immunotherapy have indicated that most patients can safely stop immunotherapy after a minimum of 3 to 5 years with only a small residual risk of future sting reaction. Golden et al (2) found that the risk of a sting reaction, which is below 5% while on immunotherapy, increases slowly to approximately 10% several years after completing a 5-year course. These investigators have concluded that discontinuation after 5 years is appropriate for most patients. However, rare patients with the most severe reactions, especially those with loss of consciousness, may be at greater risk of similar reactions to future stings if immunotherapy is discontinued. (2) Therefore, it is appropriate to consider continuing immunotherapy for longer periods in these patients. The decision of when and whether to discontinue immunotherapy can involve consideration of several factors including severity of sting reactions, duration of immunotherapy, continued presence of venom-specific IgE, coexistent medical conditions, lifestyle considerations, and patient preferences.

Anaphylactic Reactions from Fire Ant Stings

Although fewer details are known regarding the natural history and management of allergy to fire ants than allergy to flying Hymenoptera, the accumulated evidence supports that immunotherapy is also effective treatment for fire ant allergy. The annual sting attack rates vary considerably within the imported fire ants' habitat, but rates of over 50% are seen in highly endemic areas and in some areas fire ants cause more allergic reactions than any other stinging insect. (1), (5)

Although venom products have been available for diagnosis and treatment of allergy to flying Hymenoptera for more than 20 years, all commercially available materials to use for fire ant skin testing or immunotherapy are imported fire ant (IFA) whole body vaccines (WBVs). Although WBVs for the flying Hymenoptera do not contain significant quantities of relevant allergens, fire ant WBVs possess significant allergenic material. Hoffman (8) found that 1:10 wt/v vaccine contains 30 to 45 [micro]g/ml of Sol i III allergen.

Diagnosis and Management. The diagnosis of fire ant allergy, like that of allergy to the other Hymenoptera, requires a history consistent with a systemic allergic reaction and demonstration of IgE antibody to fire ant venom allergen. (4), (5), (16-18) Studies comparing skin test results using commercial WBV and venom have shown both to have high and comparable sensitivities of more than 80 to 90%. Positive skin tests have been found in 8 to 29% of control subjects with venom and 8 to 42% of control subjects with WBV. (1), (5) Whether these reactions represent true false-positives or asymptomatic sensitivity is unclear. RAST assays using WBV are less sensitive than skin tests, but RAST assays using venom produce sensitivities similar to skin testing. A CAP-RAST system using WBV has been reported to yield results approaching those of venom RAST. Skin testing is usually initiated with prick testing. If prick tests are negative, intradermal testing is begun, usually by injecting 0.02 ml, and starting with a concentration in the range of 1:1,000,000 wt/v. The concentration is increased by 10-fold increments until a positive test occurs or until a maximum of 1:1,000 wt/v is reached. (1), (5) If a fire ant is clearly identified as the stinging insect, testing is not indicated for the flying Hymenoptera. Conversely, if a flying Hymenoptera can be implicated, testing for fire ants is not indicated. (4)

Immunotherapy for fire ant sting allergy, as for flying Hymenoptera allergy, is generally indicated for patients with a history of a systemic reaction to a fire ant sting and a positive skin test or in vitro assay for fire ant allergen. (1), (5), (18) The indications are less clearly established because treatment efficacy and natural history are less well defined than for flying Hymenoptera. However, since immunotherapy with IFA WBV was first reported 30 years ago, evidence has continued to accumulate that immunotherapy with IFA WBV is effective in preventing future sting reactions. (1), (5), (16-18) The strongest support for its efficacy is provided by reports from Freeman et al (16) and Tankersley et al. (17) In the report by Freeman et al, (16) 47 of 65 patients on immunotherapy using a conventional schedule for dosage advancement received field stings and only one had an anaphylactic reaction. In addition, 30 of the patients treated with immunotherapy underwent observed sting challenges and none reacted. In contrast, 6 of 11 study patients who did not receive immunotherapy subsequently received field stings and all 6 had anaphylactic reactions. Tankersley et al (17) reported treatment results on 58 patients treated with IFA WBV using a rush protocol. Fifty-six of the study patients subsequently were stung, and only one experienced a reaction.

