Fire ant stings are frequent in pediatric age: 32% to 54% of the surveyed population25.
In this study, systemic reactions after fire ant stings were also more prevalent in patients (n=17) under 15 years (51.51%). If we expand the age group up to 20 years old, the frequency of the systemic reactions rises to 75.9%. Among Grade-IV reactions, the patient's age has not positively correlated with the grade of the sting reaction.
In literature, male sex is an independent risk factor for severe systemic reactions to the field sting. The effect of male sex in insect sting induced anaphylaxis presumably results from a selection effect. Because of a different degree of exposure, adult men are stung more frequently than women. They might, therefore, be at higher risk for sensitization or severe allergic reactions to honeybee or wasp venom. There is no data on fire ant venom26. In this study, there was no gender influence on the severity of the reaction; there was only a slight predominance of males: 51.5% over females: 48.5%, probably due to the greater exposure.
Concerning atopy, it is known that it is a risk factor for anaphylaxis triggered by food, exercise, and latex27. It has not yet been established that atopic disease increases the risk of anaphylaxis associated with Hymenoptera venom allergic reaction28.
According to an international anaphylaxis consensus (ICON)29; cardiovascular disease and uncontrolled asthma are well-recognized risk factors for severe anaphylaxis in general. In the current study, there was no correlation between asthma with a Grade-IV systemic reaction.
Considering the previous systemic reaction, in literature, 18% of the mild systemic reactions in previous stings evolved into severe systemic reactions30. In the current study, the percentage was lower, 11.11%. In the same study mentioned above, a third of patients (24%) developed the same severity as the previous reactions30; meanwhile, we obtained a percentage of 22.22%, data similar to the literature.
Considering the previous large local reactions, Golden et al31 observed that 7% of children who had large local reaction progressed to a systemic reaction in subsequent stings. Graft and collaborators32 reported 2% of systemic reaction when they had large local reactions previously. Our findings showed that 11.11% of the patients had experienced a large local reaction in the previous sting. The vast majority (55.56%) reported only local reactions in previous reactions. Therefore, in our patients, there was no correlation between having a certain severity of reaction in previous stings and subsequently evolving to a more severe reaction in subsequent stings (p = 1.207). The vast majority reported only a local reaction in the sting prior to anaphylaxis.
In literature, a history of large local reactions carries a lower risk of a systemic reaction than in all other sensitized patients. When a large local reaction results after bee venom, the likelihood of anaphylaxis from a future sting is approximately 5%. For comparison, when there is a history of anaphylaxis from a previous Hymenoptera sting and the patient has positive skin test results to venom, at least 60% of adults and 20-32% of children will develop anaphylaxis with a future sting33. A fact that draws attention in our study is in 4 out of 18 patients, the first systemic reaction was already severe, and that these patients were not referred to a specialist for investigation. Only in the subsequent reaction, two patients were referred to a specialist for investigation, and the other two patients were not referred, looking for a specialist willingly.
Comparing the results of specific serum IgE measurements against fire ant venom with skin tests results in patients with grade-IV systemic reactions, our findings corroborate with the literature34,35,36 that there is no correlation between the degree of sensitization and severity of the reaction.
Changes in specific IgE and IgG4 antibodies measurements
The levels of fire ant IgE antibody decreased in the period observed in 73.3% of the patients, while specific IgG4 increased in that period. Thus, the specific IgE/IgG4 ratio at baseline and 12 months after the maintenance phase showed significant differences.
After an initial increase in the first months of treatment, specific IgE levels tend to decrease during immunotherapy37,38 and generally remain low even after discontinuation of treatment39. On the other hand, specific serum IgG4 levels increase during immunotherapy with venom40,41,42. It is known that high levels of specific IgG4 are positively correlated with the number of stings, previously described in beekeepers43,44,45. Thus, the specific IgG4 antibody is considered a tolerance indicator in allergic individuals because it has been suggested in the literature that these antibodies can block the interaction between the allergen and the specific IgE antibodies, thus preventing reactions with the participation of IgE. These effects should be reflected in the specific IgE/IgG4 ratio46,47. The explanation for this is due to the regulatory cell populations that form a suppressive environment: a slight decrease in the production of allergen-specific IgE and early switch to B cells to produce IgG4 and, consequently, an increase in IgG4 antibodies, which is a non-inflammatory agent in allergic disorders7,48.
Serum tryptase levels
In literature, about 80% of patients with Muller's Grade-IV reaction to Hymenoptera venoms (bees and wasps) are diagnosed with mastocytosis. In these severe reactions, 20% of patients could not show clinical signs of mastocytosis49. Bonadonna et al50 reported a correlation between a systemic reaction to Hymenoptera sting and mast cell tryptase. Three hundred seventy-nine patients presented a history of systemic reactions after being stung by these insects, 11.6% had serum mast cell tryptase that exceeded 11.4 ng/mL. In this group, the rate of anaphylaxis (Muller's grade IV) was 70.5%. Blum et al51 confirmed these findings in a 5-year retrospective study, with 868 patients who had severe reactions after insect stings (758 patients had both: total IgE and baseline tryptase level above the reference values). Elevated basal tryptase (> 11.4 ng/mL) was associated with severe systemic reactions (p <0.03). Due to this strong association, the guidelines on allergy to Hymenoptera venoms always recommend evaluating serum tryptase for these patients.
