Insect Bites and Stings

Quick Reference

Critical Alerts

• Anaphylaxis requires immediate IM epinephrine: Most critical intervention [1]
• Large local reactions (> 10 cm, > 24 hours) are NOT anaphylaxis: Distinct clinical entities [2]
• Systemic reactions defined by symptoms AWAY from sting site: Urticaria, bronchospasm, hypotension [1,2]
• Venom immunotherapy reduces recurrent anaphylaxis risk by 75-95%: Disease-modifying treatment [3,4]
• Remove bee stinger by scraping, not squeezing: Minimizes additional venom injection [5]
• Tick removal within 36 hours prevents most Lyme transmission: Early removal critical [6]
• Single-dose doxycycline 200 mg effective for Lyme prophylaxis: When criteria met [6,7]
• Prescribe epinephrine auto-injector after systemic reaction: Essential for all patients [1,8]

Hymenoptera Reaction Classification

Emergency Treatment Protocols

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Definition and Classification

Overview

Insect bites and stings represent a spectrum of clinical presentations ranging from minor local reactions to life-threatening anaphylaxis. Hymenoptera (bees, wasps, hornets, ants) account for the majority of clinically significant envenomations, causing 40-100 deaths annually in the United States from anaphylaxis. [1,8] Tick bites transmit multiple vector-borne diseases including Lyme disease (approximately 476,000 cases annually in the US). [6,9] Spider envenomations are frequently overdiagnosed, with true medically significant bites being rare. [10]

Taxonomic Classification

Hymenoptera (Stinging Insects):

Arachnida (Spiders and Ticks):

Epidemiology

Hymenoptera Stings:

• Lifetime prevalence of sting: 56-94% in adults [2]
• Systemic reactions: 0.4-3% in adults, 0.4-0.8% in children [1,2]
• Fatal anaphylaxis: 40-100 deaths/year in US (0.03-0.48 per million population) [8]
• Large local reactions: 2.4-26% of general population [2]
• Occupational risk highest in beekeepers (32-43% systemic reaction rate) [11]

Fire Ant Envenomation:

• Endemic in southern United States (305 million colonized acres) [12]
• Estimated 14 million people stung annually in endemic areas [12]
• Anaphylaxis prevalence: 0.6-6% in exposed populations [12]
• Higher rates of systemic reactions than flying Hymenoptera in endemic regions [12]

Spider Bites:

• True incidence unknown due to frequent misdiagnosis [10]
• Black widow: Most bites cause only local symptoms [13]
• Brown recluse: Majority of suspected bites are actually MRSA or other conditions [10,14]
• Dermonecrotic lesions without witnessed bite usually NOT spider-related [10]

Tick-Borne Disease:

• Lyme disease: ~476,000 cases/year in US (incidence increasing) [6,9]
• Rocky Mountain spotted fever: 4,000-6,000 cases/year [15]
• Anaplasmosis: ~5,000 cases/year [15]
• Alpha-gal syndrome: Emerging, prevalence increasing in endemic areas [16]

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Pathophysiology

Hymenoptera Venom Mechanisms

Venom Composition:

Honeybee (Apis mellifera): [1,2]

• Melittin (40-50% dry weight): Direct membrane lysis, mast cell degranulation
• Phospholipase A2 (10-12%): Major allergen, tissue destruction
• Hyaluronidase: Spreading factor, allergen
• Apamin: Neurotoxic polypeptide
• Mast cell degranulating peptide: Non-IgE mediated histamine release

Vespid (Wasps, Hornets): [1,2]

• Phospholipase A1: Major allergen
• Hyaluronidase: Spreading factor
• Antigen 5: Major allergen, species-specific
• Mastoparan: Direct mast cell activation
• Kinins: Vasodilation, pain

Fire Ant (Solenopsis): [12]

• 95% alkaloids (solenopsins): Cytotoxic, hemolytic, pustule formation
• 5% proteins: Allergens (Sol i 1-4), cross-reactivity minimal with other Hymenoptera

Immunologic Response:

Type I Hypersensitivity (IgE-mediated): [1,2]

1. Primary exposure: Sensitization occurs, specific IgE production
2. Re-exposure: Cross-linking of IgE on mast cells and basophils
3. Mediator release: Histamine, tryptase, prostaglandins, leukotrienes
4. Clinical manifestations: Within minutes (early phase) to hours (late phase)
5. Severity factors: Total venom dose, rate of exposure, baseline tryptase (hereditary alpha-tryptasemia)

Anaphylaxis Pathophysiology: [1]

• Massive mast cell/basophil degranulation
• Histamine → vasodilation, increased vascular permeability, bronchospasm
• Tryptase → marker of severity (peak 1-2 hours post-event)
• Platelet-activating factor → cardiovascular collapse in severe cases
• Biphasic reactions: 1-20% of cases, typically 4-6 hours after initial event

Large Local Reactions: [2]

• IgE-mediated but localized response
• Complement activation, cytokine release
• NOT predictive of future systemic reactions in most cases
• Distinct immunologic mechanism from systemic anaphylaxis

Spider Venom Mechanisms

Black Widow (Latrodectus): [13]

α-Latrotoxin Actions:

1. Binds to neurexin and latrophilin receptors on presynaptic terminals
2. Massive calcium influx into nerve terminals
3. Uncontrolled neurotransmitter release (acetylcholine, norepinephrine, GABA)
4. Neurotransmitter depletion leads to muscle paralysis

Clinical Manifestations:

• Local: Minimal (pinprick sensation, target lesion with central pallor)
• Systemic: Muscle fasciculations → rigidity → severe cramping pain
• Autonomic: Hypertension, tachycardia, diaphoresis, salivation
• CNS: Headache, agitation, rarely seizures
• Resolution: 1-3 days typically (antivenom shortens course)

Brown Recluse (Loxosceles): [10,14]

Sphingomyelinase D Actions:

1. Enzymatic cleavage of sphingomyelin in cell membranes
2. Formation of ceramide-1-phosphate (pro-inflammatory)
3. Complement activation (C5a chemotactic factor)
4. Neutrophil recruitment and activation
5. Platelet aggregation and thrombosis
6. Gravitational spread of venom with ischemic necrosis

Clinical Progression:

• 0-2 hours: Mild sting, erythema develops
• 2-8 hours: Pain increases, blister formation, surrounding erythema
• 12-24 hours: Central ischemia begins ("red, white, and blue sign")
• 3-7 days: Eschar formation, necrotic ulcer ("volcano lesion")
• Systemic loxoscelism (rare less than 1%): Hemolysis, DIC, acute kidney injury, death [14]

Hemolytic Mechanism (Systemic Loxoscelism):

