Stings of imported fire ants: Clinical manifestations, diagnosis, and treatment

INTRODUCTION — Imported fire ants (IFAs) are aggressive, venomous ants that sting with little provocation and are difficult to avoid in endemic areas. Their venom causes painful local reactions and induces a high rate of allergic sensitization. Patients who become allergic to IFA venom can experience a range of reactions, including life-threatening anaphylaxis.

The term "imported fire ant" refers to two members of the Solenopsis species (figure 1) [1,2]:

●The red imported fire ant (RIFA), Solenopsis invicta

●The black imported fire ant (BIFA), Solenopsis richteri

This topic review discusses the medical consequences of IFA stings and the treatment of IFA venom allergy. The entomology of IFAs and the chemical and biologic control of these pests are discussed separately. (See "Entomology and control of imported fire ants".)

TERRITORY — Regularly updated maps of the fire ant range and agriculture quarantine areas within the United States are available online.

Red imported fire ants — In the United States, the red imported fire ant (RIFA) is the most abundant, widespread, and damaging species. The RIFA is found in 14 states (Alabama, Arkansas, California, Florida, Georgia, Louisiana, Mississippi, New Mexico, North Carolina, Oklahoma, South Carolina, Tennessee, Texas, and Virginia) with limited territory in Arizona, Maryland, and Delaware [3].

Infestations also occur in Mexico [4], as well as several Caribbean islands, including Puerto Rico, the Bahamas, the British and United States Virgin Islands, Antigua, and Trinidad. In addition, RIFAs are now established in Australia [5], Taiwan [6], and China [7]. They have been detected in India, Japan, and South Korea as well [8].

Black imported fire ants — The habitat of the black imported fire ant (BIFA) is relatively limited to a small area of northern Alabama, northern Mississippi, and southern Tennessee.

APPEARANCE AND BEHAVIORS OF IMPORTED FIRE ANTS — Worker ants vary in size from ⅛ to ¼ inches (3 to 6 mm) long and are reddish-brown to black in color. They all have stingers (figure 2) and will attack anything that disturbs them. A single ant can deliver multiple stings.

Fire ants are difficult to avoid in endemic areas. Stings of imported fire ants (IFAs) can be sustained both outdoors and indoors. Available data suggest that 50 to 89 percent of people residing in an IFA-infested area will be stung each year. In one report, 51 percent of 107 previously unexposed subjects were stung within three weeks of arrival in an endemic area [9].

Children are stung more often than adults. Patients in long-term care facilities are also at risk, as they may not be aware of their surroundings and may be immobilized by disease or otherwise unable to respond if they come into contact with ants.

When their nests are disturbed, IFAs swarm out and sting anything they encounter, including humans, pets, livestock, and wildlife [3]. Once foraging fire ants have made contact with a potential victim, a variety of stimuli, including simple movement of the patient, may trigger a stinging event, leading to multiple stings in a very short period of time.

Stings occur most frequently during summer, most commonly in children, and typically on the lower extremities. Off-season stings (eg, during winter months) often do not cause as much pain and may go unnoticed until the local reaction develops. This may reflect seasonal differences in IFA venom [10,11]. (See 'Protein allergens' below.)

During a sting, the ant uses its powerful mandibles to hold onto the skin, arches its body, and injects venom through the stinger located at the tip of its abdomen (picture 1). The ant will sting repeatedly if not quickly removed and often leaves a circular pattern of stings as it rotates its body. The human victim characteristically experiences an immediate, intense burning (the "fire" inspiring the name of the ant) and itching at the sting site.

Fire ant avoidance — IFAs will not sting through fabric, stockings, or tights [12]. Thus, wearing shoes (not sandals) with socks and long pants are helpful avoidance measures. Hands and arms should be covered with gloves and sleeves when gardening or doing outdoor work. Available insect repellents are not effective [12]. When a sting sensation is noted, the ant should be quickly killed with a slap to prevent multiple stings.

VENOM — The venom of imported fire ants (IFAs) is approximately 95 percent water-insoluble alkaloids by volume, with the remaining 5 percent being an aqueous solution of proteins. This differs markedly from the venoms of yellow jackets, hornets, wasps, and bees, which are largely aqueous protein solutions. The alkaloids cause the sterile pustule but are not allergenic (see 'Venom alkaloids' below). The allergenic portion of the venom is the protein component [13]. (See 'Protein allergens' below.)

The volume of injectate positively correlates with body size in S. invicta (red imported fire ant [RIFA]). Direct measurements suggest that the venom volume delivered per sting from an S. invicta worker is approximately 0.66 nanoliters, containing 0.56 mcg of venom alkaloid and 10 to 100 nanograms of protein [10].

