bee stings immunology allergy and treatment marterre

Although its part of the business, few of us actually look forward to being stung. Asbeekeepers we need to know about the various reactions to bee stings and be responsible toourselves, family, neighbors and friends in regard to bee stings. I hope this article will servesome of those purposes and be informative to both the beginner beekeeper and the most expe-rienced scientist. The first part will cover insects that sting, honey bee stings in particular, beevenom biochemistry, precautions and sting prevention, the management of beekeepingemergencies, and basic immunology and allergy. The second part will cover sting reactiontypes and treatments, allergy testing and desensitization results, and specific recommenda-tions for beekeepers.

Hymenoptera stings

The order Hymenoptera includesants, bees, hornets, and wasps,many of which inflict stings (Table

1). Although solitary bees, such as sweatbees and carpenter bees, can inflict asting, the risk of an allergic response totheir venom is low because they are bothunaggressive and the amount of venomthey inject is low. More aggressive, prim-itively social paper wasps, yellow jackets,bald-faced hornets and European hornetsfrom the Family Vespidae (Figures 1 4) as opposed to eusocial honey bee work-ers from the Family Apidae can stingmore than once. If the flying stinginginsect that inflicts a sting is unidentified,most often (unless the sting is still present

Table 1Hymenoptera Species with Venoms for Immunotherapy

Vespidae WaspsVespinae

Vespula ground-nesting yellow jacketsDolichovespula aerial yellow jacketsVespa hornets

PolistinaePolistes paper wasps

Formicidae AntsMyrmicinaeSolinopsis fire ants

Apidae BeesApinaeApis honey bees

Figure 1. Wasp (Polistes sp.), BuddyMarterre, MD

Figure 2. Yellow Jacket (Vespula vul-garis), courtesy of Jarmo Holopainen

Figure 3. Bald Faced Hornet(Dolichovespula maculata), courtesy ofChris Wirth

Figure 4. European Hornet (Vespacrabro), Buddy Marterre, MD

by BUDDY MARTERRE, MD

Part I of Two Parts

marterre article bee stings 1.qxp 6/14/2006 3:29 PM Page 1

in the victim) the culprit was not a honeybee. Sting incidence in America varieswith region. Yellow jackets are more pop-ulous than honey bees in the north, waspsare more prevalent in the southwest, andfire ants are more prevalent in thesoutheast. Imported fire ants - FamilyFormicidae, genus Solenopsis - also havea sting apparatus (Figure 5). And theirvenom is the most potent venom known inthe animal kingdom! A general approxi-mation of flying insect sting incidencethroughout the US is yellow jackets(Vespula and Dolichovespula) 50 %,honey bee (Apis) 25 %, paper wasp(Polistes) 15 %, bumble bee (Bombus) 5%, and European hornet (Vespa) 5 %.

Honey bee stingsBees sting defensively when their

hive, nest, or mound is thought to beunder attack. For example, foraging beeswill only sting if directly injured whenthey are away from the hive. Mature,adult, female worker bees in the hivedeploy the sting from its sheath inresponse to alarm pheromone. This chem-ical messenger release is usually accom-panied by a short buzz and an astute bee-keeper may even smell the banana oil-like

pheromone. Guard bees are attracted todark colors, contrast (like hairlines), cer-tain body odors (and perhaps the carbondioxide you exhale), all drawing themtoward your face and eyes. Certain per-fumes, cosmetics, and banana oil maymimic alarm pheromone. Vibrations andfast movements further aggravate the situ-ation.

Stinging bees flex their abdomens tojab the sting into their target. The honeybee sting (unlike the sting of other insects)has a barb which leaves it attached to itsvictim - complete with venom sac (Figure6). The sting apparatus is also covered bymuscles which continue to thrust the stingfurther into the victim. The venom thentravels down through the hollow, hypo-dermic needle-type shaft (Figure 7). nine-ty % of the venom sac empties in the first20 seconds. Alarm pheromone (highlyvolatile isopentyl acetate and other alco-hols and esters) is released from theattached Koschevnikov gland, leaving thevictim marked for further injury. In thisway, many old guards can be recruited inan exponential defensive response whentheir hive is being threatened. And ofcourse, the primary perceived threat isyou the beekeeper!

Honey bee queens have more poorlydeveloped barbs than workers on theirlonger stings. The queen sting apparatushas a stronger attachment to theirabdomen and queens do not producealarm pheromone. They reserve theirstings for other queens, but have largervenom sacs than workers, and can stingmultiple times. Worker bees die in theprocess of stinging, as their sting andsometimes other abdominal contents areextruded.

