STINGING INSECT HYPERSENSITIVITY Objectives SHASHANK SHETH, MD • To understand difference between local and systemic reactions to insect stings • To identify indications for allergist referral and testing for venom allergy and immunotherapy • To review signs/symptoms of anaphylaxis • To review acute management of anaphylaxis Case 1 Case 1 • RC is a 44 y/o male presented to ER unresponsive – Leaf blowing in the yard – Felt a sting on his scalp and he swatted the insect – In 5 minutes, he had acute shortness of breath – Sat down and was found unresponsive by daughter • Daughter called 911 • EMS found pt unresponsive with a BP of 70/40 • Treated with injectable epinephrine on the field – Started to improve • Transferred to ER and given antihistamines and steroids and discharged home in a few hours 1 Case 1 • Never had angioedema or urticaria • PMH: – Hypertension • SH: – Contractor – No smoking or alcohol • Venom skin test: – Negative for honeybee – + wasp (0.01); WFH (0.1); YH (0.1); YJ (0.01) Types of Insect Sting Reactions • Local • Large local • Systemic – Anaphylaxis – Toxic Case • Meds: quinapril / hydrochlorathiazide • PE: normal • Serum tryptase – 7ng/ mL [2-10] • Assessment: – Anaphylaxis due to stinging insect venom • Plan: – Venom IT – Change to non- ACE – inhibitor – Auto-injector of epinephrine – Insect sting precautions Local reactions • Vast majority of insect stings produce transient local reaction that can last up to several days and resolve without treatment – Risk of future anaphylaxis is ~ 5% • Treatment: – Cold compresses – antihistamines 2 Large Local Reactions • Extensive local swelling extending from the site of the sting • Peaks in 24-48 hours; may last one week • Frequency: 5-15% • IgE mediated late-phase reaction – Risk of future anaphylaxis is 5% 10% 1 • Treatment: cold compresses, antihistamines, and prompt use of oral steroids 1 Green A, Reisman R, Arbesman C. Clinical and immunologic studies of patients with large local reactions following insect stings. J Allergy ClinImmunol 1980; 66:186-9. 3 Anaphylaxis EPIDEMIOLOGY • Vary from cutaneous to lifethreatening • Can be biphasic or protracted • Slower time of onset will reduce chance of progression to a lifethreatening reaction 1 • Anaphylaxis from stinging insect – At least 40 fatalities per year 1 • Potential life threatening systemic reactions – 0.4% – 0.8% of children 2 – 3 % of adults • Possibly underrecognized 1 Lockey RF, Turkeltaub PC, Baird-Warren IA, et al. The Hymenoptera venom study. I, 1979-82. J Allergy Clin Immunol 1988; 82: 370-81. Risk of systemic reaction in untreated patients with a history of sting anaphylaxis and positive venom skin tests Original Sting reaction Risk of Systemic Reaction (%) Risk of Systemic Reaction (%) Severity Age 1-9 yr 10-20 yr post-sting post-sting No reaction Adult 17 Large Local All 10 10 Cutaneous systemic Child 10 5 Adult 20 10 Child 40 30 Adult 60 40 Anaphylaxis 1 Graft DF. Insect sting allergy. Med Clin North Am 2006; 90:211-32. 2 Bilo BM, Bonifazi F. Epidemiology insect venom anaphylaxis. Curr Opinion Allergy Clin Immunol 2008;8:330-7. Anaphylaxis - Signs / symptoms Cutaneous: flushing, pruritus, urticaria, angioedema, and pilor erecti; pruritus in unusual places (scrotum, vagina, ear) Cardiovascular: feeling of faintness, syncope, chest pain, arrhythmia, hypotension and shock 4 Anaphylaxis - Signs / symptoms Anaphylaxis - Signs / symptoms Respiratory • Laryngeal: pruritus and “tightness” in the throat, tongue or throat swelling Other: periorbital pruritus, erythema, (laryngeal edema), dysphagia, and edema; conjunctival erythema dysphonia and hoarseness/stridor, and tearing; aura of impending dry “staccato” cough “doom,” seizures; lower back pain • Lungs: shortness of breath, chest and uterine contractions in women tightness, cough, and wheezing Treatment • Venom Immunotherapy • Carry Injectable epinephrine – NO CONTRAINDICATION to epinephrine in life-threatening situation • Lifestyle precautions Immediate treatment • Removal of stinger in first 10-20 seconds might prevent injection of additional venom 1 • Flick or scrape • Don’t grasp! 