In this study, two patients (6.25%) presented a tryptase level higher than 11.4 ug/ml; however, due to the specific investigation of hematology in our hospital, the diagnosis of Systemic Mastocytosis was ruled out. As already mentioned, in literature, there is a high correlation between severe anaphylaxis and Hymenoptera stings but being reported by bees and wasps. There is no data on fire ant venom so far.
Adverse reactions during immunotherapy
Adverse events are frequently observed when unpurified extracts are utilized, and the aqueous formulations tend to cause more local reactions than depot diluents 52,53,54.
The main risk factors that provoke serious reactions in the literature55 were very well-reviewed at each patient visit and controlled in this study: dosage error, administration of the injection without supervision by a trained professional, presence of uncontrolled asthma, the high degree of sensitivity, concomitant use of β-blockers, systemic reactions prior to immunotherapy and use of lots with new products.
When a local reaction was greater than 50mm, patients were instructed to use fexofenadine 180mg (adults), and for children, the dose was adjusted according to the weight presented. Only one adult patient took the oral antihistamine because she had a bother local reaction; other patients did not need the medication.
In a multicenter study56 evaluating data from 840 patients, side effects of immunotherapy (systemic reactions) with venom (seventy-one percent were treated with Vespula-venom extract and 27% with honeybee-venom extract) were observed in a total of 20% of patients; 26,601 injections in 840 patients, systemic reactions were observed in 1.9% of the injections during the build-up phase and in 0.5% the maintenance phase (p <0.05). Most of these reactions were mild, and only a third of patients required medical treatment. A similar frequency of systemic adverse effects was observed in a published study analyzing data from 178 patients57. The build-up phase of venom immunotherapy has more adverse effects than the maintenance phase.
In our study, the systemic reaction rate during immunotherapy was lower than the literature, comparing extracts of honeybee or wasp venoms. Our results showed a systemic reaction in 6.06% during the build-up phase. It was also lower when compared by injection (0.017%). In the maintenance phase, there were no systemic reactions. The similarity remained in the slight severity of these reactions.
Thus, the severity of side effects due to immunotherapy does not necessarily correlate with the severity of the treated allergic disease symptoms. Systemic reactions induced by venom immunotherapy may occur, but most patients tolerate this treatment without relevant side effects.
Accidental Field stings
Reaction evaluation after a sting during or after the treatment (either by a challenge test with culprit insect or by accidental sting) is an available method to determine the degree of response to venom immunotherapy58.
When the challenge test with culprit insect was performed in a series of patients undergoing immunotherapy with bee and wasp venom, about 75 to 85% 8,59,60 or even more 95% 61,62 of patients were protected.
Arseneau at el20 evaluated 66 patients submitted to 1-day rush immunotherapy protocol using fire ant whole-body extract, and the conclusion was that the immunotherapy was efficacious (1 of 53 confirmed fire ant sting challenges (1.9%) resulted in a reaction) and had a low rate of systemic reactions.
In Brazil, for ethical reasons, we could not perform the provocation test with the culprit insect; it is possible only to observe reactions by accidental stings during treatment.
In this study, 20 patients were stung, 35 stings in total, as some of them were stung more than once.
During the build-up phase, the patient still has an increased chance of having systemic reactions if he is stung at that moment. The patient who had a systemic reaction in the build-up phase in our study had a mild reaction (only hives, with no need to seek immediate attention or use adrenaline auto-injectable). Thus, we had one systemic reaction (in an accidental sting), out of 5 patients stung during this phase: 20% treatment failure.
During the maintenance phase, two patients were accidentally stung. They had systemic reactions (10.5%) and described as mild reactions: only hives, without the need to seek emergency care or the use of an adrenaline auto-injectable.
The percentage of reactions in the maintenance phase (10.5%) is lower than the percentage found in the literature, which considers approximately a 25% risk of a new generalized systemic reaction in subsequent stings in patients who received venom immunotherapy for 1 or 2 years63.
The optimal length of treatment with fire ant immunotherapy is not known. The treatment with fire ant immunotherapy commonly used often is 3–5 years based on extrapolation from flying Hymenoptera immunotherapy data. A 3- to 5-year course of flying Hymenoptera (e.g., honey bee, hornet, wasp, and yellow jacket) venom immunotherapy has been shown to provide protection against systemic reactions64.
Forester et al65 grouped patients into those who received < 3 years (reduced course) and those who received > 3 years (complete course) of imported fire ant immunotherapy (IFA). All subjects on IFA immunotherapy received a maintenance dose of 0.5 mL of a 1:100 w/v concentration of IFA whole-body extract. No difference in the incidence or severity of systemic reactions to field stings after immunotherapy discontinuation for the two groups studied. The systemic reaction rate was low for both the complete and the reduced course groups (7 and 6%, respectively) after discontinuation of IFA immunotherapy.
Our patients will be in immunotherapy for 3 years. After this period, new data will be gathered.