The majority of insect sting reactions in children are mild and frequently only dermal (hives, angioedema).
Children who have only dermal reactions have a very benign prognosis and generally do not retain their allergic sensitivity.
Children with more severe reactions have a 30% to 40% risk of recurrent anaphylaxis.
Venom immunotherapy (VIT) provides more than 95% protection against subsequent re-sting reactions in children, and if there are reactions, they are milder.
For most individuals, 3 to 5 years of therapy appears adequate despite the persistence of specific IgE.
VIT is associated with an improvement in quality of life in contrast to use of an epinephrine autoinjector ( EAI).
In children, the prescription of an EAI should carefully take into account the risks of the disease versus the risks of having an EAI (diminished quality of life) versus the benefits (preparedness for treating a potentially life-threatening event).
Allergic reactions to insect stings are common. An allergic reaction can occur at any age, often after a number of uneventful stings. It is estimated to affect at least 0.3% to 3% of the population. The severity of the reaction ranges from a local reaction to anaphylaxis. Children tend to suffer from less serious reactions, a large local reaction being the most common presentation in this age group. The incidence of insect anaphylaxis in children is estimated to constitute 0.3% to 1.0% of all cases of childhood anaphylaxis, in contrast to adults where anaphylaxis to insect stings makes up 3% to 34% of all adult anaphylaxis cases. Stinging insect allergy is responsible for considerable anxiety that is detrimental to lifestyle.
This chapter reviews the general concepts relating to insect sting allergy and, in particular, addresses those aspects that are more relevant to children.
Biting insects are different to stinging insects. The former primarily cause reactions due to the saliva they inject when feeding, while stinging insects inject venom with the stinging apparatus at the back of their abdomen. Salivary gland secretions have no relation to venom allergens. While the venom of a sting typically causes an intense, burning pain, the saliva of a biting insect is a chemical cocktail of substances designed to make blood flow quickly and painlessly to avoid being squished. Unlike insect stings, insect bites rarely cause anaphylaxis.
The most common biting insects are mosquitoes, flies, midges, gnats, fleas, ticks and bedbugs.
Itching and a wheal may develop immediately and mostly disappear after about 2 hours, but they are often followed by a small itchy lump (papule) that develops up to 24 hours later and may last for several days before fading away. Large local reactions from mosquito bites are more common in young children. Over time, and with repeated exposure, the reactions become less intense and are less frequent problems in adolescents and adults. Anaphylaxis has been described after the bites of mosquitoes, deer flies, bed bugs and black flies.
Mosquito bites may be associated with IgE and perhaps IgG antibodies. Elevated titers correlate with the intensity of the local reactions and appear to be the immunologic mediators responsible for the reactions.
Skeeter syndrome describes a localized (allergic) reaction to mosquito bites masquerading as cellulitis and accompanied by lethargy, fever and general malaise. Skeeter syndrome usually progresses over the course of hours while cellulitis typically will evolve over the course of several days. Diagnosis can therefore be made clinically by the course of the symptoms and can be confirmed by measuring IgE and IgG antibodies to mosquito saliva antigens.
A mild reaction to an insect bite will probably resolve itself within a day or two without any need for treatment. In some cases, the use of a topical steroid may assist in reducing inflammation and an antipruritic may relieve itchiness. There is a scarcity of quantitative scientific studies into the various treatments for insect bite reactions.
Insects that sting are members of the order Hymenoptera of the class Insecta. It is almost exclusively the social Aculeata of the families Apidae, Vespidae and Formicidae that cause significant allergic reactions in human beings. Aculeata from other families can cause painful stings to people, but repeated stings from the same species are so unlikely that allergy to them is practically unheard of. There are three major subgroups: Vespidae, which include the yellow jacket, hornet and wasp; Apidae, which include the honeybee and bumblebee; and the Formicidae ( Figure 57-1 ). An overview of the Hymenoptera is given in Figure 57-2 .