• Direct hemolysis via sphingomyelinase D
• Complement-mediated intravascular hemolysis
• Hemoglobinuria → acute tubular necrosis
• Associated with higher mortality (6-7% if hemolysis occurs) [14]

Tick-Borne Disease Transmission

Lyme Disease (Borrelia burgdorferi): [6,9]

Transmission Dynamics:

• Ixodes tick must attach ≥36 hours for transmission [6]
• Spirochete migrates from tick midgut to salivary glands during feeding
• Inoculation into skin → local replication → hematogenous/lymphatic dissemination
• Erythema migrans (EM): Inflammatory response to spirochete at bite site (70-80% of cases)
• Dissemination: Cardiac (1-10%), neurologic (10-15%), arthritic (60%) manifestations [9]

Rocky Mountain Spotted Fever (Rickettsia rickettsii): [15]

Pathophysiology:

• Transmission can occur within 4-6 hours of tick attachment
• Rickettsiae invade vascular endothelial cells
• Increased vascular permeability → edema, hyponatremia
• Vasculitis → petechial/purpuric rash (starts wrists/ankles, spreads centrally)
• Multi-organ involvement: CNS, kidneys, lungs, heart
• Mortality 20-25% if untreated, less than 1% with early doxycycline [15]

Alpha-Gal Syndrome: [16]

• Lone star tick (Amblyomma americanum) saliva contains alpha-gal (galactose-α-1,3-galactose)
• Repeated exposure induces IgE to alpha-gal
• Alpha-gal present in mammalian meat (beef, pork, lamb)
• Delayed anaphylaxis 3-6 hours after meat consumption (lipid digestion required)
• Also reactions to gelatin-containing medications, cetuximab

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Clinical Presentation

Hymenoptera Stings - Reaction Patterns

Normal Local Reaction: [1,2]

Large Local Reaction: [2]

• Definition: Contiguous swelling > 10 cm diameter, lasting > 24 hours
• Peak swelling: 48 hours post-sting (may progress for 24-48h despite treatment)
• Location-specific severity: Face/neck (airway concern), hand (functional impairment)
• May involve entire extremity (e.g., hand sting → swelling to shoulder)
• Resolution: 5-10 days typically
• Recurrence risk: 40-50% with subsequent stings [2]
• NOT predictive of systemic reaction: Only 5-10% progress to anaphylaxis with future stings [2]

Systemic Reactions (Anaphylaxis): [1]

Cutaneous (80-90%):

• Generalized urticaria (hives distant from sting site)
• Angioedema (face, lips, tongue, throat)
• Generalized flushing, pruritus
• Erythroderma

Respiratory (40-60%):

• Upper airway: Throat tightness, hoarseness, stridor
• Lower airway: Dyspnea, wheezing, chest tightness
• Respiratory arrest (late finding)

Cardiovascular (30-40%):

• Hypotension (systolic less than 90 mmHg or > 30% decrease)
• Tachycardia (compensatory) or bradycardia (terminal event)
• Syncope, presyncope
• Cardiac arrest (severe cases)

Gastrointestinal (25-30%):

• Nausea, vomiting
• Abdominal cramping
• Diarrhea

Severity Grading (Ring and Messmer): [17]

• Grade I: Cutaneous-mucosal symptoms only
• Grade II: Cardiovascular, respiratory, or GI symptoms (moderate)
• Grade III: Life-threatening (severe bronchospasm or hypotension)
• Grade IV: Cardiopulmonary arrest

Unusual Reactions:

• Serum sickness-like: 1-2 weeks post-sting (fever, arthralgias, urticaria, lymphadenopathy)
• Vasculitis: Rare, immune complex mediated
• Neurologic: Guillain-Barré, transverse myelitis (case reports)
• Renal: Acute interstitial nephritis, glomerulonephritis (very rare)

Fire Ant Stings

Characteristic Presentation: [12]

• Multiple stings typical (ant attaches with mandibles, pivots, stings repeatedly)
• Immediate: Intense burning pain, wheal and flare reaction
• 4-8 hours: Sterile pustule formation (pathognomonic for fire ant)
• Pustules: 2-4 mm, umbilicated, persist 24-72 hours
• Rupture → risk of secondary infection
• Scarring or hyperpigmentation may occur

Systemic Reactions: [12]

• Anaphylaxis risk 0.6-6% (higher than other Hymenoptera in endemic areas)
• Patients with mastocytosis: Markedly increased risk
• Large local reactions common (can involve entire limb)

Spider Envenomations

Black Widow (Latrodectus): [13]

Immediate (0-60 minutes):

• Bite sensation: Pinprick or not felt
• Local: Target lesion (central pallor, surrounding erythema), minimal swelling
• Pain: Local burning pain develops within 30-60 minutes

Early Systemic (1-8 hours):

Peak Symptoms: 2-12 hours Resolution: 1-3 days (may persist weeks without antivenom) Severe Cases: Respiratory failure, rhabdomyolysis (rare), pregnant patients (uterine contractions)

Brown Recluse (Loxosceles): [10,14]

Cutaneous Loxoscelism (> 90% of bites):

Timeline:

• 0-2 hours: Often painless initially, erythema begins
• 2-8 hours: Pain increases (burning, stinging), blister forms
• 8-24 hours: "Red, white, and blue sign" (erythema, ischemic center, violaceous ring)
• 24-72 hours: Central necrosis develops, eschar forms
• 3-7 days: Eschar separates, necrotic ulcer ("volcano lesion")
• Healing: Weeks to months, often with scarring

Severity Predictors:

• Bite location: Fatty areas (thigh, buttock, abdomen) → larger necrosis
• Amount of venom: Larger spiders, defensive vs feeding bites
• Patient factors: Very young, elderly, comorbid vascular disease

Systemic Loxoscelism (less than 1% of bites): [14]

• Onset: 24-72 hours post-bite
• Hemolysis: Hemoglobinuria (dark "Coca-Cola" urine), jaundice
• Laboratory: Anemia, elevated LDH, decreased haptoglobin, hyperbilirubinemia
• Coagulopathy: Thrombocytopenia, DIC (rare but associated with mortality)
• Renal: Acute tubular necrosis from hemoglobinuria
• Mortality: 6-7% if hemolysis occurs [14]

Tick Bites and Tick-Borne Diseases

Local Reaction (Tick Bite):

• Small papule or macule at attachment site
• Erythema (may persist days after removal)
• Pruritus common
• Granuloma formation (rare, retained mouthparts)

Lyme Disease: [6,9]

Early Localized (3-30 days post-bite):