Protein allergens — There are seasonal variations in the protein content of the IFA venom, with higher protein levels in summer than at other times [11]. S. invicta venom has four dominant allergenic proteins: Sol i 1, Sol i 2, Sol i 3, and Sol i 4 (table 1) [14].

●Sol i 1, which has a molecular weight of 37 kD, comprises approximately 2 to 4 percent of venom allergen by weight and possesses both phospholipase A and B activities [15]. Some of the N-terminal sequences of Sol i 1 share sequences with the venom phospholipase of Vespula maculifrons, and sera from some patients with allergy to vespid venom contain immunoglobulin E (IgE), which binds to Sol i 1 by radioallergosorbent test (RAST) or immunoblot studies [14,16,17]. The close structural similarity of portions of the Sol i 1 molecule to portions of vespid phospholipase may explain this immunologic cross-reactivity.

Little is known about the clinical significance of the immunologic cross-reactivity between fire ant and vespid venom. However, it could explain the rare occurrence of anaphylaxis to the first recognized fire ant sting in isolated patients with existing allergy to vespid stings.

●Sol i 2 comprises one-half to two-thirds of all venom protein [15,18]. No other proteins of similar structure have been found in the Protein Identification Resource or Swiss-Prot databases.

●Sol i 3 is a single chain molecule consisting of 212 amino acids that comprises approximately 15 to 25 percent of total venom protein that has almost 50 percent identity with vespid antigen 5 [15]. However, it lacks immunologic cross-reactivity with vespid antigen 5 [17]. Its complementary DNA (cDNA) has been successfully cloned.

●Sol i 4 is a single chain 117-amino acid protein of molecular weight 13,340 and comprises between 8 and 10 percent of venom protein content [15]. Although it shares approximately 35 percent identity with Sol i 2, it lacks immunologic cross-reactivity. Sol i 2 and 4 are unrelated to any proteins found in venoms from other insect genera [15].

S. richteri (black imported fire ant [BIFA]) venom contains proteins designated as Sol r 1, 2, and 3, which are chemically and antigenically very similar to Sol i 1, 2, and 3. A protein corresponding to Sol i 4 has not been found in S. richteri venom (table 1).

Venom alkaloids — The alkaloids in IFA venom are toxic to human epithelium and induce a sterile pustule at the sting site. These compounds are alkaline 2-methyl-6-n-alkyl and alkenyl piperidines [10,19-21] and are classified as solenopsins and dehydrosolenopsins [22,23]. Venom alkaloids have hemolytic, cytotoxic, and antibacterial properties [24-28].

RIFA workers produce the most complex and toxic venom alkaloids of any of the North American Solenopsis species [29]. The relative composition of fire ant venom alkaloids varies with the size and age of the individual worker ant, as well as between species and among castes within a species [21,22,30].

Venom alkaloids have various other properties, as shown in animal and human studies. These include activation of platelets, neutrophils, and the alternate complement pathway, histamine release from peritoneal mast cells, irreversible inhibition of neuromuscular transmission, and inhibition of nitric oxide synthase [29,31-35]. Direct convulsant, cardiotoxic, and respiratory depressant actions of two synthetic venom alkaloids, solenopsin A and isosolenopsin A, have been demonstrated in rodents [36]. Recently, solenopsin A has been shown to inhibit angiogenesis and solenopsin analogs, to demonstrate topical anti-inflammatory properties in psoriasis [37,38].

The data reviewed in the above section indicate that substantial pharmacologic activity is present in the alkaloid fraction of S. invicta venom. However, direct, nonallergic, toxic effects resulting from S. invicta envenomation in humans have not been reported. Although human systemic toxicity has not been convincingly demonstrated, the substantial pharmacologic activity of IFA venom alkaloids may underlie the poor clinical outcome seen in some cases of massive attacks.

Cross-reactivity with other Hymenoptera species — Cross-reactivity between antigens in IFA venom and antigens in the venoms of other Hymenoptera species is limited [17,39]. Thus, if a patient was able to identify an IFA as the insect that caused a reaction, there is no need to also evaluate the patient for allergy to other Hymenoptera species. Unique peptides of IFA venom proteins (Sol I 2 and Sol r 2) have been used to identify IFAs entomologically with a lateral flow immunoassay that is now commercially available [40].

CLINICAL REACTIONS — Clinical reactions to imported fire ant (IFA) stings can range from mild discomfort to life-threatening anaphylaxis.

Local reactions — Local reactions are divided into three types: the wheal and flare reaction, the sterile pustule, and the large local reaction. By definition, local reactions involve signs and symptoms at or contiguous with the sting site.