The Aculeata share in common a stinging apparatus that originates in the abdomen of the female insect and actually is a modified ovipositor; therefore only female insects can sting. The sting consists of a sac containing venom attached to a barbed stinger. The honeybee’s stinger has multiple barbs, which usually cause the stinging apparatus to detach from the insect, leading to its death. In contrast, the stingers of vespids have few and finer barbs than the Apidae, and do not commonly autotomize, so vespids can inflict multiple stings ( Figure 57-3 ).
The Vespidae are divided into the subfamilies Vespinae (yellow jackets and hornets) and Polistinae (wasps). The Vespinae are split into three genera: Vespula (yellow jackets), Dolichovespula and Vespa (hornets). The common names in general usage can be misleading: in Europe the term ‘wasps’ refers generally to any of the social wasps rather than just to Polistes species ( Table 57-1 ).
|Dolichovespula||Wasp||Hornet, white-faced hornet, aerial yellow jacket|
In most parts of the USA and Europe, yellow jackets are the principal cause of allergic reactions, whereas Polistes are more commonly implicated in the Gulf Coast areas of the USA and along the Mediterranean coast of Europe. In Australia yellow jackets were only introduced around 20 years ago, but are already found in every state.
The Vespula (yellow jackets) preferably build their nests underground, but can also be found under the roof and in window shutters. They live mostly in proximity to humans. Their nests are often encountered by children playing in the garden, or are disturbed by lawn mowing, gardening or other outdoor activities. Yellow jackets are scavengers and are often encountered at outdoor events when food and drinks abound. Most stings occur in summer.
Vespa include the European hornet ( V. crabro ) which also exists in significant numbers in eastern North America, and the Asian hornet ( V. orientalis ). Hornets nest in shrubs, trees and birds’ nest-boxes. Near their nests, hornets are very aggressive. However, they are attracted much less to meat and sweet foodstuffs than the Vespula . Therefore hornet stings are rare.
The common paper wasps ( Polistes ) build honeycomb nests in shrubs or under the eaves of houses. Their nests are generally limited to a single layer of open cells (or comb) with minimal outer covering. They are important predators, preying on agricultural and horticultural pests. Important Polistes species in Europe are P. dominula and P. gallicus , whereas in North America other species such as P. annularis, P. apachus, P. exclamans, P. fuscatus and P. metricus are dominant. In the last decades, P. dominula has increasingly spread across the North American continent and central and northern parts of Europe. The coloring of wasps varies greatly: they can be brown, black, red or striped. The European species, the Mediterranean wasp ( P. dominula ), is difficult to distinguish from a yellow jacket because it has the same bright yellow and black stripes. Outwardly they are distinguishable by differences at the junction of thorax and abdomen: the waist becomes thicker more rapidly in the Vespinae compared to the Polistinae and they have characteristic dangling legs when in flight ( Figure 57-4 ). Polistes are more prevalent early in the summer season. In some areas of the USA, such as Texas, they are the most frequent cause of sting reactions.
The Apidae are divided into the genera Apis (honeybees) and Bombus (bumblebees). Honeybees and bumblebees are docile and sting only when provoked. The most significant species in causing allergic reactions is the domesticated A. mellifera , cultured all over the world for honey production and to pollinate fruit trees.
Africanized honeybees, or ‘killer bees’, have received much publicity. They are a cross between the European A. mellifera mellifera and the African A. mellifera adansoni . They were introduced into Brazil from Africa in 1956 for the purpose of more productive pollination and have gradually spread north into the USA. The venom components of the Africanized honeybees and the domesticated European honeybees are similar. African honeybees are much more aggressive. Massive stinging incidents have occurred, leading to death from venom toxicity.
Members of the genus Bombus, the bumblebees, also live in colonies. The nests are usually in the earth. Most bumblebee species are bigger than honeybees, more heavily built and more hairy. Bumblebees are not aggressive; children can incur stings when walking on grass. Systemic reactions occur in particular in owners of greenhouses where bumblebees are kept for pollination of plants (e.g. tomatoes).
