Paul F. Kolecki
The order Hymenoptera (“membrane-winged”) includes bees, wasps, hornets, yellow jackets, and ants. Honeybees and bumblebees belong to the family Apidae, although wasps, hornets, and yellow jackets belong to the family Vespidae. Ants belong to the family Formicidae; fire ants are the most medically important species in this family. Anaphylaxis to Hymenoptera species affects up to 0.5% of the US population and causes about 50 deaths annually (1).
Winged Hymenoptera species are found throughout the United States, although fire ants are localized mainly in the southern states. Yellow jackets live in nests in the ground and in walls, while hornets live in nests built in trees or under branches. Wasps often build nests under roofs, behind shutters, and in dryer vents. Domestic honeybees in the United States are generally passive and do not sting unless provoked. Africanized honeybees (also called “killer bees”), indigenous to Central and South America and the southwestern United States, attack animals and humans in large; aggressive swarms cause mass envenomation.
The venom of winged Hymenoptera insects consists mainly of proteins, enzymes, and vasoactive amines; there is strong cross-reactivity between the venom within families. The venom of Africanized honeybees is very similar to that of domestic honeybees. Winged Hymenoptera species inject their venom quickly, typically causing immediate reactions. The main constituents of fire ant venom are piperidine alkaloids, which differs from the other Hymenoptera. Fire ants are named because of the burning pain inflicted by their unique venom, which they inject more slowly, taking seconds to minutes. Significant morbidity and even mortality may occur in allergic individuals after a single envenomation by any of the Hymenoptera species.
Reactions to Hymenoptera stings are classified by the time of onset and the severity of the clinical reaction. Classification by time is subdivided into immediate and delayed reactions. Immediate reactions occur within minutes to a few hours after an envenomation and are mediated by IgE and vasoactive compounds within the venom. Delayed reactions are much less common than immediate reactions and typically develop several days to a week after the sting. These reactions are not IgE mediated.
Classification of a Hymenoptera reaction by severity is subdivided into three groups: local, systemic (e.g., anaphylactic), and toxic. Local reactions are common, with swelling, erythema, and a burning sensation at the sting site. These reactions are benign, resolve within hours to a couple of days, and are not predictive of systemic reactions to subsequent stings (2). Large local reactions can occur, perhaps involving an entire extremity. Patients suffering a large local reaction are at minimal risk (approximately 5%) of systemic anaphylaxis from subsequent stings.
Systemic reactions to Hymenoptera stings are either generalized or develop at a site remote from the sting site. Systemic reactions that produce life-threatening signs and symptoms are IgE mediated and commonly known as anaphylaxis. Potential physiologic effects associated with an immediate and severe systemic reaction include bronchiolar constriction, vasodilation, myocardial depression, increased capillary permeability, and the production of mucous. Most anaphylactic fatalities are a result of laryngeal edema and bronchospasm. An envenomation in someone with no history of a previous systemic reaction results in an anaphylactic reaction <1% of the time. However, a negative history of prior systemic reaction does not rule out the possibility of a severe reaction in the future. The risk of anaphylaxis to a subsequent Hymenoptera sting for a patient who has previously suffered venom-induced anaphylaxis is 30% to 60%. Because of the very strong cross-reactivity between the venoms within each Hymenoptera family, individuals sensitized to one species may also react to a sting by another species. Envenomation victims with Hymenoptera venom allergy and high levels of total IgE predominantly develop mild and moderate systemic reactions and may be protected from developing severe systemic reactions (3).
Toxic reactions, also known as direct systemic reactions, typically follow a massive envenomation, as seen with Africanized honeybees and result in the absorption of larger amounts of venom. Depending on the size of the victim, 10 to 50 simultaneous stings may be serious or fatal. The dose that will be lethal to 50% of humans (LD50) for honeybee stings has been estimated to be between 500 and 1,200 stings. Toxic reactions may occur immediately or may be delayed, and fatalities are a result of multisystem organ failure (4).