• Erythema migrans (EM): 70-80% of cases [9]
  • Expanding erythematous patch or plaque
  • "Bull's-eye" appearance (central clearing) in 20% only
  • Typically > 5 cm diameter (median 16 cm)
  • Warm but not painful
  • Expands over days to weeks if untreated
• Flu-like symptoms: Fever, fatigue, myalgias, headache (50% of cases)

Early Disseminated (days to weeks):

• Multiple EM lesions (secondary lesions smaller than primary)
• Facial nerve palsy (unilateral or bilateral) [9]
• Meningitis: Headache, neck stiffness, CSF lymphocytosis
• Carditis: AV block (1-10% of cases), myopericarditis
• Arthralgias (migratory)

Late Disseminated (months to years):

• Arthritis: Large joints (knee 90%), oligoarticular, recurrent [9]
• Neurologic: Encephalopathy, polyneuropathy, encephalomyelitis
• Acrodermatitis chronica atrophicans (Europe primarily)

Rocky Mountain Spotted Fever (RMSF): [15]

• Incubation: 2-14 days (median 7 days)
• Classic triad (only 3% have all at presentation):
  • Fever (99%)
  • Headache (severe, 90%)
  • Rash (appears day 3-5)
• Rash evolution:
  • Starts wrists/ankles (60%)
  • Spreads centripetally (to trunk)
  • Maculopapular → petechial/purpuric
  • May involve palms/soles (40-60%)
  • Absent in 10-15% (especially early presentation)
• Systemic: Myalgias, nausea, vomiting, abdominal pain, confusion
• Severe: Meningoencephalitis, ARDS, acute kidney injury, gangrene

Anaplasmosis/Ehrlichiosis: [15]

• Fever, headache, myalgias
• Rash uncommon (unlike RMSF)
• Laboratory: Leukopenia, thrombocytopenia, elevated transaminases
• Morulae on blood smear (20-80% of cases)
• Severe: ARDS, meningoencephalitis, septic shock

Alpha-Gal Syndrome: [16]

• Delayed anaphylaxis 3-6 hours after mammalian meat ingestion
• Urticaria, angioedema, GI symptoms, anaphylaxis
• Associated with Lone star tick bites (Amblyomma americanum)
• Diagnosis: Elevated IgE to galactose-α-1,3-galactose

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Red Flags and Emergency Recognition

Immediate Life-Threatening Presentations

Anaphylaxis Criteria (any one of following): [1]

1. Acute onset (less than 4 hours) of skin/mucosal symptoms AND respiratory compromise OR hypotension
2. Two or more systems involved after likely allergen:
   • Skin/mucosal (urticaria, angioedema, flushing)
   • Respiratory (dyspnea, wheeze, stridor)
   • Cardiovascular (hypotension, syncope)
   • Gastrointestinal (cramping, vomiting)
3. Hypotension after known allergen exposure

Anaphylaxis High-Risk Features: [1]

Spider Envenomation Red Flags

Black Widow: [13]

• Severe abdominal rigidity ("acute abdomen" mimicry)
• Hypertensive emergency (> 180/110 mmHg)
• Respiratory muscle involvement (rare but critical)
• Pregnant patients (risk of uterine contractions, fetal distress)
• Rhabdomyolysis (elevated CK, myoglobinuria)

Brown Recluse: [10,14]

• Systemic symptoms (fever, rash, arthralgias) within 72 hours
• Hemoglobinuria ("Coca-Cola" urine)
• Rapidly expanding necrosis (> 10 cm)
• Laboratory hemolysis (anemia, elevated LDH, low haptoglobin)
• Coagulopathy (DIC)
• Acute kidney injury

Tick-Borne Disease Red Flags

Rocky Mountain Spotted Fever: [15]

• Fever + headache + rash (especially petechial on wrists/ankles)
• Altered mental status, seizures
• Any delay in treatment increases mortality
• Empiric doxycycline should NOT be delayed for diagnostic confirmation
• Mortality 20-25% untreated vs less than 1% with early treatment

Lyme Carditis: [9]

• New AV block (any degree) in endemic area with tick exposure
• Syncope (high-grade AV block)
• Temporary pacemaker may be required

Tick Paralysis:

• Ascending flaccid paralysis
• Often tick attached at hairline (difficult to find)
• Complete resolution with tick removal

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Differential Diagnosis

Misdiagnosis of Spider Bites

MRSA Skin Infection (Most Common Misdiagnosis): [10]

Other Necrotizing Conditions:

• Necrotizing fasciitis: Rapidly progressive, severe pain out of proportion, crepitus, systemic toxicity
• Pyoderma gangrenosum: Inflammatory bowel disease, autoimmune history
• Cutaneous anthrax: Black eschar, painless, occupational exposure (wool, hides)
• Diabetic ulcer with necrosis: Pressure points, neuropathy
• Warfarin necrosis: Anticoagulation initiation, protein C/S deficiency

Anaphylaxis Mimics

Tick-Borne Disease Mimics

Erythema Migrans vs Other Rashes:

• Tinea corporis: Scaly border, KOH positive
• Granuloma annulare: Non-scaling, chronic, no tick history
• STARI (Southern tick-associated rash illness): Similar to EM but Borrelia burgdorferi negative
• Contact dermatitis: Pruritic, linear distribution

RMSF vs Other Febrile Rash Illnesses:

• Meningococcemia: Petechiae earlier, more rapid progression
• Measles: Cough, conjunctivitis, coryza, rash starts face
• Viral exanthem: Rash starts trunk, no tick history
• Drug eruption: Medication history, no acral distribution

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Diagnostic Approach

Hymenoptera Stings

Clinical Diagnosis (History + Examination):

• Witnessed sting or characteristic findings
• Timing of symptom onset
• Progression pattern (local vs systemic)
• Previous sting reactions

Laboratory Testing:

Acute Anaphylaxis (Emergency Setting): [1]

• Serum tryptase: Draw 30 minutes to 2 hours post-event (peak 1-2 hours)
  • Elevated > 11.4 ng/mL supports anaphylaxis diagnosis
  • Normal tryptase does NOT exclude anaphylaxis (sensitivity 60-80%)
  • "Baseline tryptase: Obtain > 24 hours post-event (rule out mastocytosis)"
• No other acute testing required for diagnosis

Allergy Evaluation (Outpatient, ≥4-6 weeks post-reaction): [2,3]

• Skin testing: Gold standard

  • "Intradermal testing: 0.001-1.0 μg/mL concentrations"
  • High sensitivity (> 90%) and specificity
  • "Test all relevant venoms: Honeybee, Vespula, Polistes, hornet, fire ant"
  • "Negative initially: Repeat 1-2 months later (10% become positive)"

• Serum specific IgE: [2]