Most immunotherapy schedules to treat IFA allergy use dosage advancements similar to those for aeroallergens. Gradually increasing SC injections are usually given weekly until reaching a maintenance dose. (1), (5), (16) Rush immunotherapy schedules can be used. (17) Eventually, the interval between doses can be increased to 4 to 6 weeks. (1), (5), (16-18)

It has not been established whether children with isolated cutaneous reactions after fire ant stings face only a small risk of more serious reactions from future stings. Therefore, there are no definitive guidelines about immunotherapy for this group. Although most allergists do not usually recommend immunotherapy for these children, some do, presumably influenced by the high sting attack rates. (1) The decision regarding immunotherapy in these children may involve consideration of lifestyle issues, parental preferences, and other factors.

Criteria for discontinuation of fire ant immunotherapy are not established. A survey indicated that almost four-fifths of allergists consider discontinuing immunotherapy, whereas the other one-fifth who use immunotherapy to treat fire ant allergy continue it indefinitely. The decision regarding duration of immunotherapy for fire ant allergy can involve several factors including severity of sting reactions, presence of continued sensitivity to fire ant allergen, age and coexistent medical conditions of the patient, lifestyle considerations, and patient preferences. (1), (5)

Stinging Insect Avoidance Measures

Insect-allergic patients should take precautions to prevent further stings. Colognes, perfumes, and scented hair sprays and floral prints can attract insects. Wearing shoes, socks, and long pants when outside may minimize the risk of being stung. Patients are encouraged to avoid known insect nests and to be cautious around outdoor areas where food is served, trash or compost areas, and flowers. Known nests near their homes should be destroyed. Fire ant avoidance is especially difficult, as the colonies are so ubiquitous in endemic areas. In addition to protective clothing, a diligent and ongoing effort is needed to control fire ant populations in patients' yards and gardens.

Insect Bite Allergy

Anaphylaxis from insect bites is much less common than from insect stings. The biting insects most often implicated as causes of anaphylaxis are Triatoma bugs and mosquitoes and other biting flies. (7), (19), (20)

Triatoma bugs are types of kissing bugs found throughout the southern portion of the United States. Although several different species have been identified as causing allergic reactions, most reports involve two species, T. rubida and T. protracta, and originate from the Southwest. A major allergen has recently been identified and allergenic activity is present in extracts of the bugs' salivary glands. The insects' principal hosts are small mammals and birds, but they can enter indoor environments. Typically, their bites are painless and occur at night on uncovered skin. Although immunotherapy using an extract of salivary glands appeared to be effective in a small number of patients, no commercial antigen product is available. (19)

Mosquitoes and flies belong to the Diptera family. Their bites have been reported to cause immediate- and delayedonset local skin reactions and immediate systemic allergic reactions. At least some of the reactions appear to be IgE mediated. Immunotherapy using a mosquito WBV was reported to prevent recurrence of mosquito bite anaphylaxis in two patients. (20)

Horsefly (Tabanus) bites have been reported to cause anaphylaxis in several patients. Skin testing and RAST using commercial allergens have not yielded consistently reliable results. Several other biting insects have also been reported to cause allergic reactions including the tsetse fly (Glossina) and the deer fly (Chrysops). (7) Immunotherapy was apparently successful in protecting one patient from anaphylaxis to deer fly bites. (21)

The more grains of rice on a stem, the lower it bends. The fewer grains, the higher it stands.

--Malayan Proverb

Key Points

* Imported fire ant allergy is a growing problem, as the habitat of fire ants now extends from coast to coast.

* Large local reactions to insect stings imply only a small risk for future anaphylaxis.

* Allergy to bees, yellow jackets, hornets, wasps, and imported fire ants can be confirmed and treated with immunotherapy.

Table 1. Likelihood of anaphylactic reaction to future insect stings

                                                        %

Normal population                                      0.5-3

Large local reactions                                    5-10

Asymptomatic sensitization (a)                            17

Untreated patients with insect allergy                  30-60

Untreated insect-allergic children with isolated          10
  cutaneous reactions

Insect-allergic patients on maintenance immunotherapy     <5

Patients 10 yr after completing a 5-yr course of          10
  immunotherapy

(a) Patients with detectable venom-specific immunoglobulin E but no
history of abnormal sting reaction.