The family Formicidae has a subfamily Myrmicinae , which subsequently can be divided in two genera: Myrmecia (jack jumper ants [JJA] and bull ants) and Solenopsis (imported fire ants [IFA]). Myrmecia are solitary roamers, do not appear in ant trails, and attack when aggravated. JJA cause the highest rate of anaphylaxis in the world from a single insect sting/bite.
The main two members of the Solenopsis genus are the red fire ant ( S. invicta ) and the black fire ant ( S. richteri ) . Fire ants build characteristic nests, which can grow to 40 cm in height, and often migrate in trails.
Red fire ants are found in the southeastern and south central USA, especially along the Gulf Coast. They have now spread to California. In Australia they are only found in Brisbane.
Stings occur most frequently in summer, most commonly in children and typically on the lower extremities. The fire ant attaches itself to a person by biting with its powerful mandibles to hold onto the skin. It then pivots around its head and stings at multiple sites in a circular pattern with the stinger located at the tip of its abdomen. Within 24 hours a sterile pustule develops, which is diagnostic of the fire ant’s sting. Allergic reactions to fire ant stings are becoming increasingly common in the southern USA.
Venoms contain vasoactive amines (e.g. histamine, dopamine, norepinephrine), acetylcholine and kinins, which account for the burning, pain and itching normally experienced from a sting. They increase permeability, allowing the spread of the venom through the body of the victim. The different venom components known to date are listed in Table 57-2 .
|Allergen||Name/Function||MW (kDa)||% DW||Potential N-Glycosylation||Eukaryotic Expression|
|BEES ( Apis mellifera, A. cerana, A. dorsata )|
|Api m 1, Api c 1, Api d 1||Phospholipase A2||17||12||1||+|
|Api m 2||Hyaluronidase||45||2||3||+|
|Api m 3||Acid phosphatase||49||1–2||2||+|
|Api m 4||Melittin||3||50||0||−|
|Api m 5||Allergen C/DPP IV||100||< 1||6||+|
|Api m 6||Protease inhibitor||8||1–2||0||+|
|Api m 7||Protease||39||?||3||+|
|Api m 8||Carboxylesterase||70||?||4||+|
|Api m 9||Carboxypeptidase||60||?||4||+|
|Api m 10||CRP/icarapin||55||< 1||2||+|
|Api m 11.0101||MRJP 8||65||?||6||+|
|Api m 11.0201||MRJP 9||60||?||3||+|
|Api m 12||Vitellogenin||200||?||1||+|
|BUMBLEBEE ( Bombus pennsylvanicus, B. terrestris )|
|Bom p 1, Bom t 1||Phospholipase A2||16||1||−|
|Bom p 4, Bom t 4||Protease||27||0, 1||−|
|YELLOW JACKETS ( Vespula vulgaris, V. flavopilosa, V. germanica, V. maculifrons, V. pensylvanica, V. squamosa, V. vidua )|
|Ves v 1, Ves m 1, Ves s 1||Phospholipase A1||35||6–14||0, 0,2||+|
|Ves v 2.0101, Ves m 2||Hyaluronidase||45||1–3||4||+|
|Ves v 2.0201||Hyaluronidase *||45||?||2||+|
|Ves v 3||DPP IV||100||?||6||+|
|Ves v 5, Ves f 5, Ves g 5, Ves m 5, Ves p 5, Ves s 5, Ves vi 5||Antigen 5||25||5–10||0||+|
|Ves v 6||Vitellogenin||200||?||4||+|
|WHITE-FACED HORNET, YELLOW HORNET ( Dolichovespula maculata, D. arenaria )|
|Dol m 1||Phospholipase A1||34||2||−|
|Dol m 2||Hyaluronidase||42||2||−|
|Dol m 5, Dol a 5||Antigen 5||23||0||+|
|HORNETS ( Vespa crabro, V. magnifica, V. mandarinia )|
|Vesp c 1, Vesp m 1||Phospholipase A1||34||0||−|
|Vesp ma 2||Hyaluronidase||35||4|
|Vesp c 5, Vesp ma 5, Vesp m 5||Antigen 5||23||0||−|
|EUROPEAN PAPER WASPS (Polistes dominula, P. gallicus)|
|Pol d 1, Pol g 1||Phospholipase A1||34||1||−|
|Pol d 4||Protease||33||6||−|
|Pol d 5, Pol g 5||Antigen 5||23||0||−|
|AMERICAN PAPER WASPS ( Polistes annularis, P. exclamans, P. fuscatus, P. metricus )|
|Pol a 1, Pol e 1||Phospholipase A1||34||0||−|
|Pol a 2||Hyaluronidase||38||2||−|