  • Sensitivity 80-95% (lower than skin testing)
  • Useful when skin testing contraindicated or unclear
  • "Whole venom IgE: Honeybee, Vespula, Polistes"
  • "Component-resolved diagnostics (CRD): [2,18]"
    • Api m 1, 2, 3, 10 (honeybee)
    • Ves v 1, 5 (yellowjacket)
    • Pol d 5 (paper wasp)
    • Improves identification of true sensitization vs cross-reactivity

• Baseline serum tryptase: [2]

  • All patients with systemic reactions
  • Elevated (> 11.4 ng/mL) suggests clonal mast cell disorder
  • Higher risk of severe reactions, consider genetic testing (hereditary alpha-tryptasemia)

Indications for Allergy Referral: [1,2]

• All systemic reactions (candidate for venom immunotherapy)
• Large local reactions with impaired quality of life or high re-exposure risk
• Patients with elevated baseline tryptase
• Unclear diagnosis or multiple venom sensitivities

Spider Bites

Black Widow: [13]

• Clinical diagnosis based on:
  • Characteristic bite appearance (target lesion)
  • Typical symptom progression (muscle rigidity, autonomic symptoms)
  • Spider identification if captured
• Laboratory (if severe):
  • "CBC: Leukocytosis common"
  • "CMP: Electrolytes, renal function"
  • "CK: Rule out rhabdomyolysis (rare)"
  • "Consider ECG: Ischemic changes reported in severe cases"

Brown Recluse: [10,14]

• Clinical diagnosis (definitive only if spider captured and identified)
• Most suspected bites are NOT brown recluse
• Consider alternative diagnoses (MRSA most common)
• Laboratory (if systemic symptoms): [14]
  • "CBC: Anemia, thrombocytopenia"
  • "Reticulocyte count: Elevated if hemolysis"
  • "LDH, haptoglobin, indirect bilirubin: Hemolysis markers"
  • "Urinalysis: Hemoglobinuria"
  • "Coagulation panel: DIC evaluation if severe"
  • "CMP: Renal function, electrolytes"
  • "Blood culture: Rule out secondary infection"
• Biopsy: NOT recommended (worsens necrosis)

Tick-Borne Diseases

Lyme Disease: [6,9]

Erythema Migrans (Early Localized):

• Clinical diagnosis - no testing required for EM rash [9]
• Serology negative in first 2-4 weeks (antibodies not yet formed)
• Do NOT delay treatment for serology results
• Testing erythema migrans is NOT recommended (may cause false reassurance)

Disseminated/Late Disease:

• Two-tier serology: [9]
  • "Screen: ELISA for IgM and IgG antibodies"
  • "Confirmatory: Western blot if ELISA positive or equivocal"
  • "IgM alone: High false positive rate, only relevant less than 30 days symptoms"
  • "IgG: Appears 4-6 weeks, persists indefinitely (past infection vs active)"
• CSF analysis (if neurologic symptoms):
  • Lymphocytic pleocytosis
  • Intrathecal antibody production
• Cardiac evaluation (if suspected carditis):
  • "ECG: AV block (first, second, or third degree)"
  • Telemetry monitoring
  • Lyme serology

Rocky Mountain Spotted Fever: [15]

• Empiric treatment essential - do NOT delay for testing
• Serology: Acute and convalescent (2-4 weeks apart)
  • IgG appears 7-10 days after symptom onset
  • Four-fold rise diagnostic
  • Negative acute serology does NOT exclude RMSF
• PCR: Available but low sensitivity (less than 50%)
• Skin biopsy (with immunofluorescence): Research settings only
• Laboratory clues: Thrombocytopenia, hyponatremia, elevated transaminases

Anaplasmosis/Ehrlichiosis: [15]

• Blood smear: Morulae in neutrophils (anaplasmosis) or monocytes (ehrlichiosis)
  • Present in 20-80% of cases
• PCR: High sensitivity during acute illness
• Serology: Acute and convalescent
• Laboratory: Leukopenia, thrombocytopenia, elevated transaminases

Alpha-Gal Syndrome: [16]

• Specific IgE to galactose-α-1,3-galactose
• Elevated > 0.35 kU/L diagnostic
• Also test specific IgE to beef, pork, lamb (confirmatory)

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Management

Principles of Treatment

1. Immediate recognition and treatment of anaphylaxis: Epinephrine is first-line [1]
2. Rapid stinger/tick removal: Minimizes venom/pathogen inoculation [5,6]
3. Supportive care for local reactions: Ice, elevation, analgesics
4. Specific treatments for severe envenomations: Antivenoms when indicated
5. Prophylaxis for disease prevention: Tick-borne illness protocols
6. Long-term management: Venom immunotherapy for systemic reactions [3,4]
7. Patient education: Prevention, emergency action plans

Hymenoptera Stings - Acute Management

Stinger Removal: [5]

• Remove IMMEDIATELY (do not delay for method consideration)
• Method: Scrape with fingernail or credit card edge
• Do NOT squeeze with fingers/tweezers (may inject more venom)
• Evidence: No difference in outcomes between methods if done immediately [5]
• Honeybee stinger remains embedded; wasps/hornets can sting repeatedly

Local Reactions: [1,2]

Tetanus prophylaxis: Update if > 5 years since last dose

Large Local Reactions: [2]

All above measures PLUS:

• Oral corticosteroids: Prednisone 40-60 mg daily × 3-5 days
  • Shortens duration of swelling
  • More effective if started within 24 hours
  • Taper not required for short course
• Antibiotics: NOT routinely indicated
  • Secondary infection rate less than 3%
  • Only if purulence, warmth, expanding erythema beyond 72 hours
  • "If needed: Cephalexin 500 mg QID or doxycycline 100 mg BID × 7-10 days"
• Elevation critical for extremity involvement
• Mark borders of erythema (monitor for cellulitis vs expected progression)

Anaphylaxis (Systemic Reactions): [1,8]

Immediate Treatment:

1. Epinephrine IM (First-line, DO NOT DELAY): [1]

   • Dose: 0.3-0.5 mg (1:1,000 concentration)
   • Route: Intramuscular, lateral thigh (vastus lateralis)
   • Onset: 3-5 minutes
   • Repeat: q5-15 minutes if inadequate response
   • Evidence: Reduces mortality, more effective than any other intervention [1]
   • Delays in epinephrine associated with worse outcomes [8]
   • IM superior to subcutaneous (faster absorption, higher peak levels)

2. Positioning:

   • Supine with legs elevated (improves venous return)
   • If vomiting: Lateral decubitus (aspiration prevention)
   • Do NOT sit upright (sudden cardiac death risk - "empty ventricle syndrome")