Bee (and other insect) venom biochem-istry

Each European bee venom sac containsabout 140 micrograms of venom (onlyabout 100 micrograms per Africanizedbee venom sac), but the average venomdelivered is a dose of about 50 micro-grams. Needless to say, there are a lot ofvery potent chemicals in bee venom thatare bad for you (Table 2). Many of thesechemicals are peptides (small proteinchains) and enzymes (larger proteins

that facilitate biochemical reactions).Together they cause the reaction that yourbody has to the sting (pain, swelling, itch-ing, redness, etc). Some of these chemi-cals (or the bodys response to them) canalso initiate very rapid reactions. Anexample would be the clotting cascade,which forms a clot within minutes of acut. Many of these proteins are also rec-ognized as foreign by the human immunesystem (antigens) and lead to allergicreactions in some individuals.

Forty fifty percent of honey beevenom is mellitin. Mellitin is a chemicalthat is unique to bee venom and is acytolytic, which means that it directlybursts cells. It contributes to itching andswelling, and is the primary cause of thestings pain. Mellitin can also dilate bloodvessels, leading to low blood pressure.ten twelve percent of honey bee venomis Phospholipase A2 (the most potentallergen). Phospholipases are enzymesthat help mellitin destroy cell membranes(cell membranes have lots of phospho-lipids in them). Apamin is also unique tobee venom (3 %) and is a neurotoxin itis toxic to nerve conduction.Hyaluronidase (2 %) is an enzyme thatbreaks down hyaluronic acid, which isone of the components of connective tis-sue or the tissue in between your cellsthat hold you together (like little micro-scopic tendons). Hyaluronidase con-tributes to the spread of the reaction.Phosphatases are enzymes that break offthe phosphate portions of high-energychemicals. Frequently these phosphatemolecules begin cascades of other, veryinflammatory biochemical reactions inyour body (like the clotting cascade).Mast cell degranulating (MCD) peptidesdo just what theyre named for theycause the mast cells in your body torelease the many biochemicals (includinghistamine) in their granules. Mast cellswill be covered more in the immunologysection later. Histamine causes leakycapillaries and contributes to the familiarwheal and flare reaction (slightly raisedred area that itches) in allergic or atopicindividuals.

Venoms from hornets (Vespa), aerialyellow jackets (Dolichovespula), ground-nesting yellow jackets (Vespula), andpaper wasps (Polistes) lack mellitin,phospholipase A2, acid phosphatase,apamin, and MCD peptide. Their venomcontains 10 - 25 % phospholipase A1 and

Table 2Honey Bee Venom Biochemistry

Melittin *Phospholipase A2Apamin *HyaluronidaseAcid and Alkaline PhosphatasesMast Cell Degranulating Peptide *Histamine, Dopamine, Norepinephrine* unique to honey bees

Figure 5. Imported Fire Ant (Solenopsisinvicta), courtesy of Deyrup and Cover,antweb.org

Figure 6. Honey Bee Stinging an Arm,courtesy of Zachary Huang, PhD

Figure 7. Sting Apparatus, courtesy ofZachary Huang, PhD


B as well as antigen 5, which honey beevenom does not contain, however. Theproteins in the venoms of individual yel-low jacket and hornet species (subfamilyVespinae) are quite similar. This leads toa lot of cross reactivity in the humanimmune response to them. Thus, venomsfor testing hypersensitivity andimmunotherapy desensitization are typi-cally available separately for honey bees,wasps, and mixed vespids.

Precautions and sting preventionGood technique can reduce the number

of bee stings you receive (Table 3).Realize that the mood of the hive can beaffected by many things, such as season,weather, and many factors that may onlybe apparent to the bees. A long time ago Igave up trying to predict the mood of thefive females I live with, much less the50,000 females in a bee hive! Therefore,dont assume that a given hive will begentle just because it had a good tempera-ment the last time you inspected it. Also,if you are a suburban beekeeper (like me),only keep very gentle bees near yourhouse. And inquire as to your neighborspossible venom allergies.

Work hives on warm, sunny, calm days.

Cold, windy conditions and impendingthunderstorms make for irritable bees.Approach bee hives from the back. Donot stand in their flight paths. Wear whiteand ALWAYS WEAR YOUR VEIL.Avoid using perfumes and eating bananasbefore bee work. Use smoke judiciously,but use it almost every time you work ina hives brood nest (queen inspectionsvery soon after introduction and quick,gentle feeding operations are exceptions).Work slowly and deliberately, avoidingquick movements and hive vibrations.Remove stings quickly without squeezingthem and smoke the stings as soon as pos-sible. And wash your bee suit (and glovesif you use them) frequently particularlyif youve received a bunch of stings!