1 Schumacher MJ, Tveten MS, Egen NB. Rate and quantity of delivery of venom from honeybee stings. J Allergy Clin 1994; 93; 831-35. 5 Immediate Treatment • Aqueous epinephrine 1:1,000 is the standard of care • IM epinephrine if systemic reaction Immediate Treatment • H1 antihistamines: diphenhydramine IM or IV – Adults: 25 to 50 mg Children: 1-2 mg/kg – Adults: 0.3ml to 0.5ml q5 minutes up to 3 times • H2 blockers p.o. or IV (ranitidine, famotidine) – for epinephrine – resistant hypotension or erythroderma – Children: 0.01ml/kg body weight q5 minutes up to 3 times • Oxygen and bronchodilators • Supine position • Tourniquet • Intravenous fluids or vasopressors as needed for vascular collapse • Depending upon the reaction, consider PO or IV steroids (prednisone) Epinephrine • IM in anterolateral thigh [83] • Delayed use can lead to more serious anaphylaxis or be ineffective [85] • NO contraindication in setting of anaphylaxis • Antihistamines and oral corticosteroids are second lines of treatment WHEN IN DOUBT, INJECT EPINEPHRINE 6 Outdated epinephrine loses efficacy • As time passes, percent of labeled dose and epinephrine bioavailability are reduced. • • Inadequate knowledge of epinephrine • Healthcare professionals and patients have inadequate knowledge about outpatient use. Improper storage and exposure to sunlight and - 76% of physicians are unaware that two auto- heat increase degradation. injector dose formulations exist Degradation often occurs without a color - Only 55% of patients at risk have in-date change in the epinephrine solution. auto-injectors on hand - Only 30%-40% know how to use autoinjectors correctly Simons FER et al. J Allergy Clin Immunol 2000;105:1025-30 Grouhi M et al. J Allergy Clin Immunol 1999; 104:190-3; Sicherer SH et al. Pediatrics 2000; 105:359-62; Huang SW. J Allergy Clin Immunol 1998;102:525-6 Types of stinging insects • Order Hymenoptera – Apids The PLAYERS • Honeybees • Bumblebees – Vespids NAME THAT STINGING INSECT • Yellow jackets • White-faced and yellow-faced hornets • Wasps – Formicids • Fire ants 7 Yellow jackets • Nests in ground • Yardwork, farming, gardening • Wall tunnels, crevices, hollow logs • Aggressive; sting with minimal provocation • scavengers – picnics, food and drink Hornets • Large papermaiche nests in trees or shrubs – Extremely aggressive – Will chase subjects for some distance before stinging – Open beverage containers • Most common cause in most pasts of the US Wasps • Build honeycomb nests in shrubs and under eaves of houses or barns • In pipes on playgrounds and under patio furniture • Florida, Texas, Louisiana Insect identification • Fire ant (red or black) – Build nests in mounds of fresh soil – Aggressive – Sting multiple times in circular fashion – Sterile pseudopustules – Southern US 8 Fire ant Apids (bees) • Honeybees – Leave a barbed stinger and attached venom sac in the skin • Occasionally with other insects too – Nonaggressive away from hives • Domestic honeybees – Commercial hives • Wild honeybees – Tree hollows and old logs – Stings on feet when barefoot on grass Honeybee • More sensitizing • VIT less effective • Higher risk of reactions • More severe reactions • Longer duration VIT • Africanized honeybees – Hybrids between domestic and African honeybees – Attack in swarms; hostile and aggressive – Mexico and the South 9 Bumblebees • • • • Different venom than honeybees Less aggressive In greenhouses Requires specific testing History • How long ago did sting occur? • How many stings occurred at the same time? • How much time between sting and onset of symptoms • Where on the body did the sting occur? • Ask about all potential systemic symptoms. • Which insect was it? • How was the reaction treated? • Any delayed symptoms? • Previous stings and reactions? • Any stings subsequent to the reaction? Diagnosis of Stinging Insect Allergy Insect venom skin testing • Stings are painful and