|Pol e 4||Protease||?|
|Pol a 5, Pol e 5, Pol f 5, Pol m 5||Antigen 5||23||0||+|
|FIRE ANTS ( Solenopsis invicta, S. geminata, S. richteri, S. saevissima )|
|Sol i 1||Phospholipase A1||35||< 1||3||−|
|Sol i 2, Sol g 2, Sol r 2, Sol s 2||14||0||+|
|Sol i 3, Sol g 3, Sol r 3, Sol s 3||Antigen 5||26||2||+|
|Sol i 4, Sol g 4||12||0||−|
The major allergenic components of Hymenoptera venoms are phospholipase A in honeybee venom and antigen 5 in vespids.
The venom of fire ants differs markedly from the other venoms by consisting approximately of 95% water-insoluble alkaloids. The alkaloids produce a sterile pustule. The protein content is only 5%, with a higher content in summer.
Commercial Hymenoptera venom products are available in many countries as lyophilized protein extracts of honeybee, yellow jacket and Polistes wasp venoms.
A common problem of in vivo and in vitro diagnosis of insect venom allergy using venom extracts is that patients may have double positive test results for honeybee venom (HBV) and yellow jacket venom (YJV). This double positivity may reflect true double sensitization to HBV and YJV, or may be based on IgE cross-reactivity.
Cross-reactivity may be based on IgE reactivity to homologous single venom allergens present in venoms of different families or on IgE reactivity to cross-reactive carbohydrate determinants (CCD). Causative for the latter are IgE antibodies that are directed against an alpha 1,3-linked fucose residue of the N -glycan core established by insects and plants. Most HBV and YJV allergens are glycoproteins with one or more such carbohydrate structures ( Table 57-2 ). CCD-specific IgE antibodies have been reported to be responsible for more than 50% of double sensitizations to HBV and YJV. The clinical relevance of CCD-reactive IgE antibodies in the case of insect venom allergy appears to be low or nonexistent. Polistes species seem to lack the alpha 1,3-linked fucose residue that is responsible for IgE reactivity to CCDs.
Recombinant allergens lack CCDs, allowing for a more precise distinction between true double sensitization and cross-reactivity between different venoms. By using CCD-free, correctly folded Ves v 2.0101 and Ves v 2.0201, it could also be demonstrated that hyaluronidases – contrary to previous assumptions – do not play a significant role as major allergens of YJV.
Vespid venoms have been extensively analyzed. Venom allergens of diverse Vespidae species such as the white-faced hornet ( Dolichovespula maculata ) or the European hornet ( V. crabro ) are fairly similar to those of the yellow jacket, allowing V. crabro allergic patients to be treated with yellow jacket venom.
The IgE cross-reactivity between European and American Polistes species is described as low because they belong to different subgenera. In contrast, cross-reactivity between Polistinae and Vespinae ( Vespula , Dolichovespula and Vespa ) venoms and purified venom proteins is frequently observed, especially for Vespula and both American and European Polistes venoms. Polistes VIT is not necessary. The converse is also true: half of the people who have had Polistes sting reactions have positive skin tests to yellow jacket or hornet venom and require treatment with Polistes venom only.
Within the Apidae there is cross-reactivity in that people initially sensitized to honeybee venom then react to bumblebee venom due to cross-reactive allergens. Honeybee venom should be effective immunotherapy. Bumblebees have particular importance for pollination industry workers; it has turned out that some of these patients need to be treated with specific bumblebee venom.