Management of emergenciesIts better to be prepared for a major bat-

tle and not have one than to only preparefor a minor skirmish and experience amajor war. What do you do if you drop orknock over a hive and there are moreangry, stinging bees than you ever thoughtpossible coming at you? Table 4: Close thehive if you can (easily). Cover up. Getyour smoker and smoke yourself (if itsstill lit). Calmly walk at least 20 yards

away into some brush. Evergreens are par-ticularly good at distracting bees. Walk. Donot run (unless you can run a 5 minute mile)!Dont swat bees. Dont return to the scene ofthe crime until you and the bees have calmeddown (this takes about 10 or 20 minutes forthe bees I cant say for you)!

If a bee gets inside your veil, kill itbefore it can sting your face. If you donthave a veil on (heaven forbid) and bees areflying into your face, close your eyes andwalk away (and get your veil). If you havea bunch of bees inside your veil (more thantwo or three), take it off, cover your faceand let them sting your hands. And remem-ber, every sting leaves you marked formore!

Immunology and allergyThe human immune system is highly

complex. Its basic function is to recognizeand destroy foreign tissue (like bacteria orviral-infected cells). In order to do this, itmust not only recognize proteins that

belong to the body (self), but distinguishthese from proteins that dont belong (non-self). The specialized white blood cells inthe immune system that do this are calledlymphocytes. Lymphocytes utilize com-plex protein receptors on their surface torecognize self and non-self and they gener-ate two integrated responses to foreignproteins (such as those from bee venom).One effector arm of the immune responseis the production of antibodies and theother is the production of other controllingand effector lymphocytes.

Antibodies are produced by B lympho-cytes and are large complex proteins calledimmunoglobulins (Ig). Immunoglobulinsor antibodies have a hypervariable regionthat fits around a small piece of a foreignprotein (antigen) like a lock fits over a key.The fit is even more specific than a keyand lock, however, because it is in threedimensions and also includes charge affin-ity (areas of negative charge on the antigenline up with areas of positive charge in thecleft of the antibody). There are many dif-ferent classes of antibodies, but the pri-mary class in the bloodstream that isinvolved with a normal immune responseis IgG and the class that is involved withan allergic or hypersensitivity response isIgE.

The controlling cells of the immuneresponse are called T lymphocytes. Theyrecognize the foreign antigen with recep-tors on their surface (very much like anti-bodies) and can induce B cells to make

Table 3Precautions and Sting Prevention

Wear whiteand ALWAYS WEAR YOUR VEIL

Avoid using perfumes and eating bananasUSE SMOKE judiciouslyWork slowly and deliberatelyRemove and smoke stings ASAPWash your bee suit and gloves frequently

Table 4Management of Emergencies

Close the hive if you canCover upKill any bees inside your veilGet your smoker Walk at least 20 yards away into brush

(evergreens)Return when calm (20 minutes)

Figure 8. Electron Micrographs of Mast Cells with Granules Left is scanning em,Right is transmission em (showing granules), courtesy of Soman N Abraham, DukeUniversity Medical Center

Figure 9. Diagram of Allergic Immune Response, by Rachel Alexandra Marterre


specific antibodies to the antigen. Theirresponse may include recruiting other cellsto destroy it (using chemical messengerscalled cytokines similar to pheromonesin a bee hive) or by directly attacking theforeign antigen themselves. In both thecase of antibody production by B cells andT lymphocyte generation, memory cells(both B and T) are generated that can thenrecognize the foreign antigen decadeslater. This is how immunity to a virus orbacteria or venomous sting can last a life-time, even though exposure to it may havebeen years before or even in childhood.

The effector cells that are recruited bythe T cells and the antibody classes that Bcells make differ with different people,even in response to the same foreign anti-gen. The cytokine messenger profiles (thatrecruit other effector cells) also differ fromindividual to individual. Thus, some indi-viduals may make allergic IgE antibodiesto bee venom antigens even though mostpeople make non-allergic IgG antibodies.

An allergic response to a venom antigen(now called an allergen) is also quite com-plex. It begins with IgE antibodies andmast cells. Mast cells are already presentin the sting site (Figure 8). Mast cell sur-faces are loaded with IgE antibodies thatmay react with many different types ofantigens or allergens. After venom isinjected into the skin, at least two IgE anti-bodies on the surface of a mast cell eachreact with the venom allergen, causing theimmediate release of preformed sub-stances in the granules of the mast cell, aswell as the production of other new sub-stances. Refer to the Figure 9 for a basicdiagram of an allergic immune response.And recall, the mast cell degranulatingpeptide in bee venom can cause this reac-tion all by itself even without a typicalallergic response! With just a few stings,mast cell degranulating peptides effectsare only local, but with hundreds of stingsthe venom dose can cause toxic effects.