3. Oxygen:

   • High-flow oxygen 10-15 L/min via non-rebreather
   • Target SpO2 > 94%

4. IV Access and Fluids: [1]

   • Large-bore IV (18g or larger)
   • Hypotension: Rapid bolus 1-2 L normal saline or lactated Ringer's
   • May require multiple liters (profound vasodilation and capillary leak)
   • Pediatric: 20 mL/kg boluses

Adjunctive Medications (NOT substitutes for epinephrine): [1]

Refractory Anaphylaxis (No response to 2-3 epinephrine doses): [1]

• IV epinephrine infusion: 0.1 mcg/kg/min, titrate to effect
• Vasopressors: Norepinephrine, dopamine
• ICU admission
• Consider: Methylene blue (case reports for refractory vasodilation)

Observation and Disposition: [1,8]

• Minimum 4-6 hours observation after last epinephrine dose
• Biphasic reactions: 1-20% of cases (median onset 4-6 hours)
• Extended observation if: Severe reaction, delayed presentation, poor access to emergency care
• Discharge criteria:
  • Symptom resolution
  • Normal vital signs
  • Epinephrine auto-injector prescribed and training provided
  • Oral antihistamines/steroids prescribed (3-5 days)
  • Allergy referral arranged
  • Written emergency action plan provided

Discharge Medications:

• Epinephrine auto-injector: Two devices (EpiPen, Auvi-Q, or generic)
  • 0.3 mg for adults/children > 30 kg
  • 0.15 mg for children 15-30 kg
• H1 antihistamine: Cetirizine 10 mg daily × 3-5 days
• Corticosteroid: Prednisone 40-60 mg daily × 3-5 days
• Medical alert bracelet strongly recommended

Venom Immunotherapy (VIT)

Indications: [3,4]

• Strong indication (95-98% effective, should be offered): [3]
  • Systemic reactions (any grade) in adults
  • Systemic reactions beyond cutaneous in children (respiratory, CV, severe cutaneous)
• Relative indication:
  • Large local reactions with significant impairment (occupational, quality of life)
  • Cutaneous-only systemic reactions in children (individualized)
• Contraindications:
  • Uncontrolled asthma
  • Active malignancy
  • Severe cardiovascular disease
  • Pregnancy (do not initiate, can continue if already on maintenance)

Efficacy: [3,4]

• Field sting protection: 75-95% (vs 10-20% with placebo)
• Persistent protection after 5 years treatment: 80-90%
• Honeybee: Slightly less effective than vespid (75-85% protection)
• Quality of life improvement: Significant reduction in anxiety, improved outdoor activities

Protocols:

Conventional (Outpatient) [3]:

• Weekly injections
• Buildup phase: 12-16 weeks to maintenance dose (100 μg)
• Lowest systemic reaction rate (5-12%)

Rush (Inpatient) [19]:

• 2-3 days to maintenance dose
• Requires hospitalization, intensive monitoring
• Systemic reaction rate: 9-13%
• Used for urgent protection needs

Ultrarush [19]:

• 3.5-6 hours to maintenance dose
• Higher systemic reaction rates (12-29%)
• Reserved for specific circumstances (e.g., beekeepers, high-risk patients needing rapid protection)

Maintenance Phase [3]:

• 100 μg venom every 4 weeks × 12 months
• Then extend to every 6-8 weeks if tolerated
• Duration: Minimum 3-5 years
• Extended duration (> 5 years) for:
  • Honeybee allergy (higher relapse)
  • Previous severe reactions
  • Systemic reactions during VIT
  • Elevated baseline tryptase

Monitoring and Adverse Effects: [3]

• Systemic reactions during VIT: 5-15% of patients overall
• Most occur during buildup phase
• Adjust protocol if reactions occur (slower escalation, lower doses)
• Premedication (antihistamines, montelukast, omalizumab) for high-risk patients

Spider Envenomations

Black Widow (Latrodectus): [13]

Mild Cases (Local pain only):

• Ice application to bite site
• Oral analgesics: Ibuprofen 600 mg q8h or acetaminophen
• Tetanus prophylaxis
• Observation 4-6 hours
• Discharge if no progression

Moderate to Severe (Muscle spasms, rigidity, autonomic symptoms):

Supportive Care:

• Hypertension: Usually transient, avoid beta-blockers (unopposed alpha)
  • "If severe/symptomatic: Short-acting agents (nitroglycerin, nitroprusside)"
• Tetanus prophylaxis
• Wound care (minimal local care needed)

Disposition:

• Admit: Severe symptoms, pregnancy, elderly, inadequate pain control
• Discharge: Mild symptoms controlled, reliable follow-up
• Resolution typically 1-3 days (may persist weeks without antivenom)

Brown Recluse (Loxosceles): [10,14]

Cutaneous Loxoscelism (Local management):

NOT Recommended (Lack of Evidence or Harmful): [10,14]

• Dapsone: No proven benefit, risk of hemolysis and methemoglobinemia [14]
• Systemic corticosteroids: No proven benefit for necrosis [10]
• Prophylactic antibiotics: Secondary infection rate low (less than 5%), not indicated [10]
• Hyperbaric oxygen: No proven benefit [10]
• Early excision: Worsens outcomes, delays healing [10,14]

Surgical Management: [10,14]

• Delayed debridement (after eschar demarcation, typically 2-4 weeks):
  • "Indicated for: Large necrotic areas, infected wounds, functional impairment"
  • Allows clear demarcation of viable tissue
  • Better cosmetic outcomes than early surgery
• Skin grafting: May be needed for large defects
• Avoid: Early excision within first week (worsens necrosis)

Systemic Loxoscelism (Hemolysis, DIC): [14]

• Hospital admission (ICU if severe)
• Supportive care:
  • "IV fluids: Maintain urine output > 2 mL/kg/h (prevent ATN from hemoglobinuria)"
  • "Transfusion: Packed RBCs if symptomatic anemia"
  • "Dialysis: If acute renal failure"
  • "Coagulopathy management: FFP, platelets if DIC"
• No specific antivenom available (not in production)
• Experimental therapies: None proven effective
• Antibiotics: Only if secondary infection documented (culture-directed)

Disposition:

• Discharge: Isolated cutaneous loxoscelism, reliable follow-up
• Admit: Systemic symptoms, hemolysis, extensive necrosis, immunocompromised
• Follow-up: Wound check 48-72 hours, surgical referral if extensive necrosis

Tick Removal and Tick-Borne Disease Management

Tick Removal Technique: [6]

Proper Method (Evidence-based): [6]

1. Use fine-tipped tweezers or commercial tick removal tool
2. Grasp tick as close to skin surface as possible (at mouthparts, not body)
3. Pull straight upward with steady, even pressure (no twisting or jerking)
4. Clean bite area with antiseptic
5. Save tick in alcohol or plastic bag (for identification if symptoms develop)