CLINICAL PRESENTATION
Local reactions caused by Hymenoptera envenomations are characterized by pain, wheal and flare formation, warmth, and pruritus at the sting site. These types of reactions occur in nonallergic individuals. Reactions to stings by winged species typically begin immediately and last for several hours. Fire ant stings often occur in clusters and develop into painful vesicles and sterile pustules during the first 24 hours and require up to 10 to 14 days for resolution. Large local reactions from fire ants typically are pruritic, erythematous, edematous, and indurated.
Local allergic reactions result in persistent swelling, pain, and erythema at the site of the sting. These reactions may progress to involve a large area (e.g., an entire extremity) during the first 2 to 3 days and may last for more than a week. Stings after accidental insect inhalation or ingestion by sensitive individuals may cause life-threatening swelling and obstruction of the pharynx, larynx, or esophagus.
Most anaphylactic reactions develop within minutes of envenomation and peak within an hour. Rarely, reactions may be delayed as long as 6 hours after the envenomation. Recurrent reactions may occur for up to 2 days. Mild anaphylactic reactions are characterized by generalized flushing and urticaria, although moderate reactions are characterized by generalized weakness, chest or throat tightness, nausea, vomiting, diarrhea, and generalized angioedema. Cyanosis, dyspnea, stridor, hoarseness, confusion, coma, and collapse are seen in severe cases of anaphylaxis. Physical findings include hypotension, tachycardia, urticaria, wheezing, and laryngeal and pulmonary edema. Secondary complications associated with severe Hymenoptera-induced anaphylaxis include cerebral and myocardial infarction and coagulopathies (5,6). Systemic reactions also occur from fire ant stings and anaphylaxis occurs in 0.6% to 6% of envenomated fire ant victims.
Signs and symptoms of direct venom-induced systemic toxicity usually begin within minutes and include vomiting, diarrhea, generalized edema, collapse, loss of consciousness, confusion, headache, muscle spasms, and seizures. Vital signs typically reveal hypotension and tachycardia. Severe cases of direct systemic toxicity may be complicated by hemolysis, thrombocytopenia, disseminated intravascular coagulation (DIC), rhabdomyolysis, acute renal failure, hepatotoxicity, and encephalopathy. Systemic toxicity from mass envenomation may be delayed by many hours (4). A study of pediatric patients suffering mass Hymenoptera envenomations reported that vomiting does not portend involvement of other organ systems (7).
Serum sickness is an unusual delayed reaction that typically occurs within 1 week of envenomation Serum sickness is characterized by fever, arthralgia, myalgias, rash, and adenopathy and may include headache, glomerulonephritis, nephrotic syndrome, and necrotizing vasculitis. Delayed atypical hematologic and/or neurologic reactions may also occur following envenomations. These types of reactions include hemolytic anemia, thrombocytopenic purpura, Guillain–Barré syndrome, optic neuritis, other neuropathies, parkinsonism, and transverse myelitis (8).
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for local reactions and anaphylaxis resembling Hymenoptera envenomations is extensive. Fortunately, the history of an encounter with a bee, yellow jacket, wasp, or fire ant is typically present.
Virtually any stinging or biting insect may produce limited local reactions of similar appearance. Extensive local reactions must be differentiated from an infectious cellulitis. Progressive extension of the initial reaction beginning shortly after the envenomation usually indicates an allergic component to the reaction. Inflammation, fever, leukocytosis, and lymphangitis beginning more than 24 hours after envenomation suggest a superimposed infection.
Anaphylactic reactions may be caused by a wide variety of drugs, foods, and environmental allergens. Anaphylaxis from Hymenoptera envenomation should be considered in any patient discovered outdoors during the spring and summer months with unexplained hypotension, urticaria, wheezing, and/or airway obstruction.
Patients who present with delayed reactions should be asked about recent insect stings, illnesses, and medication use within the previous several weeks.