Once activated, mast cells release a lotof very potent preformed chemicals fromtheir granules immediately, including his-tamine, proteases (enzymes that destroy

proteins or initiate other cascades), heparin(an anticoagulant), and chemicals thatattract eosinophils (another allergic effec-tor cell) (Table 5). These primary media-tors are released within minutes and theireffects on the human body begin veryquickly. Histamine dilates blood vessels,makes them leaky, and activates theendothelium (or lining of the capillaries).This leads to local edema (swelling),warmth, redness, and the attraction ofother inflammatory cells to the site. Inlarge amounts, it can drop blood pressure,and cause rapid swelling of the airway(leading to stridor or an inability tobreathe) and constrict bronchial tubes(causing an asthmatic attack). Histaminealso irritates nerve endings (leading toitching or pain).

Upon activation, mast cells also begin tosynthesize secondary chemicals whichhave more delayed effects includingprostaglandins, leukotrienes, and cy-tokines. Some of these secondary chemi-cals (particularly the cytokines) areresponsible for the late phase of allergy,which typically begins 2 4 hours after theinsult. The prostaglandins and leukotrienes like histamine also cause bronchialconstriction, dilation of blood vessels andleaky capillaries, but their onset is hourslater and their effects more long-lasting.Aspirin can actually exacerbate theseeffects by causing more leukotrienes andfewer prostaglandins to be produced by themast cells. The cytokines which are made

and released by the mast cells are primari-ly responsible for the late phase of anaphy-laxis. They attract other effector cells ofallergies, like eosinophils, basophils, andneutrophils (which significantly contributeto allergic responses). Once these process-es get initiated, they can snow-ball in ahurry and cause a lot of problems veryquickly. Again, if the allergic reactionbecomes systemic (throughout the entirebody), it is called anaphylaxis.

Thats enough science for one article.In part two, well discuss sting reactiontypes and treatments, allergy testingand desensitization results, and specificrecommendations for beekeepers.

About the authorIve had allergies all my life. I became

very interested in bees while I was in col-lege at Virginia Tech. But the beekeepingcourse I wanted to take interfered with bio-chemistry lab (my major), so instead I tookgraduate courses in immunology. Aftermedical school and a general surgery resi-dency, I did a fellowship in and then prac-ticed transplant surgery. So while I learnedand practiced more immunology (by trans-planting foreign organs), my personalexperience with bee stings was still lack-ing. After my fellowship, I married anexperienced intensive care nurse, who isnow a certified pulmonary-allergy nurse.Then, I finally became a beekeeper and amnow a Master Beekeeper in NorthCarolina. I have large local reactions to beestings and have experienced quite a fewof those! Being concerned about my risk ofmore serious reactions, I went back to theimmunology and allergy journals. Then,last year, I had an anaphylactic reaction(fortunately not to bee stings, but tosalmon which I had eaten many timesbefore)! Thus, I am a doctor, a beekeeper,and a patient. In addition to all the photocredits, Id also like to thank two excellentallergists for their review of this article:Aneysa Sane, MD from Wake ForestUniversity Medical Center, and LarryWilliams, MD from Duke UniversityMedical Center.

Table 5Mast Cell Granule Contents and ProductsHistamine, SerotoninEnzymes (that destroy proteins or initiate

cascades)Heparin (anticoagulant)Eosinophil Chemotactic Factor of

AnaphylaxisNeutrophil Chemotactic FactorLeukotrienesProstaglandinsCytokines (which recruit other inflam-

matory cells)


Although its part of the business, few of us actually look forward to being stung. As beekeeperswe need to know about the various reactions to bee stings and be responsible to ourselves, family, neighbors and friends in regard to bee stings. I hope this article will serve some of thosepurposes and be informative to both the beginner beekeeper and the most experienced. The firstpart of this article covered insects that sting, honey bee stings in particular, basic bee venom biochemistry, precautions and sting prevention, management of beekeeping emergencies, andbasic immunology and allergy. This second part will cover sting reactions and types, sting treatments, allergy testing and desensitization results, and specific beekeeper recommendations.

Sting reaction types and treatments

The NORMAL reaction to a ven-omous insect sting is one of localpain and up to a few centimeters of

edema (swelling) that resolves in a fewhours to a few days (Figure 10). Any stingcan become secondarily infected, but for-tunately, this is fairly uncommon.Parenthetically, fire ant stings form apseudopustule (Figure 11). These blistersmay last for 10 days and should not beconfused with a true infection (pustule).The pseudopustules from fire ant stingsshould be left intact (not unroofed or surgi-cally drained).

The first treatment of a normal reac-tion is to quickly remove the sting andsmoke the area. Many local remedies havebeen suggested for the treatment of beestings. These generally fall into 4 cate-

gories: 1) venom removal or suctiondevices, 2) bases such as urea, ammonia,and baking soda (to neutralize the acidityof the venom), 3) hygroscopic agents (todraw out the fluid) such as honey, mud,and various pastes, and 4) lotions todecrease the itch such as calamine lotion,Anusol, and Benadryl cream. All topicaltreatments require immediate application,so they are probably best used in non-bee-keeping situations. And as far as localapplications for sting prevention is con-cerned, DEET-containing bug sprays donothing to deter vespid stings. Normalreactions are not an allergic response, andallergy testing and desensitization are notindicated after these.