Do NOT:

• Apply petroleum jelly, nail polish, heat (ineffective, may cause tick regurgitation) [6]
• Squeeze tick body (increases pathogen transmission)
• Twist or jerk (may break mouthparts)

Retained Mouthparts:

• Usually harmless (work out like a splinter)
• Do not excavate (causes more tissue damage)

Lyme Disease Prophylaxis: [6,7]

Single-Dose Doxycycline Prophylaxis (ALL criteria must be met):

Dosing: [6,7]

• Adults: Doxycycline 200 mg PO single dose
• Children ≥8 years: Doxycycline 4 mg/kg (max 200 mg) single dose
• Efficacy: 87% reduction in Lyme disease [7]
• NNT: 50 (in endemic areas with > 20% Ixodes infection rate)

Lyme Disease Treatment: [9]

Early Localized Disease (Erythema Migrans):

Azithromycin: Less effective, only if others contraindicated (500 mg daily × 7-10 days)

Early Disseminated Disease:

• Facial palsy (isolated): Oral regimen as above (steroids NOT beneficial) [9]
• Meningitis/encephalitis: Ceftriaxone 2 g IV daily × 14-28 days
• Carditis (AV block): Ceftriaxone 2 g IV daily × 14-21 days (may switch to oral after improvement)
  • Temporary pacemaker if high-grade AV block with hemodynamic compromise
• Arthritis: Oral regimen × 28 days (IV if refractory)

Late Disseminated Disease:

• Arthritis: Doxycycline 100 mg BID × 28 days
• Neurologic: Ceftriaxone 2 g IV daily × 2-4 weeks

Rocky Mountain Spotted Fever: [15]

Empiric Treatment (DO NOT DELAY):

• Doxycycline 100 mg PO/IV BID (first-line, ALL ages including children less than 8) [15]
• Start immediately if suspected (fever + headache ± rash + tick exposure)
• Duration: Until afebrile × 3 days AND clinical improvement (minimum 5-7 days)
• Mortality: 20-25% untreated → less than 1% with prompt doxycycline [15]
• Delay > 5 days after symptom onset increases mortality

No Alternative: Doxycycline is ONLY effective treatment [15]

• Chloramphenicol (historical alternative): Less effective, more toxic, not recommended
• Fluoroquinolones: NOT effective

Anaplasmosis/Ehrlichiosis: [15]

• Doxycycline 100 mg PO/IV BID × 7-14 days
• Empiric treatment recommended if clinical suspicion
• Response typically within 24-48 hours (supportive of diagnosis)

Alpha-Gal Syndrome: [16]

• Avoidance of mammalian meat (beef, pork, lamb)
• May also need to avoid dairy, gelatin
• Epinephrine auto-injector prescription
• IgE levels may decrease over time if no further tick bites (avoid tick exposure)
• Allergy specialist referral

Fire Ant Stings

Local Management: [12]

• DO NOT rupture pustules (increases infection risk)
• Clean with soap and water
• Ice application
• Topical antihistamine or corticosteroid
• Oral antihistamines if pruritus
• Antibiotics only if secondary infection (culture-guided)

Systemic Reactions: [12]

• Manage as Hymenoptera anaphylaxis (epinephrine, etc.)
• Venom immunotherapy available:
  • Whole-body extract (no purified venom available)
  • Efficacy 80-95% for systemic reaction prevention
  • Protocol similar to other Hymenoptera VIT

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Prevention

Behavioral Modifications

Hymenoptera Sting Prevention: [20]

• Avoid perfumes, scented lotions, bright colors when outdoors
• Wear closed-toe shoes, long sleeves/pants in high-risk areas
• Do not disturb nests (professional removal)
• Cover food/drinks outdoors (attracts yellowjackets)
• Do not swat at flying insects (remain calm, move slowly away)
• Beekeepers: Protective equipment, proper technique

Tick Bite Prevention: [6,20]

• Wear light-colored clothing (easier to spot ticks)
• Long sleeves, long pants tucked into socks
• Stay on cleared trails (avoid tall grass, brush)
• Tick checks after outdoor activity (entire body, especially hairline, groin, axillae)
• Shower within 2 hours of exposure (remove unattached ticks)
• Launder clothing in hot water

Spider Bite Prevention:

• Shake out clothing and shoes before wearing
• Wear gloves when moving stored items, firewood
• Inspect bedding in endemic areas
• Seal cracks/crevices in homes
• Reduce clutter (spiders prefer undisturbed areas)

Chemical Prophylaxis

Insect Repellents (for mosquitoes, ticks, some biting flies): [20]

Evidence: DEET and picaridin most effective, permethrin-treated clothing highly effective for tick prevention [20]

Tick Repellent Strategy: [6,20]

• Permethrin on clothing (boots, pants, socks)
• DEET or picaridin on exposed skin
• Combination provides highest protection (> 90% tick bite reduction)

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Special Populations

Pregnancy

Hymenoptera Stings: [1]

• Epinephrine safe in pregnancy (Class C, but benefit outweighs risk)
• Maternal hypotension/hypoxia greater fetal risk than epinephrine
• Aggressive treatment of anaphylaxis essential
• Supine positioning increases aortocaval compression (left lateral tilt if hypotensive)
• Fetal monitoring recommended after significant reaction
• VIT: Do not initiate during pregnancy, continue if already on maintenance

Lyme Disease: [9]

• Doxycycline contraindicated (use amoxicillin 500 mg TID × 14-21 days)
• No evidence for higher transmission or fetal harm if treated appropriately
• Avoid prophylactic doxycycline (use amoxicillin 500 mg TID × 7 days if prophylaxis indicated)

RMSF: [15]

• Doxycycline still recommended despite pregnancy (life-threatening condition)
• Short course unlikely to cause fetal harm
• Untreated RMSF has high maternal and fetal mortality

Spider Envenomations:

• Black widow: Antivenom pregnancy category C (use if severe symptoms)
• Pregnant patients at risk for uterine contractions from black widow venom
• Brown recluse: Supportive care, increased risk of complications

Children

Hymenoptera Stings: [1,2]

• Epinephrine dosing: 0.01 mg/kg IM (max 0.3 mg)
  • less than 15 kg: 0.15 mg auto-injector
  • ≥15 kg: 0.3 mg auto-injector
• Cutaneous-only systemic reactions: Lower risk of progression (less than 10%), VIT individualized [2]
• Respiratory/cardiovascular reactions: VIT strongly recommended (same as adults) [3]

Tick-Borne Diseases:

• Doxycycline safe in children ≥8 years (all ages for RMSF - life-threatening) [15]
• Age less than 8 with Lyme: Amoxicillin 50 mg/kg/day divided TID (max 500 mg/dose) × 14-21 days