Toxic reactions (e.g., direct systemic reactions or massive envenomation) can be differentiated from anaphylaxis in that systemic toxicity typically progresses more slowly, requires many stings, and causes multiorgan failure. Urticaria, pruritus, and wheezing are not part of a direct systemic reaction and suggest anaphylaxis.
Fire ant envenomations produce pustules within 24 hours. The differential diagnosis for pustule formation is also extensive, although the history of fire ant exposure is often evident. Risk factors for exposure include outdoor activities in endemic areas, especially when the affected areas are not covered by protective clothing.
ED EVALUATION
The history should include information pertaining to the time of stinging, estimated number of stings, previous Hymenoptera reactions, and past medical history. The time of onset, progression, and nature of symptoms should be noted. The physical examination should focus on the vital signs, airway patency, the cardiovascular system, and the skin. Lateral soft tissue neck radiographs and/or nasopharyngoscopy should be considered for patients experiencing stridor or voice changes without complete obstruction.
Patients with hypotension, loss of consciousness, or who suffer multiple envenomations (10 or more for children, 50 or more for adults) should have measurements of the complete blood count (CBC), serum creatine phosphokinase (CPK), liver function tests (LFTs), prothrombin time (PT), partial thromboplastin time (PTT), urinalysis (UA), and a metabolic panel to check for various manifestations of systemic toxicity (4). Measurements of the fibrinogen level and fibrinogen split products (FSP) should be considered with massive envenomation. Patients who experience hypotension, chest pain, or loss of consciousness should have an electrocardiogram (ECG) to rule out myocardial injury, ischemia, or infarction.
KEY TESTING
• Local reactions do not need any testing.
• Neck film or laryngoscopy is helpful for stridor or voice change.
• Systemic laboratories are important with hypotension and mass envenomation.
ED MANAGEMENT
The treatment of local reactions includes general wound care and symptomatic therapy for pain, swelling, and pruritus with analgesics, cool compresses or ice packs, elevation, and antihistamines. Envenomation sites should be cleaned, and tetanus prophylaxis should be updated, if necessary. Large local reactions can be treated with a short course of antihistamines, analgesics, and steroids. Secondary infections are unusual; if present, they should be treated with appropriate antibiotics to cover skin flora.
With honeybee envenomation, the stingers often remain embedded in the victim’s skin, and these should be removed. Previous recommendations were to remove stingers by scraping with the edge of a needle, scalpel, or credit card, rather than by pinching or use of tweezers, to avoid injecting any remaining contents from the attached venom sacs. However, in vivo experiments show that nearly all venom is injected within several seconds, and by the time a patient presents for emergency department (ED) care, stinger removal by pinching does not increase envenomation effects. Bee stinger removal by any method is acceptable.
The treatment for anaphylaxis as a result of Hymenoptera stings is very similar to that for anaphylaxis of other etiologies. Advanced life-support measures should be instituted as necessary. Prehospital personnel should give epinephrine at the first sign of an anaphylactic reaction. The dose and route of epinephrine depend on the severity of the symptoms and the victim’s underlying medical problems; patients suffering from anaphylaxis should receive intramuscular or intravenous (IV) epinephrine (see Chapter 175).
Hypotensive patients should receive aggressive volume replacement with IV crystalloid. In addition, envenomated patients suffering anaphylaxis should receive an oral or IV antihistamine (e.g., diphenhydramine 0.5 to 1 mg/kg) and steroids (e.g., oral prednisone 0.5 to 1 mg/kg or methylprednisolone 1 to 4 mg/kg IV). A H2-blocker (e.g., ranitidine) may also be helpful.