A LARGE LOCAL reaction is confinedto the general area of the sting, but over 24 48 hours it develops into a much larger

area (sometimes the entire extremity) thana normal reaction (Figure 12). It starts aspain and a wheal (a several centimeterswollen itch). A few hours after the stingmore redness, edema (swelling), and itch-ing develop. Over 12 48 hours, the areacan become quite swollen, painful, andmay also have some associated ecchymo-sis (flecks of purple or red from a bruisewithin the skin itself). The swelling gener-ally begins to resolve after two days, butthe site may remain tender (and continue toitch) for a few more days. The total reac-tion lasts 4 7 days. Large locals aroundthe face and mouth or on the hands maycause temporary disability. The large localis IgE-mediated, and therefore is an aller-gic response.

Treatment of a large local includes iceand elevation. Taking an anti-histamine or

by BUDDY MARTERRE, MD

Part II of Two Parts

Figure 10. Normal Sting Reaction of Face Buddy Marterre, MD

Figure 11. Pseudopustules of Arm fromFire Ant Stings Courtesy of Murray SBlum

Marterre article Bee Stings part 2.qxp 7/13/2006 2:42 PM Page 1

a leukotriene-receptor antagonist verysoon after the sting may decrease the latephase reaction. Personally, this is what Ido and it works for me! Oral steroids areuseful in treating large locals to stingsaround the face and hands. Anti-Histamine choices are sedating drugs suchas diphenhydramine (Benadryl), and non-sedating ones, such as fexofenadine(Allegra), loratidine (Claritin), and ceter-izine (Zyrtec). Benadryl and loratidinemay be obtained without a prescription(over the counter). Caution is advised withdriving (or continued beekeeping) aftertaking a sedating anti-histamine (particu-larly if high doses are taken), however.Oral steroids in the form of prednisoneshort courses and dose packs require eval-uation by a physician and prescription. Asmentioned above, another class of pre-scription drugs that may help are theleukotriene-receptor antagonists mon-telukast (Singulair) and zafirlukast(Accolate). These drugs block theleukotriene receptors on mast cells andeosinophils and both have peak activity 3 4 hours after taking them. People whohave (only) had a large local response,have little or no risk of a severe, life-threatening anaphylactic response in thefuture. Therefore, even though a largelocal reaction is an allergic response,allergy testing and desensitization are notindicated after these.

SYSTEMIC ALLERGIC responsesinvolve two or more organ systems ofthe body and are called ANAPHYLAX-IS. They can be mild and manifest aspurely cutaneous (skin) responses, ormay include symptoms of the gastroin-testinal system or nervous system, orworse, the cardiorespiratory systems. Asystemic cutaneous (or skin) responsemust be distant from the sting site (todifferentiate it from a large local reac-tion) and typically involves the trunk orscalp. Generalized cutaneous responsesinclude urticaria or hives (the familiar,itchy 5 40 millimeter red wheals andslightly raised flares Figure 13) and/orangioedema (a rapidly-developing mas-sive swelling of the face Figure 14).Gastrointestinal symptoms include ametallic taste, nausea, vomiting, diar-

rhea, and abdominal cramps. Neurologicsymptoms include light-headedness,dizziness, and tremor, but light-headed-ness and dizziness can also be due to adrop in blood pressure, which would be acardiovascular effect.

Fortunately, cardiorespiratory systemresponses (severe ANAPHYLAXIS) occurin less than 1 % of people incurring a beesting. Anaphylaxis may be preceded bygeneralized itching, hives, and edema, andthe specific cardiovascular and respiratorysystem reactions can progress fairly rapid-ly (over 1 to 30 minutes). They includewheezing, stridor (airway compromise andinability to breathe), shock (very lowblood pressure causing collapse), loss ofconsciousness, and death. Beekeepers,family members (or anyone) who has hada moderate or severe systemic allergy to

bee stings should see an allergist for skintesting and immunotherapy.

Anaphylaxis to insect venom accountsfor about 40 deaths per year in the US.About 40 % (or about 16) of those areattributable to honey bees, but this may bean underestimate (due to some un-wit-nessed venom-related deaths being falselyattributed to heart attacks). In comparison,lightning strikes account for about 85, ani-mal bites 100, poisonings 3,600, smokingover 150,000, and cancer almost 500,000deaths per year in the US!