Immunocompromised

General Considerations:

• Higher risk of severe tick-borne infections
• Lower threshold for admission
• Extended antibiotic courses may be needed
• Babesiosis risk markedly increased in asplenic patients (can be fatal)

Patients with Mastocytosis/Elevated Baseline Tryptase

Risk Factors: [2]

• Baseline tryptase > 11.4 ng/mL
• Hereditary alpha-tryptasemia (genetic disorder)
• Systemic mastocytosis (rare)

Implications: [2,21]

• Higher risk of severe anaphylaxis
• Lower threshold for epinephrine use
• Prescribe multiple epinephrine auto-injectors (may need > 2 doses)
• VIT: Extended duration (> 5 years, possibly lifelong)
• Consider premedication during VIT (H1/H2 blockers, montelukast)
• Omalizumab may be beneficial in select cases

Beta-Blocker Use

Anaphylaxis Concerns: [1]

• May blunt response to epinephrine (beta-receptor antagonism)
• Paradoxical hypertension (unopposed alpha effects)
• Refractory hypotension possible

Management: [1]

• Epinephrine still first-line (higher doses may be needed)
• Glucagon 1-5 mg IV/IM (bypasses beta-receptors, inotropic effect)
• Higher volume IV fluid resuscitation
• Consider: Discontinue beta-blocker if recurrent anaphylaxis risk (cardiology consultation)

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Disposition and Follow-Up

Discharge Criteria

Hymenoptera Stings:

• Local/large local reactions: Immediate discharge with instructions
• Anaphylaxis: After 4-6 hour observation period, symptoms resolved, epinephrine auto-injector provided

Spider Bites:

• Black widow (mild): Discharge if pain controlled, no progression after 4-6 hours
• Brown recluse: Outpatient management unless systemic symptoms

Tick Bites:

• Routine tick bite: Discharge with education, ± prophylaxis
• Tick-borne disease: Most treated outpatient (except severe RMSF, Lyme carditis)

Admission Criteria

Intensive Care:

• Refractory anaphylaxis (requiring epinephrine infusion)
• Respiratory failure, intubation
• Severe hypotension requiring vasopressors
• Cardiac arrest
• Severe RMSF with encephalitis/ARDS

General Admission:

• Severe black widow envenomation (intractable pain, respiratory involvement)
• Systemic loxoscelism (hemolysis, DIC)
• Lyme carditis with high-grade AV block
• RMSF with altered mental status
• Anaplasmosis with severe leukopenia/thrombocytopenia
• Multiple comorbidities with concern for decompensation
• Poor access to emergency care with high-risk features

Follow-Up

After Systemic Reaction to Hymenoptera: [1,3]

• Allergy referral: Within 4-6 weeks (for VIT consideration)
• Baseline tryptase: At least 24 hours post-event
• Education: Epinephrine auto-injector use, sting avoidance, medical alert bracelet
• Prescription: Two epinephrine auto-injectors at all times

After Tick-Borne Disease Diagnosis:

• Lyme disease: Assess response at 2-3 weeks (may have Jarisch-Herxheimer in first 24h)
• RMSF: Daily until afebrile, then weekly until resolution
• Alpha-gal: Allergy referral, dietary counseling

After Spider Bite:

• Brown recluse: Wound check 48-72 hours, weekly if necrosis developing
• Surgical referral: If extensive necrosis (after demarcation)

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Patient Education

Anaphylaxis Action Plan

Recognition (teach patients to identify):

• Symptoms AWAY from sting site
• Difficulty breathing, throat tightness
• Dizziness, fainting
• Widespread hives

Action:

1. Use epinephrine auto-injector IMMEDIATELY (lateral thigh)
2. Call 911
3. Lie down (legs elevated)
4. Second dose if no improvement in 5-10 minutes
5. Go to emergency department even if symptoms improve

Epinephrine Auto-Injector Training: [8]

• Demonstrate technique with trainer device
• Practice with patient
• Educate family members, teachers, coworkers
• Carry two devices at all times
• Check expiration dates (replace annually)
• Avoid extreme temperatures (store room temperature)

Sting Avoidance

High-Risk Activities:

• Outdoor eating (yellowjackets attracted to food/drinks)
• Gardening, yard work
• Hiking in wooded areas
• Swimming (ground nests near water)
• Fruit picking

Protective Measures:

• Closed-toe shoes outdoors
• Avoid bright colors, floral patterns
• No perfumes/scented products
• Inspect drinks before sipping
• Professional nest removal (do not attempt self-removal)

Tick Checks and Removal

When to Check:

• After any outdoor activity in endemic areas
• Daily during camping/hiking trips
• Focus on: Scalp, hairline, ears, axillae, groin, behind knees

What to Watch For:

• Expanding rash (especially "bull's-eye") → seek medical attention
• Fever within 2 weeks of tick bite → seek urgent evaluation
• Severe headache + rash → EMERGENCY (possible RMSF)

Proper Removal:

• Use fine tweezers
• Grasp at skin level (not body)
• Pull straight up
• Clean with soap and water
• Save tick in plastic bag or alcohol (for ID if symptoms develop)

When to Return to Emergency Department

Immediate Return:

• New difficulty breathing
• Swelling of face/throat
• Dizziness, fainting
• Confusion, severe headache
• Chest pain
• Widespread rash or new hives

Return Within 24 Hours:

• Expanding redness beyond expected (> 24-48h after sting)
• Fever
• Pus or drainage from bite site
• Increasing pain

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Quality Metrics and Documentation

Performance Indicators

Essential Documentation Elements

Hymenoptera Sting:

• Type of insect (if known)
• Time of sting
• Number of stings
• Symptoms and onset timing
• Local vs systemic classification
• Treatments administered (doses, times, response)
• Epinephrine auto-injector: Prescribed (yes/no), training provided
• Allergy referral arranged
• Baseline tryptase ordered (if systemic reaction)

Spider Bite:

• Spider identified (yes/no, species if known)
• Location and timing of bite
• Appearance of lesion (target sign, necrosis, size)
• Systemic symptoms (if any)
• Alternative diagnoses considered
• Treatment plan
• Follow-up arranged

Tick Bite:

• Tick removed (when, how, by whom)
• Tick species (if identified)
• Estimated attachment duration
• Prophylaxis given (criteria met, agent, dose)
• Endemic area assessment
• Return precautions (EM rash, fever)