●Wheal and flare – Nearly all individuals stung by IFAs develop hive-like lesions with surrounding erythema at the sting site. This reaction develops within 20 minutes and is accompanied by painful burning and then pruritus (picture 1). The burning sensation is characteristic and helps differentiate the stings of IFA from those of other insects. Symptoms are more pronounced during the summer months when the ants have more venom. The initial symptoms are followed in the succeeding 24 hours by development of the sterile pustule.

●Sterile pustule – A pustule filled with yellow fluid containing epithelial debris and few cells develops at the site of a sting within the first 24 hours. These pustules are sterile and caused by the venom alkaloids. The presence of these pustules with an appropriate history of a painful sting is relatively pathognomonic for the sting of the IFA (picture 2 and picture 3 and picture 4 and picture 5). The pustule peaks in size at 24 hours and can last for one week or more. It is not necessary to culture these pustules unless the patient has scratched the site and denuded the pustules and there is concern about superinfection with skin flora. The epidermis overlying the pustule usually remains intact for 48 to 72 hours before it erodes, which generally allows sufficient time for new epidermis to cover the base of the lesion.

●Large local reaction – In individuals with venom-specific immunoglobulin E (V-IgE), large local reactions may develop at the sting site over 6 to 24 hours, simultaneously with the development of the sterile pustule. The pustule ultimately sits atop an area of intensely pruritic, painful inflammation (picture 1). Although usually self-limited, swelling can be severe, and vascular compromise can occur in extremities. This topic will refer to severe large local reactions as "extreme local reactions." Extensive and spreading edema can be a source of confusion in extreme local reactions. However, by definition, the swelling is contiguous with the site of the sting.

Histopathologic studies have demonstrated that large local reactions are IgE-mediated, late cutaneous allergic reactions like those that can occur after stings of flying Hymenoptera. On histologic examination, the lesions are composed of a dense fibrin gel and a mixed cellular infiltrate of eosinophils, neutrophils, and lymphocytes [41].

Systemic allergic reactions — Systemic allergic reactions may range from cutaneous (generalized urticaria, angioedema, pruritus, erythema) to life-threatening bronchospasm, laryngeal edema, or vascular collapse (table 2). Anaphylaxis may occur within minutes or may rarely develop hours after a sting. A single sting is sufficient to cause anaphylaxis [42]. Pathognomonic pustules can later identify the fire ant as the culprit.

Reliable estimates for the incidence of fire ant anaphylaxis are not available, because anaphylaxis is not a reportable disease. Published studies have reported rates ranging from 0.6 to 16 percent of those stung [43-45].

IFA stings represent a leading cause of anaphylaxis for populations residing in endemic areas [46-48]. One blinded survey of random adult blood donors in an IFA-endemic area demonstrated allergen-specific IgE to IFA in the reference population was 1.7 times more common than IgE for other allergens associated with fatal allergic reactions [48].

Anaphylactic reactions to IFA stings usually occur in individuals who have been stung at least once before without eliciting anaphylaxis. However, some subjects have had anaphylactic reactions in response to their first stings [14]. Clinical and laboratory studies suggest that most of these subjects have been sensitized previously to Vespula (yellow jacket) venom [14]. Vespula venom cross-reacts with Solenopsis venom in vitro. There is also evidence that the venom of the common striped scorpion, Centruroides vittatus, may be cross-reactive with IFA venom and that this may be responsible for reported episodes of anaphylaxis upon an initial scorpion sting [49].

Toxic reactions — Conditions that have been associated with fire ant stings in humans include serum sickness, nephrotic syndrome, seizures, mononeuritis, and worsening of pre-existing cardiopulmonary disease [41,50-52]. The pathogenesis of these sequelae is unclear.

Massive attacks — Massive attacks by foraging fire ants have been increasingly reported in the medical literature and the lay press [53]. These attacks usually occur in the late summer months and frequently after it rains. Victims can be found in the early morning hours covered with ants. Massive attacks can occur indoors and generally affect debilitated or very young patients who cannot ward off the attack. Individuals can sustain hundreds to thousands of fire ant stings.

The reason for these massive attacks is unclear. Our group has hypothesized that IFA attacks on humans reflect normal foraging predatory behavior of the ants during periods of food scarcity, behavior that may reflect the increasing density of the ants in the environment. Examples of this behavior exist in the field. A Texas study reported 19 percent of cotton rats captured in traps in fire ant endemic areas were attacked by ants within a few hours [54]. Over one-half of the attacked rats were found dead or partially eaten.