Severe anaphylactic reactions or marked local reactions that involve the nose, mouth, and/or throat require immediate airway control. Because most deaths are as a result of airway obstruction, early airway control by endotracheal intubation may be lifesaving in patients with respiratory distress from upper obstruction. A delay in airway control may result in further swelling, an unstable and difficult airway, and the potential need for a surgical airway. Patients who are wheezing or who have decreased lower-airway movement should have inhaled α-1 adrenergic agonists (e.g., nebulized albuterol 2.5 mg). Continuous infusions of vasopressors (e.g., epinephrine, norepinephrine) may be necessary for recurrent or refractory hypotension. Higher-than-usual doses of α-adrenergic agents may be required when treating patients taking β-adrenergic blocking agents and those patients on chronic β-agonist medications.
The treatment of direct toxic reactions associated with multiple or massive envenomation is entirely supportive. These patients need to be monitored closely. These patients are potentially at risk for delayed organ dysfunction. Serial laboratory determinations of CBC, metabolic profile, LFTs, CPK, UA, fibrinogen, and FSP every 6 to 8 hours for 24 hours should be considered (4).
Delayed hypersensitivity reactions typically are treated with analgesics, antihistamines, and a tapering dose of corticosteroids.
Local fire ant reactions can be treated with cool compresses and cleansing with soap and water. Large local reactions may be treated with oral corticosteroids, antihistamines, and analgesics. Secondary infections should be treated with antibiotics. Anaphylactic reactions should be treated in the manner previously described.
CRITICAL INTERVENTIONS
• Administer epinephrine, corticosteroids, antihistamines, and IV fluids to patients with anaphylaxis who have abnormal vital signs, oxygen saturation, or dyspnea.
• Assess patients with dyspnea for upper airway obstruction, and perform endotracheal intubation in patients with severe or progressive signs and symptoms.
DISPOSITION
Patients who present immediately after envenomation should be observed for 1 to 2 hours for signs and symptoms of anaphylaxis. Asymptomatic patients may then be discharged. Milder anaphylactic reactions may be delayed, and patients should be instructed to return immediately if systemic symptoms ensue. In asymptomatic patients with a history of previous anaphylactic reactions or severe local reactions, a prophylactic 3-day course of antihistamines and corticosteroids, beginning with a dose before discharge, should be considered.
Patients with mild to moderate anaphylaxis should be treated and observed for 4 to 6 hours or until asymptomatic. Patients suffering persistent or recurrent symptoms (excluding isolated urticaria), life-threatening reactions, persistent hypotension, or cardiac complications should be hospitalized with level of care determined by the severity of symptoms. All patients with anaphylactic reactions should be treated with a 3-day course of antihistamines and corticosteroids to prevent a relapse.
Patients with anaphylactic or severe local reactions should be given an epinephrine prescription (e.g., EpiPen or Ana-kit) and instructions for use. They should be cautioned about outdoor work and recreation, advised to wear shoes, long-sleeved shirts, and long pants, and to avoid wearing bright colors and perfumes. The use of insect repellents may be helpful. Referral to an allergist (directly or through the primary care physician) for possible desensitization immunotherapy should also be provided prior to discharge. Finally, the patient should be advised to obtain and wear a Hymenoptera allergy identification bracelet.
Patients suffering direct toxic reactions and multiple envenomations need careful observation for delayed end-organ damage and may need to be hospitalized depending on the number of stings and symptoms. Patients with local or delayed hypersensitivity reactions can be treated as outpatients with ED or primary care follow-up. Atypical reactions may require admission and referral to an allergist.
Common Pitfalls
• Failure to consider Hymenoptera-induced anaphylactic reaction in an unconscious or hypotensive patient found outdoors during the warm seasons.
• Failure to prescribe antihistamines and corticosteroids for 3 days after anaphylaxis.
• Failure to prescribe an emergency epinephrine kit for victims of severe local and anaphylactic reactions.
• Failure to refer patients with severe local and anaphylactic reactions to an allergist.
ACKNOWLEDGMENTS
The author gratefully acknowledges the contributions of Paul A. Janson and Richard J. Iseke to the content of this chapter.
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