Table 2. General indications for immunotherapy for venom skin test or
in vitro assay-positive patients

Reaction type                                Immunotherapy

Adult

  Any generalized allergic reaction              Yes

Children

  Generalized reaction not limited to            Yes
    cutaneous system

  Generalized reaction limited to cutaneous     No (a)
    system (flying Hymenoptera)

  Generalized reaction limited to cutaneous     Optional
    system (fire ant)

Local reactions                                 No

(a) Optional at parents' request.

From the Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS.

Reprint requests to John E. Moffitt, MD, Department of Pediatrics, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216-4505. Email: [e-mail]

Accepted August 19, 2003.

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9611-1073

References

1. Portnoy JM, Moffitt JE, Golden DB, et al; The Joint Force on Practice Parameters, the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. Stinging insect hypersensitivity: A practice parameter. J Allergy Clin Immunol 1999;103:963-980.

2. Golden DB, Kagey-Sobotka A, Lichtenstein LM. Survey of patients after discontinuing venom immunotherapy. J Allergy Clin Immunol 2000;105:385-390.

3. Hunt KJ, Valentine MD, Sobotka AK, et al. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978;299:157-161.

4. Reisman RE. Insect stings. N Engl J Med 1994;331:523-527.

5. Kemp SF, deShazo RD, Moffitt JE, et al. Expanding habitat of the imported fire ant (Solenopsis invicta): A public health concern. J Allergy Clin Immunol 2000;105:683-691.

6. Yates AB, Moffitt JE, deShazo RD: Anaphylaxis to arthropod bites and stings. Immunol Allergy Clin North Am 2001;21:635-651.

7. Yunginger JW: Insect allergy, in Middleton E, Reed CE, Ellis EF, et al (eds): Allergy: Principles and Practice. St. Louis, Mosby, 1998, vol 2, ed 5, pp 1063-1072.

8. Hoffman DR. Fire ant venom allergy. Allergy 1995;50:535-544.

9. Mauriello PM, Barde SH, Georgitis JW, et al. Natural history of large local reactions from stinging insects. J Allergy Clin Immunol 1984;74:494-498.

10. Golden DB, Kagey-Sobotka A, Norman PS, et al. Insect sting allergy with negative venom skin test responses. J Allergy Clin Immunol 2001;107:897-901.

11. Reisman RE. Insect sting allergy: The dilemma of the negative skin test reactor. J Allergy Clin Immunol 2001;107:781-782 (editorial).

12. Hamilton RG, Golden DB, Kagey-Sobotka A, et al. Case report of venom immunotherapy for a patient with large local reactions. Ann Allergy Asthma Immunol 2001;87:134-137.

13. Valentine MD, Schuberth KC, Kagey-Sobotka A, et al. The value of immunotherapy with venom in children with allergy to insect stings. N Engl J Med 1990;323:1601-1603.

14. Golden DB. Stinging insect vaccines: Patient selection and administration of Hymenoptera venom immunotherapy. Immunol Allergy Clin North Am 2000;20:553-570.

15. Reisman RE, Livingston A. Venom immunotherapy: 10 years of experience with administration of single venoms and 50 [micro]g maintenance doses. J Allergy Clin Immunol 1992;89:1189-1195.

16. Freeman TM, Hylander R, Ortiz A, et al. Imported fire ant immunotherapy: Effectiveness of whole body extracts. J Allergy Clin Immunol 1992;90:210-215.

17. Tankersley MS, Walker RL, Butler WK, et al. Safety and efficacy of an imported fire ant rush immunotherapy protocol with and without prophylactic treatment. J Allergy Clin Immunol 2002;109:556-562.

18. Stafford CT. Hypersensitivity to fire ant venom. Ann Allergy Asthma Immunol 1996;77:87-99.

19. Moffitt JE, Venarske D, Goddard J, et al. Allergic reactions to Triatoma bites. Ann Allergy Asthma Immunol 2003;91:122-130, 194.

20. McCormack DR, Salata KF, Hershey JN, et al. Mosquito bite anaphylaxis: Immunotherapy with whole body extracts. Ann Allergy Asthma Immunol 1995;74:39-44.

21. Hrabak TM, Dice JP. Use of immunotherapy in the management of presumed anaphylaxis to the deer fly. Ann Allergy Asthma Immunol 2003;90:351-354.

John E. Moffitt, MD