It is unclear whether massive attacks can result in morbidity, secondary to relatively large doses of venom components. Such toxic reactions following 50 to 100 simultaneous stings by winged Hymenoptera species (bees, wasps, yellow jackets, and hornets) have been reported in humans, but equivalent reactions resulting from fire ant stings are not well established. However, such reactions have been observed in small animals, such as dogs, rats, mice, and calves.

Variable clinical outcomes in humans occur after massive fire ant attacks. Some patients recover without sequelae [55,56]. In contrast, a five-day-old infant stung at home had a near-fatal response, and the death of a three-month-old infant subsequent to numerous fire ant stings in a home in Phoenix, Arizona, was reported [57].

Several cases of massive fire ant attacks within health care facilities have been reported. Of the six patients included in one report, only one fared well [56]. That patient was in good general health except for Alzheimer disease and had no obvious untoward effects. In contrast, four of the six patients died within one week of the attack. Two had worsening of pre-existing cardiopulmonary insufficiency, one developed acute respiratory distress syndrome, and one had a cardiopulmonary arrest. The fifth patient, already bedbound with multiple health problems including severe heart failure, had progressive deterioration and died 13 months later.

INDICATIONS FOR REFERRAL — All patients with systemic allergic reactions should be referred to an allergy expert for further evaluation. Patients with extreme local reactions should also be referred to an allergy expert, since testing for venom-specific immunoglobulin E (V-IgE) may be indicated. (See 'Local reactions' below.)

DIAGNOSIS — The diagnosis of local reactions is based on clinical signs and symptoms. The diagnosis of systemic allergic reactions requires specific testing for immunoglobulin E (IgE) antibodies specific to imported fire ant (IFA) venom.

Local reactions — The diagnosis of the various types of local reactions is clinical. The sterile pustule is relatively pathognomonic for the sting of the IFA (picture 1 and picture 2). (See 'Clinical reactions' above.)

Systemic allergic reactions — Patients who have experienced a systemic/anaphylactic reaction in the recent past should be examined for the development or presence of sterile pustules, as these lesions are an important clue that an IFA sting was responsible. On rare occasions, pustules are absent.

The diagnosis of IFA venom allergy requires the demonstration of venom-specific IgE (V-IgE) by skin testing or in vitro tests, in combination with a consistent clinical history. As with all forms of allergy, the presence of V-IgE alone does not predict systemic reactivity. For this reason, subjects without a history of systemic reactions to IFA stings should not be tested for V-IgE, as there is a high rate of asymptomatic production of V-IgE in populations exposed to fire ants. In studies of skin test reactivity to IFAs, positive skin tests were seen in up to 30 to 40 percent of history-negative control subjects [1,3,5,9]. Similarly, the level of V-IgE does not predict the severity of a sting reaction in those with systemic allergy, and patients with large local reactions may have equally high levels of V-IgE.

Skin testing is the preferred method of detecting V-IgE. Skin testing should only be performed by an allergy expert, both because of the skill required for interpretation and the potential risk of severe reactions in highly sensitive patients. It is general practice to allow at least six weeks to elapse between a reaction and IFA skin testing.

Laboratory studies — We suggest obtaining a baseline tryptase level to exclude underlying mast cell disorders in patients who have had hypotension with stings. Any elevation in baseline tryptase should be evaluated further. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

Skin testing — Whole body extracts (WBE) are commercially available for skin testing as well as for use in immunotherapy. To be useful, these preparations must contain adequate amounts of venom proteins, but this has not been consistently true in the United States in the past. United States manufacturers have since agreed to verify the content of Sol i 2 and Sol i 3 in their products. Despite these measures, we recommend confirming the venom content in extracts by skin testing an individual known to be skin test-positive [13]. We test all extracts on a volunteer with a history of large local reactions before using the extract in skin testing or immunotherapy.

WBE are available as 1:10 weight/volume stock solutions. We use WBE from the more widespread species, the red imported fire ant (RIFA), for testing and immunotherapy in all patients, as there is extensive cross-reactivity between the two species. We recommend that the 1:10 weight/volume stock solutions be diluted 10-fold (to 1:100 weight/volume) and used for epicutaneous (prick/puncture) testing. If the patient has had a severe anaphylactic reaction, further dilution for the first prick/puncture test may be prudent.

If prick testing is negative, intradermal testing is then performed. For intradermal testing, we start at 1:1,000,000 weight/volume and increase 10-fold until 1:500 to 1:1000 weight/volume is reached or a positive result is obtained [58,59]. One center reported that 9.5 percent of patients undergoing skin testing to IFA venom developed systemic allergic reactions, which is higher than the reported rates (2 to 4 percent) with other types of allergens, including other Hymenoptera venoms [42].