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Key Clinical Pearls

Diagnostic Pearls

1. Anaphylaxis = Symptoms AWAY from sting site: Generalized urticaria, not just local swelling [1]
2. Large local reactions are NOT anaphylaxis: Do not predict future systemic reactions (only 5-10% risk) [2]
3. "Bull's-eye" rash is NOT required for Lyme: Only 20% have central clearing; expanding erythema is diagnostic [9]
4. Most suspected "spider bites" are MRSA: No bite witnessed = consider alternatives first [10]
5. Black widow: "Target lesion" at bite, "boardlike" abdomen: Minimal local findings, severe systemic [13]
6. Brown recluse: "Red, white, and blue sign": Erythema, central pallor, violaceous ring [14]
7. RMSF rash starts at wrists/ankles: Centripetal spread (unlike viral exanthems) [15]
8. Tick must be attached ≥36 hours to transmit Lyme: Early removal prevents most infections [6]
9. Fire ant pustules are pathognomonic: Sterile pustules 4-8 hours post-sting [12]
10. Elevated baseline tryptase = higher anaphylaxis risk: Check in all systemic reactions [2]

Treatment Pearls

1. Epinephrine IM is ONLY first-line for anaphylaxis: Antihistamines/steroids are adjuncts only [1]
2. Remove stinger immediately, method less important than speed: Scraping preferred but don't delay [5]
3. Supine positioning in anaphylaxis is critical: Upright position associated with sudden death [1]
4. Doxycycline for RMSF - DO NOT WAIT for confirmation: Delay > 5 days increases mortality [15]
5. Lyme disease with EM rash - DO NOT test, just treat: Serology negative early, delays treatment [9]
6. Single-dose doxycycline 200 mg prevents Lyme: 87% effective if given within 72 hours [6,7]
7. Venom immunotherapy is disease-modifying: 75-95% protection, should be offered to all with systemic reactions [3,4]
8. Brown recluse - Avoid early surgery: Delayed debridement (2-4 weeks) superior outcomes [10,14]
9. Black widow antivenom works rapidly: Symptom relief in 1-3 hours vs 1-3 days without [13]
10. Biphasic anaphylaxis occurs in 1-20%: Minimum 4-6 hour observation required [1]

Prevention Pearls

1. Permethrin-treated clothing + DEET = best tick protection: > 90% bite reduction [20]
2. Two epinephrine auto-injectors at ALL times: 10-20% require second dose [1,8]
3. VIT should continue minimum 3-5 years: Longer for honeybee, severe reactions, elevated tryptase [3]
4. Alpha-gal syndrome increasing with tick range expansion: Consider in delayed food anaphylaxis [16]
5. Beta-blocker patients need extra precautions: May require glucagon for refractory anaphylaxis [1]

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References

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2. Bilò MB, Martini M, Tontini C, et al. Hymenoptera venom allergy: Management of children and adults in clinical practice. J Investig Allergol Clin Immunol. 2019;29(3):180-205. doi:10.18176/jiaci.0310

3. Golden DBK, Demain J, Freeman T, et al. Stinging insect hypersensitivity: A practice parameter update 2016. Ann Allergy Asthma Immunol. 2017;118(1):28-54. doi:10.1016/j.anai.2016.10.031

4. Sturm GJ, Varga EM, Roberts G, et al. EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy. Allergy. 2018;73(4):744-764. doi:10.1111/all.13262

5. Visscher PK, Vetter RS, Camazine S. Removing bee stings. Lancet. 1996;348(9023):301-302. doi:10.1016/S0140-6736(96)01367-0

6. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: Clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43(9):1089-1134. doi:10.1086/508667

7. Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med. 2001;345(2):79-84. doi:10.1056/NEJM200107123450201

8. Turner PJ, Jerschow E, Umasunthar T, et al. Fatal anaphylaxis: Mortality rate and risk factors. J Allergy Clin Immunol Pract. 2017;5(5):1169-1178. doi:10.1016/j.jaip.2017.06.031

9. Steere AC, Strle F, Wormser GP, et al. Lyme borreliosis. Nat Rev Dis Primers. 2016;2:16090. doi:10.1038/nrdp.2016.90

10. Swanson DL, Vetter RS. Loxoscelism. Clin Dermatol. 2006;24(3):213-221. doi:10.1016/j.clindermatol.2005.11.006

11. Severino MG, Cortellini G, Bonadonna P, et al. Sublingual immunotherapy for large local reactions caused by honeybee sting: A double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2008;122(1):44-48. doi:10.1016/j.jaci.2008.03.023

12. Tankersley MS, Ledford DK. Stinging insect allergy: State of the art 2015. J Allergy Clin Immunol Pract. 2015;3(3):315-322. doi:10.1016/j.jaip.2015.03.012

13. Clark RF, Wethern-Kestner S, Vance MV, Gerkin R. Clinical presentation and treatment of black widow spider envenomation: A review of 163 cases. Ann Emerg Med. 1992;21(7):782-787. doi:10.1016/s0196-0644(05)81021-4

14. Vetter RS, Isbister GK. Medical aspects of spider bites. Annu Rev Entomol. 2008;53:409-429. doi:10.1146/annurev.ento.53.103106.093503

15. Biggs HM, Behravesh CB, Bradley KK, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever and other spotted fever group rickettsioses, ehrlichioses, and anaplasmosis - United States. MMWR Recomm Rep. 2016;65(2):1-44. doi:10.15585/mmwr.rr6502a1

16. Commins SP, James HR, Kelly LA, et al. The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose. J Allergy Clin Immunol. 2011;127(5):1286-1293. doi:10.1016/j.jaci.2011.02.019

17. Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet. 1977;1(8009):466-469. doi:10.1016/S0140-6736(77)91953-5

18. Köhler J, Blank S, Müller S, et al. Component resolution reveals additional major allergens in patients with honeybee venom allergy. J Allergy Clin Immunol. 2014;133(5):1383-1389. doi:10.1016/j.jaci.2013.10.060

19. Arzt-Gradwohl L, Čerpes U, Bokanovic D, et al. Safety and efficacy of ultra-rush bee venom immunotherapy: A retrospective study. Allergy. 2017;72(12):2033-2040. doi:10.1111/all.13237

20. Lupi E, Hatz C, Schlagenhauf P. The efficacy of repellents against Aedes, Anopheles, Culex and Ixodes spp. - A literature review. Travel Med Infect Dis. 2013;11(6):374-411. doi:10.1016/j.tmaid.2013.10.005

21. Bonadonna P, Zanotti R, Müller U. Mastocytosis and insect venom allergy. Curr Opin Allergy Clin Immunol. 2010;10(4):347-353. doi:10.1097/ACI.0b013e32833bbc48

22. Bilò MB, Bonifazi F. Epidemiology of insect-venom anaphylaxis. Curr Opin Allergy Clin Immunol. 2008;8(4):330-337. doi:10.1097/ACI.0b013e3283060119