The treatment mainstay of anaphylaxisis intramuscular epinephrine (Figure 15).Dose depends on size. Children that weighless than 30 kilograms (66 pounds) need anEpiPen Jr (0.15 mg) and larger childrenand adults need a regular EpiPen (0.30mg). In either case the injection is givenfrom the one-time-use pre-filled adminis-tration syringe into the anterolateral thighand may (and sometimes should) berepeated every five minutes en route to anemergency room. There is also a new epi-nephrine injector called TwinJect, whichcan deliver two injections, but requirespartial disassembly between injections.EpiPens and the TwinJect device require aprescription as there may be some risk toadministering epinephrine to someonewith severe heart disease. EpiPens comewith practice administration syringes andinstructions. If you, anyone in your family,or the neighbors to your bee yard have asystemic allergy, have at least one epineph-rine injector on hand and know how to useit! Other treatments for anaphylaxisinclude bronchodilator inhalers (prescrip-tion), and anti-histamines and steroids - asfor large local reactions. Anyone experi-encing anaphylaxis (epinephrine-treated ornot) needs to be transported directly to anemergency room. Most of these patientswill be admitted to the hospital overnightas sometimes the reactions recur (typicallyat 4 6 hours). Remember those secondarychemicals that the mast cells make thatcause the late phase of allergy? Allergytesting and venom immunotherapy desen-sitization is indicated for anyone with asystemic allergic response to insect stings,including diffuse hives in anyone over 16years of age. Allergy testing is not recom-

Figure 12. LargeLocal Reaction ofHand and Wrist

Buddy Marterre, MD

Figure 13. Urticaria or Hivescourtesy of Dr. Raymond J. Mullins,

allergycapital.com.au

Figure 14. Facial Angioedema Same patient, before and after treatmentcourtesy of siamhealth.com


mended for urticaria / hives alone in achild (under 16).

MASSIVE ENVENOMATION (some-times called a toxic reaction) occurs withgreater than 500 honey bee stings. This isnot an allergic response, but is related tothe large amount of venom received by thevictim. Very young children or chronicallyill elderly people may be poisoned by 150(or more) stings. The dose of bee stingsthat has been calculated to kill half of thevictims (LD50) is 19 stings per kilogramof body weight. Initial symptoms of beevenom toxicity include generalized edema(swelling), fatigue, nausea, vomiting,fever, and unconsciousness. The reaction issometimes delayed by as much as 6 daysand therefore requires immediate trans-portation to an emergency room and hospi-talization. The problems are primarily theresult of rhabdomyolysis (breakdown ofmuscle tissue) and myoglobinuria (themuscle breakdown products in the bloodleading to kidney failure). Hemolysis(burst red blood cells), DIC or disseminat-ed intravascular coagulation (abnormalclot formation inside the blood vesselswith an overuse of clotting factors and sub-sequent bleeding) can also occur. Kidneyfailure and cardiac arrest cause most toxicbee sting deaths (which are considerablyrarer than anaphylaxis deaths).

OCULAR (or eyeball) STINGS are for-tunately quite rare (because of theextremely fast human blink response), butwhen they do occur they frequently lead toblindness. Immediate attention by an oph-thalmologist is warranted. Specific ocularsting injuries include corneal edema,hyphema (blood in the anterior chamber ofthe eye), lens dislocation, cataract, andoptic neuritis (inflammation of the opticnerve). Prevention is clearly the key tothese injuries. Veils only cost a few dollarsand can be donned in seconds! Table 6summarizes venom reaction types andtreatment.

Allergy testing and desensitizationAlthough large local reactions are aller-

gic responses, allergy testing and desensi-tization immunotherapy are not indicatedafter these because the risk of a severe sys-temic reaction to re-sting is extremely low.People who have experienced a systemicallergic response (including urticaria ordiffuse hives in someone over 16) certain-ly benefit from allergy testing and subse-quent desensitization immunotherapy.Desensitization venom immunotherapy(allergy shots) is warranted in anyone whohas had a systemic reaction and in whom

the risk of a systemic reaction with re-stingis 20 % or greater and has also had a posi-tive skin test to the venom. Skin testing ismore sensitive than the RAST (which is ablood test checking for specific IgE anti-bodies to each venom). Skin testing beginswith needle pricks to each individualspecies venom and if negative, it proceedsto sequential intradermal injections of thevenom at increasing doses. People withhypersensitivities to the venom from oneHymenoptera species may also have aller-gies to another. This is called cross-reac-tivity and is quite common within the sub-families Vespinae (aerial and ground-nest-ing yellow jackets, hornets, and bald-facedhornets) and Apidae (sweat bees, honeybees, and bumble bees) since their venomsare so similar. It is less common betweenbee, vespid, and paper wasp venoms, butmost people who have an allergic responseto the venom of one Hymenoptera speciesalso have an allergy to another.