patients are almost always aware that sting occurred • Criteria • Done by allergist that is trained and qualified in diagnosis and treatment of insect allergy • Technique – History of a sting that resulted in a systemic reaction (even if remote history) • Risk of anaphylaxis may persist for decades 1 – Evidence of venom specific IgE • Skin testing • in vitro serum specific IgE – Prick at 100 mcg/mL (optional) – Intradermal ( Q 20 minutes) • • • • 0.001 mcg 0.01 mcg 0.1 mcg 1.0 mcg - careful about irritant reactions above this • Very rare systemic reactions to skin test 1 Golden DB, Breisch NL, Hamilton RG, et al. Clinical and entomological factors influence the outcome of sting challenge studies. J Allergy Clin Immunol 2006; 117:670. 10 Screening at large not indicated • Up to 27% of general adult population has venom specific IgE – Not sufficient to predict that patient is high risk for future systemic reactions Golden DB, Marsh DG, Kagey-Sobotka A, et al. Epidemiology of insect venom sensitivity. JAMA 1989; 262:240. VENOM TESTING NOT INDICATED: • No sting history • Only local reactions • Family history but no personal history • Possible exception: – Unavoidable exposure and frequent large local reactions which are disabling 11 Diagnostic Testing • Venom – Yellow jacket, white-faced hornet, yellow hornet, wasp and honeybee – Available for skin testing and immunotherapy • Whole body extract – Fire ant • Positive intradermal skin test at a concentration of less than or equal to 1.0 mcg/ mL Diagnostic Testing • Any patient that is a candidate for VIT • If negative skin test and convincing history such as airway or CV compromise, then need to repeat ST or do in vitro IgE testing before ruling out VIT as an option 1 • Tests may be falsely negative within first few weeks after a sting 1 Golden DBK, Tracy JM, Freeman TM, Hoffman DR. AAAAI Insect Committee. Negative venom skin tests results in patients with histories of systemic reaction to a sting. J Allergy Clin Immunol 2003; 112: 495-8. Diagnostic Testing • Rarely, (< 1 % of patients with a convincing history of systemic reaction) patient can have anaphylaxis from subsequent sting after negative skin and in vitro test – Consider underlying systemic mastocystosis Diagnostic Testing • Approximately 30-60% of patients with history of systemic reaction to a sting and have + SPT or in vitro test will have a systemic reaction when restung • No correlation between size of skin test or concentration of extract and severity of allergy 12 In vitro testing • Skin tests are preferred • Up to 20% with positive skin test have undetectable serum specific IgE • Recent studies: – 10-20% of patients with negative skin test have positive in vitro when using highly sensitive assays Indications for VIT • Any age with systemic reactions beyond cutaneous manifestations – extremely effective – Reduces risk of subsequent reaction to < 5 % – Reactions that occur are usually milder • NOT INDICATED for children with systemic cutaneous manifestations • Large local reactions - maybe ?? Mastocytosis • Clonal expansion of mast cells resulting in severe and recurrent anaphylaxis • Consideration in those with severe insect sting reactions • Workup: – Baseline serum tryptase – Bone marrow biopsy Children are not miniadults • Children <17 y/o with only skin manifestations have ~ 10% of systemic reaction if re-stung – Usually limited to skin – < 5% chance of more severe reaction – < 1 % chance of life-threatening anaphylaxis Golden DBK, Kagey-Sobotka A, Norman PS, Lichtenstein LM. Outcomes of allergy to insect stings in children with and without venom immunotherapy. N Eng J Med; 2004; 351: 668-74. 