Skin testing with fire ant WBE is considered diagnostic for the presence of V-IgE with a positive reaction (ie, a wheal measuring at least 3 mm greater than the negative control) at a concentration of 1:500 weight/volume or lower [59]. A general discussion of the techniques of skin testing is presented separately. (See "Overview of skin testing for IgE-mediated allergic disease".)

Skin testing is our preferred method of diagnosis. The sensitivity of testing with WBE preparations has been estimated to be between 76 and 94 percent, depending on the concentration used [60,61]. Approximately 20 percent of patients with positive skin tests will have negative in vitro tests. Conversely, up to 20 percent of patients with negative skin tests can have positive in vitro tests, depending on the assays used [62,63].

Therefore, negative skin tests in patients with highly suggestive histories of systemic reactions should be followed by in vitro testing. If in vitro testing is negative in such patients, then we recommend repeat skin testing with another manufacturer's reagent.

In vitro tests — There are multiple in vitro tests available to detect V-IgE, including enzyme-linked immunosorbent assays (ELISA), radioallergosorbent tests (RAST), and Phadia CAP solid-phase assay). All of these tests use WBE as the allergen:

●WBE ELISA

●WBE RAST

●WBE Phadia ImmunoCAP solid-phase assay (flow enzyme immunoassay or CAP-FEIA)

Assays using venom are available only in research laboratories and may be more sensitive than those using WBE [44]. The sensitivities of the three commercially available assays appear to be quantitatively similar to those of WBE intradermal skin tests [64]. The authors use the WBE Phadia ImmunoCAP assay.

The absolute titer of a positive in vitro test does not predict the severity of the clinical reaction. Patients with severe anaphylaxis can have low-positive titers.

There are specific circumstances in which in vitro testing would be the initial modality of choice, such as in patients taking significant doses of beta-adrenergic blocking medications or with extensive skin disease. A discussion of situations in which in vitro testing would be preferred can be found elsewhere. (See "Overview of in vitro allergy tests", section on 'Advantages relative to skin testing'.)

TREATMENT

Local reactions

●Wheal and flare reactions and sterile pustules – No specific treatment is required for wheal and flare reactions and sterile pustules. Application of topical anti-itch preparations, such as pramoxine hydrochloride (1%) with hydrocortisone acetate (1%) cream, and/or a topical antihistamine (doxepin cream 5%) and/or oral antihistamine treatment, provide comfort until the itching stops. Itching can last for many hours. The lesions should be left intact as scratching can lead to infection [59]. Excoriated lesions should be kept clean with soap and water. Infected lesions require appropriate antimicrobial therapy.

●Large local reactions – Large local reactions at the site of stings often require treatment. Pruritus can be treated with the topical agents listed above or, if refractory, by oral antihistamines and high potency topical corticosteroids. We prefer cetirizine and fluocinonide 0.05% or clobetasol 0.05% ointment. Topical corticosteroids are applied every four hours until the itching subsides.

In individuals with predictable large local reactions, we have found that immediate application of high potency topical corticosteroids and administration of a single dose of 20 mg of prednisone attenuates the response.

Patients who experience large local reactions uniformly have venom-specific immunoglobulin E (V-IgE); however, they are not believed to be at significantly higher risk for subsequent systemic reactions. Thus, testing for V-IgE and immunotherapy is not routinely offered.

●Extreme local reactions – Extreme local reactions may merit skin testing and venom immunotherapy for the prevention of recurrent extreme local reactions. This approach is similar to that used for large local reactions to winged Hymenoptera stings [65]. (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action", section on 'Patients with large local reactions'.)

●Potential complications – In some patients with large or extreme local reactions, there may be enough induration, pain, and heat at the site to suggest cellulitis. However, fire ant venom alkaloids have both antibacterial and antifungal properties, and cellulitis rarely occurs in nondiabetic patients. The presence of a sterile pustule is a clear indicator that these are late-phase reactions to an imported fire ant (IFA). However, if the clinician is unsure, a course of oral antibiotics may be appropriate. (See "Acute cellulitis and erysipelas in adults: Treatment".)

Massive attacks — If any fire ants are found on a debilitated patient, clinical evaluation is needed, with possible transport (depending on findings) to the nearest emergency department. We have made recommendations on how to proceed with patient care and facility management if this occurs [53].

There is no evidence that individuals who experience massive fire ant stings, in the absence of systemic allergic reactions or generalized late-phase dermal reactions, require parenteral glucocorticoid or antibiotic therapy. Treatment with large doses of glucocorticoids and intravenous fluids may complicate the management of those with pre-existing cardiovascular disease.

Treatment with oral nonsedating antihistamines and topical corticosteroids appears to be adequate in most cases. We use the medications mentioned previously for either uncomplicated local or large local reactions, depending on the cutaneous response.

