Allergic reactions to insect stings are common conditions. It is one of the most serious health problems because it includes reactions that can sometimes be life-threatening and result in dramatic results. The most serious reactions to insect stings occur with bee stings. The frequency of death events caused by bee stings is also not low. More than 40 deaths are reported in the United States of America (USA) and over 20 deaths in Europe each year. However, it is a fact that many bee sting deaths are still unrecognized (1,2).
It is known that the frequency of fatal allergic reaction (anaphylaxis) due to bee sting is between 0.4% and 5% in the general population (3). In our country, this frequency was found to be around 2% as a result of several studies (4-6).
Patients who are known to develop a general reaction following a bee sting and who have specific allergy antibodies (IgE) to bee venom are at risk for a similar reaction later on; Therefore, they must be treated. The treatment of reactions caused by bee venom can be examined under three headings: a. Protection; b. Medication; c. Bee vaccine (Venom immunotherapy=VIT) (7).
This article will focus on one of these treatment models, “VIT”.
Patient Selection and VIT Requirement:
The most important rule of allergy vaccine treatment (Allergen specific immunotherapy = ASI) is the right patient selection. In accordance with this general rule, the most important point in VIT is the right patient selection. In other words, the most important point of the VIT requirement is “who should receive this treatment?” is to answer the question correctly. Normally, an insect sting may result in a one-site (local) reaction, a major local reaction (reaction that causes severe and prolonged swelling), a reaction involving the whole body skin (with no other problem urticaria=urticaria, angioedema, rash), or a fatal reaction (anaphylaxis; hypotension, dizziness, shortness of breath or throat congestion, suffocation) (7). The details of the last reaction of the patient as a result of insect bites have an important feature in the initiation of immunotherapy, the continuation and quality of immunotherapy.
VIT requirement; The detailed history can be obtained by skin testing with venom allergens or by confirming venom-specific IgE with blood testing. Apart from this, an important point that has been emphasized more intensely lately is the quality of life. In patients who do not normally require VIT, the application of VIT can be beneficial in terms of quality of life. According to some published studies, significant improvements were found in the quality of life in patients receiving VIT (8).
VIT is currently seen as the most effective treatment for allergic diseases in terms of vaccine treatment. Two controlled clinical studies on VIT conducted in the USA and Switzerland stood out among the studies evaluating this treatment (9,10). The results of both studies appear to be very similar. According to the results of the American study, it was observed that VIT was 98% effective.
VIT is generally not recommended in patients with only extensive local reaction to bee stings, as the possibility of systemic reaction developing with subsequent bee stings is low. However, in these patients, VIT may be beneficial as it reduces the fear of death risk and increases their quality of life. Again, some of these patients choose to receive this treatment because of their excessive swelling and swelling and, many times, their need to be cortisone. In addition, according to some studies, it has been shown that VIT performed in these patients reduces the size and duration of swelling and swelling, and makes slight changes compared to those who do not receive this treatment (11,12).
VIT Models:
Physicians at the start of all immunotherapy treatments; They should examine in detail the issue of who, how, at what dose, at what interval and for how long this treatment will be given. VIT has different application models like ASI. For example, apart from regimens where the maintenance dose is reached in 4-6 months, there are rapid regimens that can be increased to this dose in 6-8 weeks. There are studies showing that rapid regimens in immunotherapy administered with Venom are safer than others (13-17). Another important issue is the maintenance dose. The maintenance dose should be 100 μg for each venom. Low doses have not been found to be fully effective.
Maintenance intervals in VIT may also vary. In immunotherapy treatment for respiratory allergies, after the maintenance dose is reached, the immunotherapy application intervals can be between 1-4 weeks, while in VIT it varies between 4-8 weeks. Although the duration of immunotherapy has not been fully studied, it can be as sustainable as immunotherapy with respiratory allergen. In fact, there has been a trend lately that this treatment should last a lifetime. Symptoms can be seen again in 35-50% of these patients 5 years after the end of immunotherapy, which is normally performed with respiratory allergen (18-21). However; 5 years after the end of VIT, 85% of bee allergy patients do not react with re-sting (22). However, other reasons other than immunotherapy may also be effective in this. For example; Although people may encounter a respiratory allergen every day, re-stings are much rarer.
There are various VIT applications. One of the methods applied for 3-6 months in the form of ultra-rush with a maintenance dose in 6 hours, rush with a maintenance dose in 2-3 days, a modified rush method with a maintenance dose in 6-8 weeks, or classical weekly injections should be chosen. The maintenance interval was determined as 4 weeks. There is no published literature on 6-8 weeks of practice accepted in practice (23). Recently, there have been publications on the safety of the application performed with 12-week intervals (24). It has been found that taking antihistamines on each injection day during immunotherapy significantly reduces both local and some systemic reactions (25,26).