13 Large local reactions • Risk of systemic reaction to a future sting is 5-10 % • Vast majority do not need to be tested • New evidence that VIT may reduce the size and duration of LLR – May be useful in those at risk for unavoidable or frequent reactions 1 Golden DBK, Kelly D, Hamilton RG, Craig TJ. Venom immunotherapy reduces large local reactions to insect stings. J Allergy Clin Immunol 2009: 123:1371-5. Duration of VIT • 3-5 years, ideally 5 years – Despite persistent positive SPT, 8090% will not have a systemic reaction after 3-5 yrs of VIT (44-52) • NO test to predict risk of relapse • Risk is lower with 5 yrs vs. 3 yrs 1 • Consider indefinite IT – h/o severe anaphylaxis with shock or LOC – High risk profession or hobbies – Honeybee allergy – Elevated tryptase – Systemic reactions to VIT – Anxiety from risk of IT Lerch E, Muller U. Long term protection after stopping venom immunotherapy. J Allergy Clin Immunol 1998; 101: 606-12. 14 VIT protocol • Shots administered once a week – Start with beginning dose 0.1 mcg – Increase to maintenance dose of 100 mcg of each venom • Interval at maintenance – 4 to 6 weeks – Some continue at 6-8 weeks Alternate protocols for VIT • Rush – 3 weeks – Beekeepers and military – No increase risk in reaction rate • Ultra-rush – 1 day – Hospital based Adverse Reactions to VIT • Systemic: 3-12% – Mild and easily treatable – Dose adjustment • Large Local: 25 % children, 50 % adults – Pretreat with antihistamine or montelukast – No dose adjustment necessary 15 Relative Contraindications • Beta-blockers – Risk of VIT is less than beta-blockers • ACE – inhibitors – Recent retrospective study showed increase of more severe anaphylaxis [142] Rx for auto-injectable epinephrine • High risk – Near fatal reactions – Systemic reactions during VIT – Severe honeybee allergy – Underlying medical conditions – Frequent unavoidable exposures • Low Risk – Large local reactions or systemic cutaneous reactions – Maintenance VIT – s/p 5 yrs of VIT Assessment of VIT Avoidance measures • Decrease is venom specific IgE to insignificant levels • Conversion to negative skin test • Neither test is required and there have been relapses despite a negative skin test • Venom specific IgG has no predictive value for discontinuing VIT • Have trained professionals remove known or suspected nests in immediate vicinity of patient’s home • Avoid wearing brightly colored or flowery prints or strong scents • Avoid walking outside barefoot or with open toes • Wear long pants, long sleeves, socks, shoes, hats, work gloves when working outdoors 16 Avoidance measures Toxic Reactions • Be cautious near bushes, eaves, and attics • Avoid garbage containers and picnic areas • Keep insecticides for stinging insects readily available • Avoid eating or drinking outdoors and be cautious in areas where food and beverages are being served • Nonallergic reaction from venom components • Cytotoxic reaction from multiple stings (>100) Mosquito Bite Reactions Normal reaction • Immunologic reaction to proteins in mosquito saliva • Very common • Immediate wheal and flare that peak at 20 min • Delayed itchy indurated papules peak at 24 hours and subside in 710 days • 5 stages of reactivity evolve over months and years – Normal Reaction – Large Local Reaction – Systemic reaction – shock – acute renal failure – ARDS – rhabdomyolysis 17 Large local reactions (Skeeter Syndrome) • Itchy or painful areas of redness, warmth, swelling and induration • 2 – 10+ cm areas • Develop within hours, progress over 8-12 hours and resolve in 3- 10 days • Possible low grade fever or malaise • Can affect entire side of face or extremity • May interfere with drinking, eating, seeing or normal use of arm or leg Skeeter Syndrome • May be hard to differentiate between secondary bacterial infection from scratching • Timing is key – LLR occur within hours – Infection takes days Systemic reactions • • • • • Very rare Generalized urticaria Asthma flare Anaphylaxis Serum sickness • Treatment – Antihistamines – Topical or systemic glucocorticoids 18 Take home points • Be educated in avoidance of stinging insects • Carry epinephrine auto-injector and be instructed in appropriate indications and administration • Undergo testing for IgE antibodies to insect venom • Initiate immunotherapy if test results are positive • Consider carrying medical identification tag 19