Measures to prevent indoor infestation by IFAs are discussed separately. (See "Entomology and control of imported fire ants".)

Allergic reactions — Treatment of an IFA-allergic patient involves acute management, education, and possible immunotherapy for prevention of recurrent systemic reactions. Patients should also obtain a medical identification bracelet or necklace stating that they have a life-threatening allergy to IFA.

Emergency treatment — Acute management of fire ant induced anaphylaxis is identical to the treatment of anaphylaxis from other causes, with epinephrine being the drug of choice. (See "Anaphylaxis: Emergency treatment", section on 'Immediate management'.)

Epinephrine autoinjectors — All patients with IFA venom allergy should be equipped with an epinephrine autoinjector and advised to have it immediately available at all times. Epinephrine must be accompanied by clear instructions for proper use of the device as well as instructions about which symptoms should prompt its use. Epinephrine should be injected intramuscularly in the thigh, preferably with the patient supine. It should be administered without delay for the following symptoms:

●Difficulty breathing/wheezing

●Throat tightness/hoarse voice

●Lightheadedness/altered mental status

●Widespread hives

Information about prescribing epinephrine autoinjectors, as well as patient information about the optimal use of these devices, is provided separately. (See "Prescribing epinephrine for anaphylaxis self-treatment" and "Patient education: Using an epinephrine autoinjector (Beyond the Basics)".)

Venom immunotherapy — Immunotherapy is recommended for the treatment of IFA allergy [65].

Indications — Immunotherapy to prevent recurrent IFA-induced systemic reactions for:

●Adults who have experienced a systemic reaction to IFA stings, including both anaphylactic reactions and generalized cutaneous reactions (ie, widespread urticaria, angioedema, pruritus, and/or erythema, but without symptoms in other organ systems).

●Children (under the age of 17 years) who have had systemic allergic reactions that extend beyond the skin.

Note that generalized cutaneous reactions are an indication for fire ant immunotherapy in adults but generally not in children, because it is believed that most children do not go on to develop anaphylaxis. With flying Hymenoptera hypersensitivity (bees, wasps, yellow jackets, and hornets), a very low risk for future systemic reactions is observed in children who experience generalized cutaneous reactions and immunotherapy is not routinely offered, but data on fire ant reactions are sparse. Not offering immunotherapy for children with generalized cutaneous reactions is the most common approach in endemic areas, and it is supported by at least one retrospective analysis [66]. However, practice varies, and approximately one-third of responding clinicians in an endemic area did recommend immunotherapy because of the greater risk of re-stings compared with nonendemic areas [9,67].

In the authors' clinic, we offer immunotherapy for children with respiratory or vascular features but not for children with generalized cutaneous reactions, with the acknowledgment that there are inadequate data and exceptions may be appropriate. For instance, for patients in agricultural areas where stings are especially common, caregivers and physicians may decide together to pursue immunotherapy for children who have had generalized urticaria without reporting other symptoms. We frequently see children under the age of six who have stumbled into fire ant mounds and are unable to communicate details about their reactions (eg, whether or not they were short of breath). By the time the child is seen by a physician, they have been medicated by their parents with antihistamines and the physical exam may not be informative either.

Whole body extracts — Whole body extracts (WBE) of IFA are used for fire ant immunotherapy because these preparations contain adequate amounts of venom, in contrast to whole body preparations of flying Hymenoptera. Pure fire ant venom is unavailable commercially and has not been studied for immunotherapy. "Whole body vaccine" (WBV) is the term used for the solution used in immunotherapy that is prepared from WBE.

Potency issues — Fire ant extracts are the only WBEs in clinical use, and the venom content of these preparations can vary from lot to lot, which is a problem unique to fire ant immunotherapy. We recommend confirming the venom content of each lot of WBE prior to use by using it to skin test an individual with known reactivity to IFA, before the extract is used for skin testing and immunotherapy in other patients. (See 'Skin testing' above.)

Protocols, efficacy, and safety — Fire ant immunotherapy can be administered using either conventional or rush protocols.

The overall efficacy of fire ant immunotherapy is very high, based on the clinical experience of our center and others, but a precise estimate is difficult because the natural history of IFA allergy is not well defined. Specifically, it is not known with what frequency an IFA-allergic individual will exhibit systemic symptoms upon subsequent stings [68]. Without this information, it is impossible to define precisely the efficacy of immunotherapy in preventing recurrent systemic reactions. However, we have encountered very few patients who underwent a course of immunotherapy and subsequently suffered recurrent systemic reactions, and patients who live in endemic areas are stung regularly because fire ants are so aggressive and difficult to avoid.