Little is known of immunologic cross-reactivity between fire ant and vespid venom.
Sol i 1 shares sequences with the venom phospholipases of Vespula maculifrons.
Demographic studies suggest that the incidence of insect sting allergy in the general population ranges between 0.4% and 3%. The majority of reactions that do occur are in younger individuals, although the fatality rate is greater in adults. Data on fatal reactions are scarce. It is estimated that 40 to 50 deaths per year occur in the USA as the result of insect sting anaphylaxis and in France 16 to 38. Most of these individuals have had no warning or indication of their allergies and had tolerated earlier stings with no difficulty. Fatal reactions are particularly associated with mastocytosis.
Development of Insect Sting Allergy
Hymenoptera stings are frequently encountered in the population. The younger the child, the more often they are (re)stung; in contrast, prevalence of systemic reactions to field stings was significantly lower in preschool (3.4%) and school-age children (4.3%) compared with adolescents (15.6%).
No immunologic criterion, such as skin test reactivity or titers of serum venom-specific IgE or IgG, distinguishes or identifies sting reactors from nonreactors.
The chance of developing an allergy increases with sting frequency. In general, no time relationship exists between the last uneventful sting and the subsequent sting that leads to an allergic reaction although multiple stings or repeated stings in close temporal proximity (only weeks apart) have been associated with a greater risk of developing an allergic reaction. A confusing observation is the occurrence of initial insect sting anaphylaxis after the first known insect sting, primarily in children, raising the issue of the cause of sensitization or the pathogenesis of this initial reaction.
Classification of Reactions
The usual reaction to an insect sting consists of localized pain, slight swelling, and erythema at the site of the sting. This reaction usually subsides within several hours. Little treatment is needed other than analgesics and cold compresses.
Large Local Reactions
More extensive local reactions are common. Large local reactions are defined as reactions extending from the sting site over a large area, often peaking at 24 to 48 hours and taking 5 to 10 days to resolve. For example, the swelling from a sting on the finger may extend to the wrist or elbow. Fatigue and nausea may develop in addition. For a general clinician it might be difficult to distinguish large local reactions from cellulitis, resulting in misdiagnosis and unnecessary antibiotic treatment.
The cause of these large local reactions has not been established, but it is thought to be an IgE-mediated late-phase reaction.
Large numbers of simultaneous stings (50–100) may result in a toxic reaction due to the vasoactive properties of the venom. Symptoms can have the same clinical characteristics as anaphylaxis, including nausea, vomiting, diarrhea, headache, vertigo, syncope, convulsions and fever. Hemolysis, cardiac complications, renal failure and rhabdomyolysis have also been described.
As insect venom is highly sensitizing, most patients will develop specific IgE, making the differentiation from an allergic reaction difficult.
There have been rare reports of vasculitis, nephrosis, neuritis, encephalitis and serum sickness occurring in a temporal relationship to insect stings. The symptoms usually start several days to several weeks after the sting and may last for a long period. Serum sickness, characterized by urticaria, joint pain and fever, may occur approximately 7 to 10 days after an insect sting.
Some patients develop cold-induced urticaria days to weeks after Hymenoptera stings, not necessarily accompanied by an allergic reaction to the sting.
A systemic allergic reaction consists of signs and symptoms distant from the site of the sting, and may range from mild to life-threatening in one or more anatomic systems. Symptoms usually start within 10 to 15 minutes; the more severe the reaction, the earlier it begins. On occasion, reactions can occur as long as 72 hours later.
The clinical features of anaphylaxis from an insect sting are the same as those of anaphylaxis from any other cause. Diagnosis of the acute reaction can be quite difficult if hypotension or cardiac manifestations occur with no other signs or symptoms.
Studies from children with venom allergy usually report a milder clinical presentation (predominantly isolated cutaneous symptoms) than in adults. In a study including more than 500 children, more than 60% suffered only from mild cutaneous reactions. In a more recent study, however, half of the children suffered from respiratory or cardiovascular symptoms.