The standard maintenance dose is 100 μg as I mentioned before. However, although it is stated that 50 μg application is effective, there are also 200 μg applications. It has been reported that this higher dose is more effective (27). However, the risks of side effects at this dose are higher as expected.
VIT Efficacy:
In terms of efficacy, mixed wasp immunotherapy was found to be 98% effective, lean venom immunotherapy 85% to 90%, and honeybee immunotherapy 75% to 85% effective (28). As an efficacy, it is mentioned that the general reactions that may occur as a result of bee stings are completely eliminated. In the study of Rueff et al., the maintenance dose was increased up to 200 μg and the patients were fully protected against systemic reactions (27). However, this application is not necessary in every patient. The main problem is that it cannot be predicted in which patients the treatment will fail. However, it has been reported that by measuring the level of specific protective antibody (IgG) formed against bee venom with treatment, it can be determined in which patients the treatment will fail (29).
When is VIT Discontinued?
In a study, clues about when to stop VIT were obtained by monitoring venom-specific IgG antibody response. Venom-specific IgG level has been used as an indicator of clinical protection in patients treated for 4 years or less. However, the fact that systemic reactions are less common in patients who have been treated with VIT for more than 4 years and even with low venom-specific IgG levels has been explained by the involvement of other protective mechanisms after 4 years. Although our knowledge about immunotherapy has increased today, our knowledge about the mechanisms that lead to immune tolerance is limited after the 4th year of immunotherapy (30,31).
Studies have shown that the mean venom-specific allergy antibody (IgE) levels decrease after the 5th year of immunotherapy. These findings suggested that immunotherapy should be discontinued after 5 years. Patients who had taken VIT for at least 5 years were included in these studies. Although there was a 10-fold decrease in both skin test and blood test results when the treatment was discontinued, 75% of the patients remained positive for the skin test (32).
How Long Does VIT Protect?
In a study on long-term prophylaxis after cessation of treatment, the situation 13 years after the end of treatment was evaluated. In this study, in which 113 patients were evaluated, systemic reaction was observed in 10% of patients after insertion in the first 4 years after cessation of treatment. The rate of systemic reaction is still around 10% during the 5 to 13 years after the treatment, on average 9.6 years. In this study, it was shown that 10 years after the cessation of treatment, the risk of developing a reaction after a single bee sting was 10%, and the risk after multiple stings was 17% (22).
In patients with general reaction as a side effect during immunotherapy, the rate of recurrence of general reactions after sting after treatment is 46%, while it is 8% in the non-observed group (33). Therefore, a general reaction as a side effect during VIT is not good news.
Bee sting reactions after VIT are less serious than before VIT; however, rarely serious reactions have been observed. The pre-treatment history of the patient is very important in assessing the risk of recurrence. In two studies, it was shown that the risk of recurrence is high in patients with a history of serious reactions before treatment (34,35). In addition, patients with a history of serious reactions were found to be more severe when reintroduced after discontinuation of treatment. Therefore, patients who have developed a fatal reaction should continue immunotherapy for life.
Duration of VIT:
Although it is stated that 3 years is sufficient, especially in children, in most studies on the duration of VIT, criteria such as decrease in blood test results and negative skin test results were sought (36,37). In addition, there are studies stating that continuing VIT for 5 years is better than 3 years (35). In the study of Lerch and Muller, it was reported that those who received treatment for more than 50 months had less reactions than those who received less treatment for this period (38). Apart from all these, Muller et al. stated that honey bee allergy is different from wasp and wasp allergy (28). It has been observed that more reactions can be seen during the treatment in honey bee allergy patients and that there may be recurrences after the treatment is stopped. In summary; Immunotherapy should not be discontinued in patients with a fatal general reaction during VIT, in patients with honey bee allergy, and in patients whose treatment duration has not been less than 5 years. Moreover; age, underlying medical problems, frequency of exposure should be considered.
In conclusion, there are similarities and differences between VIT and ASI. Immunological and environmental factors may affect treatment. In order for VIT to have a protective effect in bee allergy, the natural history of the allergy should be well known before treatment. In addition, general reactions that occur as side effects during VIT, and venom-specific IgG and IgE levels may be a guide for treatment. Although long-term protection is often achieved after treatment, there may be patients who rarely require a very long-term, sometimes even life-long, VIT.
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Wishing you a healthy day…
Prof. Dr. Cengiz KIRMAZ