Conventional — Conventional immunotherapy protocols with fire ant WBV consist of weekly subcutaneous injections of gradually increasing doses of WBV. The stock WBE is available as 1:10 weight/volume extract. We start with 0.05 mL of a 1:100,000 weight/volume solution, depending on the severity of the reaction and the degree of skin test positivity. We proceed stepwise to 0.5 mL before moving to the next 10-fold more concentrated dilution (table 3). Our target maintenance dose is 0.5 mL of a 1:100 weight/volume extract, given monthly, which contains the same amount of venom as approximately 19 fire ant stings [69]. However, the optimal maintenance dose has not been established, and one large survey of 1091 prescriptions for fire ant immunotherapy submitted by over 300 practices serving personnel in the United States military found that the most commonly prescribed maintenance dose was 0.5 mL of a 1:200 weight/volume extract [70].

Efficacy was reported in one study of 65 subjects with previous anaphylaxis who were treated with immunotherapy, in which 47 (72 percent) subsequently sustained IFA stings and only one individual had anaphylaxis [71]. In addition, 31 subjects underwent fire ant stings under direct observation, and none had anaphylactic reactions while receiving maintenance immunotherapy. In contrast, there were 11 fire ant-allergic subjects in the control group who declined immunotherapy, of whom 6 sustained field stings. All 6 had anaphylactic reactions.

The safety of conventional immunotherapy for fire ant allergy was reviewed in a retrospective series of 77 patients who had received 1887 injections. Systemic allergic reactions to the immunotherapy itself occurred in 9 percent of patients and were mild [42]. Risk factors for a systemic reaction to immunotherapy included large local reactions or a history of systemic allergic reactions during diagnostic skin testing.

We do not mix WBV with other extracts in immunotherapy. The compatibility of WBV with other allergen extracts has not been extensively investigated, but one study demonstrated that WBV degraded the proteins in timothy grass extract [72]. There was no apparent degradation of proteins in extracts of cat, ragweed, or dust mite.

Rush — Rush protocols (an accelerated form of immunotherapy) have been developed in military settings where regulations prohibit deployment of individuals with histories of anaphylaxis to insects and orders for deployment do not provide time for conventional therapy. These require informed consent and experienced practitioners with carefully planned consultant and emergency treatment available. This approach is typically more costly because it must be performed under continuous observation.

●A small number of reports of successful rush protocols have been published [73-75]. In a two-day program with 58 adult subjects, three (5.2 percent) experienced systemic reactions during the protocol, which were reported to be "mild" (table 4) [74]. Following completion of the protocol, sting challenges with IFA were performed 20 days later on 56 of the subjects with more than 112 ant stings among the group. One mild systemic reaction occurred, for an estimated clinical efficacy of 98 percent.

●A one-day rush protocol consisting of 10 injections has been described, which was successfully completed in 28 of 37 (76 percent) patients [76]. Those who developed allergic symptoms during the protocol were transitioned to a conventional immunotherapy protocol. No premedications were administered prior to the injections. Of the 9 patients who developed reactions, 7 had generalized pruritus or urticaria, and 2 had systemic reactions.

●Another report described a one-day rush protocol that was successfully administered to three children under three years of age [77]. No systemic reactions occurred during the procedure.

●A one-day protocol performed in 96 patients compared rates of systemic reactions with or without premedication with antihistamines and prednisone [75]. Reactions occurred in 9.5 percent in the premedicated group versus 24.3 percent in the nonpremedicated group, which was a nonsignificant difference but suggested benefit. Subsequent sting challenges on 53 subjects resulted in one mild reaction (isolated rhinitis), for an estimated efficacy of 98 percent.

●Case reports of military personnel described no adverse effects in individuals who were treated with rush protocols several times because their immunotherapy was interrupted by deployment or pregnancy [78].

Duration of immunotherapy — Controlled studies to make specific evidence-based recommendations on length of therapy are lacking. We offer IFA immunotherapy for three to five years in most patients, similar to practice in venom immunotherapy for other Hymenoptera (see "Hymenoptera venom immunotherapy: Determining duration of therapy"). However, we may alter our recommendations depending on the clinical scenario. For example, if a patient has been receiving immunotherapy and is stung in the field without developing symptoms, we discuss the option of stopping after three years. In patients who have completed three years of immunotherapy but have not been recently stung to determine if they are still reactive, and those who have had severe reactions, we will discuss the option of continuing immunotherapy for a 4th or even a 5th year, especially if they live in areas where fire ant stings are regular occurrences.  

We do not repeat skin testing in preparation of discontinuing treatment. If the patient is reluctant to stop immunotherapy after an appropriate interval, we offer a sting challenge under controlled circumstances in the hospital. Patients should continue to carry epinephrine autoinjectors if they have histories of anaphylaxis.