Honey bee venom for testing andimmunotherapy is currently collected by theuse of an electrical micro-current grid thatstimulates bees to deposit their venom onthe underlying pad (with alarm pheromone

greatly magnifying the colonys response).These bees do not die in the process ofstinging the grid. Vespid venom isobtained by individual venom sac dissec-tion. In the past, bee and vespid venomallergy desensitization was done withwhole body extracts. Whole body extractsfrom bees and vespids were not an effectivesource of venom immunotherapy like purevenom is today. (Fire) ant immunotherapyis still done with whole body extracts, how-ever, as different ant species do not crossreact with one another. Good, controlledeffectiveness studies have not been donefor fire ant whole body extracts as theyhave for pure venoms of the otherHymenoptera species.

Desensitization venom immunotherapy(allergy shots) entails the administration ofgradually larger doses of the venom(s) atregular intervals (usually twice a week) upto a target of 100 micrograms per dose overabout 6 months. Maintenance shots are thentypically continued (usually once a month)for at least 3 and usually 5 years. The deci-sion to discontinue immunotherapy is com-plex and treatment may be extended formany years in high risk patients (those withseveral reactions and/or increased exposure such as beekeepers).

The goal of desensitization immunother-apy is simple. Repeated exposure to thevenom leads to a change in the way theregulatory T cells in the immune systemreact to the particular offending antigen.These T cells instruct the B cells to switchantibody production against venom pro-teins from allergic IgE to non-allergic IgG.

Figure 15. EpiPen Buddy Marterre, MD

Reaction Treatments

Normal Ice, Topical

Large LocalIce, +/- Anti-Histamine, +/-

Prednisone, +/- Singulair or Accolate

Systemic Allergy (Anaphylaxis)

Cutaneous

(Hives)

If over 16, Epinephrine

Desensitization Immunotherapy

Other Systems

(GI, Neuro)

Epinephrine, Benadryl, Prednisone,


Cardiorespiratory

Epinephrine, Bronchodilators, Anti-

Histamines, Steroids,

Emergency Room/ Hospitalization,


Massive Envenomation Emergency Room/ Hospitalization

Ocular Emergency Room/ Ophthalmologist

Table 6Insect Venom Reactions and Treatments

Marterre article Bee Stings part 2.qxp 7/14/2006 7:31 AM Page 3

IgG antibodies cannot cause mast cell acti-vation, and therefore mast cells do notdegranulate and there is no subsequentanaphylaxis. As more B cells produce IgGagainst bee venom proteins, the IgG willblock the antigen from being exposed tothe IgE-laden mast cells. There is even evi-dence of IgE anti-idiotypic IgG productionin patients undergoing desensitization (andbeekeepers receiving regular stings). Anti-Idiotypic antibodies are IgG antibodiesthat are directed at the hypervariableregion of the IgE antibody itself (an anti-body to an antibody or kind of like anoth-er key to fool the IgE lock).

Venom allergy in the general populationand in beekeepers

In the general population, about 85 %people have a normal reaction to bee stings,with about 10 % having large local reac-tions, 4 % mild (cutaneous) systemic reac-tions, and 1 % severe anaphylaxis. Re-Stingreactions are typically similar in severity toearlier reactions. Certainly, beekeepers (andtheir family members and neighbors to alesser degree) have increased exposure tobee venom. About 25 % of beekeepers havehigh anti-bee venom IgE levels, and all bee-keepers have increased anti-bee venom IgG.Despite 25 % of beekeepers having highanti-bee venom IgE, anaphylaxis to beestings only occur in a minority of these indi-viduals, for unknown reasons. BeekeepersIgG levels increase and their IgE levels dropwith both the number of stings they receiveand their years of experience (thus regularstings have the same effect as allergy shotdesensitization). Because of their increasedexposure to bee venom, beekeepers havemore allergic responses to stings than thegeneral public. About 25 % of beekeepershave large locals and/or mild systemic(cutaneous) anaphylaxis to stings, and about3 % experience severe cardiorespiratoryanaphylaxis.

Skin testing is only indicated with a his-tory of systemic hives and/or a moresevere systemic reaction for patients over16. For those less than 16, systemic hivesalone is not an indication for skin testing.The history of the event and the reactionmust always be taken into account prior totesting. Also, many people with large localreactions to venomous stings, have IgEantibodies to venom proteins and wouldtherefore have a positive RAST and skintest. Because their risk of a subsequentsevere systemic reaction to re-sting isextremely low, individuals with a historyof large local reactions do not needimmunotherapy (and should not be testedin the first place). Also, neither skin pricktests nor RAST results correlate well withallergic responses in beekeepers.

One Italian study showed that beekeeperswith normal sting reactions incurred over100 stings per year whereas those with largelocals only incurred about 18. Another sur-vey found that 90 % of allergic beekeeperswore gloves as compared to 69 % of non-allergic beekeepers. Apparently, allergic

beekeepers take more precautions becauseof their heightened responses to stings.