Immunotherapy failure — "Immunotherapy failure" may be defined as one or more recurrent anaphylactic reactions to fire ant field stings while receiving fire ant immunotherapy or after completion of a full course of immunotherapy. The true failure rate of IFA-WBE immunotherapy is not known, but it must be very low, because we have seen this only rarely over many years of practice in an area where most individuals are stung every year.

●The most common reason for immunotherapy "failure" in our experience is patient noncompliance. Patients who have experienced anaphylaxis need attention, encouragement, and follow-up to assure compliance with immunotherapy [79].

●The most frequent technical reason for recurrent systemic reactions to fire ants stings, despite having received immunotherapy with IFA WBE, is use of an extract containing little or no IFA venom. The possibility that the IFA WBE used for immunotherapy contains too little fire ant venom can be empirically investigated by skin testing the patient with the extract in question at the concentration used for routine skin testing. If the patient has a negative result, the extract they have received may have an inadequate quantity if venom to be clinically effective. If this occurs, we recommend that IFA immunotherapy be reinitiated with an active extract. We prefer administering a new extract composed of two different lots of extracts known to induce positive skin test reactions in such a patient.

●If the above approach fails, increasing the volume of the maintenance extract using two separate injections up to 0.5 mL of the maintenance concentration in two separate sites may be of benefit.

●In patients with systemic reactions to IFA immunotherapy, in whom higher maintenance doses might pose a risk, omalizumab has been reported to be helpful [80,81]. These practices are based on clinical experience. There are no published data on the optimal management of such patients.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stinging insect allergy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Insect allergy (The Basics)")

●Beyond the Basics topic (see "Patient education: Imported fire ants (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Imported fire ants (IFAs) are aggressive, venomous ants that sting with little provocation and are difficult to avoid in endemic areas (throughout the southern United States). (See 'Territory' above.)

●Fire ant stings produce an immediate, intense burning (the "fire" inspiring the name) and itching at the sting site. Stings occur most frequently during summer, most commonly in children, and typically on the lower extremities. (See 'Clinical reactions' above.)

●Most people develop only local reactions, which may take several forms, including wheal and flare reactions, sterile pustules, and large local reactions. Local reactions are contiguous with the sting site. (See 'Local reactions' above.)

●Treatment of local reactions is symptomatic and not always necessary (see 'Local reactions' above):

•For patients with uncomfortable wheal and flare reactions, we suggest the application of low-potency topical corticosteroids and/or oral antihistamines (Grade 2C).

•Large local reactions often require treatment with topical agents and oral antihistamines. High-potency topical corticosteroids may be required. For severe swelling, we suggest administration of oral prednisone (20 mg given as a single dose) and elevation of the affected extremity (Grade 2C).

●Massive attacks, in which individuals sustain hundreds or thousands of stings, have been reported. Multiple stings can result in a variety of toxic reactions, such as serum sickness, nephrotic syndrome, seizures, mononeuritis, and worsening of pre-existing cardiopulmonary disease. Treatment should be individualized to the patient's symptoms, and we suggest against empirically administering large doses of glucocorticoids and intravenous fluids, particularly in debilitated patients and those with pre-existing cardiovascular disease (Grade 2C). For most patients with multiple stings, the interventions suggested for local reactions are sufficient. (See 'Toxic reactions' above.)

●Some individuals develop systemic allergic reactions, which can range from generalized cutaneous reactions (generalized urticaria, angioedema, pruritus, erythema) to life-threatening anaphylaxis. Symptoms may occur within minutes after a sting or, on rare occasions, can develop hours after. The pathognomonic sterile pustules can later identify the fire ant as the culprit. (See 'Systemic allergic reactions' above.)

●Patients with anaphylaxis must be treated on an emergency basis and equipped with an epinephrine autoinjector for self-treatment of possible future reactions. (See "Anaphylaxis: Emergency treatment".)

●Patients with allergic reactions should be referred to an allergy expert. The diagnosis of IFA venom allergy requires the demonstration of venom-specific immunoglobulin E (V-IgE) by skin testing or in vitro tests. Skin testing is the preferred method, but in vitro testing is available if the skin is compromised or if there is a medical contraindication to skin testing. (See 'Diagnosis' above.)

●In patients with confirmed IFA venom allergy, we recommend three to five years of venom immunotherapy with commercially available whole body IFA vaccines (Grade 1B). Various protocols have been established. (See 'Treatment' above.)

DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the Department of Defense of the United States Government or its components.

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges David F Williams, PhD, and Robin Rockhold, PhD, who contributed to earlier versions of this topic review.