Common allergic symptoms to inhaledallergens, such as pollen, insects andarthropods (like cockroaches and dustmites), animal dander, and fungi (molds)include runny nose, watery eyes, and anitchy face. People with these commonsymptoms are termed atopic. The risk of anallergic response to bee venom is higher inbeekeepers who are atopic, have a historyof a systemic reaction to a prior sting, andfewer years of beekeeping experience (lessthan 5 to 8 years). Atopic beekeepers canactually be allergic to beeswax, honey,propolis, and even bee parts.

In one very elegant study of 6 allergicbeekeepers, the skin within their largelocal reaction and their blood and urinewere analyzed 2 hours after a bee sting.Three of them had high histamine levelsand the other three had high leukotrienelevels, suggesting that allergic beekeeperseither have high histamine release orincreased leukotriene production, but notboth. This implies that about half of bee-keepers who have large local reactionsmight benefit from the immediate adminis-tration of a leukotriene inhibitor (Singulairor Accolate) (like me), whereas the otherhalf would benefit from anti-histamines(Benadryl, Allegra, Claritan, Zyrtec)before or very soon after the sting.

Desensitization results (general popula-tion) and beekeeper recommendations

Table 7, Approximate Risk of (Re-)Sting Reaction Type summarizes thisparagraph. It is data that I have pooled orcompiled from many different (reliable)sources, as no single study has been under-taken to define all these risks. Less than 1 - 2 % of people, who have experienced asevere systemic reaction to Hymenopteravenom, experience another severe systemicreaction to re-sting during immunotherapy.Venom immunotherapy or allergy shotsmarkedly reduce the risk of a systemicreaction to re-stings. After immunotherapyhas been undertaken for five years, the risk

of a systemic reaction is about 10 % (andonly 3.5 % severe cardiorespiratory) to are-sting. This is compared to a 50 60 %risk of re-experiencing a severe cardiores-piratory systemic reaction without anyimmunotherapy. If a systemic reactiondoes occur to a re-sting in someone despite100 microgram per month maintenancevenom immunotherapy, the dose is typical-ly increased to 200 micrograms. The risk ofsystemic reaction in people who have had alarge local reaction in the past is about 7 %,but none of those documented in large stud-ies have been severe responses.

Beekeepers with large local reactionswould be well advised to wear gloves.They may also consider a trial of takingeither a leukotriene inhibitor and/or ananti-histamine immediately after beingstung. They do not need to be evaluated ortreated with immunotherapy by an aller-gist. With time (5 8 years) and occasion-al repeated sting exposure (just like withallergy shots), large local reactions willprobably decrease in severity.

Anyone over 16 (beekeepers especially),who has experienced a generalized or sys-temic reaction (hives or anaphylaxis) tobee venom, should seek the advice of anallergist. Anaphylactic beekeepers who areinsistent on continuing to manage beesmight heed advice similar to that given byEich-Wanger and Muller:

1. Give up beekeeping (temporarily).2. Complete bee venom immunothera-

py (with a higher than usual mainte-nance dose of 200 micrograms ofvenom).

3. Return to beekeeping only after awell-tolerated sting challenge in theallergists office.

4. Always wear protective clothingwhile beekeeping and avoid morethan two stings at a time.

5. Keep one or two EpiPens availablewhen working hives or near beesand know how to use them.

6. Inform family members of your andyour bee yards whereabouts andcarry a cellular phone.

Table 7Approximate Risk of (Re-)Sting Reaction Type (Pooled Data)

Normal Large Mild - Mod SeverePopulation Reaction Local Anaphylaxis Anaphylaxis

General Public, NO VIT 85 % 10% 4 % 1 %

Beekeepers, NO VIT 70 % 20 % 7 % 3 %

History Large Local, NO VIT 7 % 0 %*

History Any Anaphylaxis, NO VIT 40 % 20 %

History Severe Anaphylaxis, NO VIT 20 % 55 %

History Any Anaphylaxis, 5 Years VIT 7 % 3.5 %

VIT = venom immunotherapy

* none reported


Eich-Wanger and Muller reported on 69beekeepers with an allergic reaction to beestings, 42 of whom had had a severe reaction.Thirty-one of the 69 allergic beekeepers con-tinued beekeeping. Twenty-two of the 31,who continued beekeeping, received venomimmunotherapy and none of them developeda systemic reaction to re-stings, whereas 4 ofthe 9 who insisted on beekeeping withoutimmunotherapy did. Interestingly, the 22allergic beekeepers, who received allergyshots and successfully returned to beekeep-ing, then gave themselves one or two stingsper week during the active season and onesting per month during the winter (as contin-ued self-administered maintenance therapy).

About the authorIve had allergies all my life. I became

very interested in bees while I was in col-lege at Virginia Tech. But the beekeepingcourse I wanted to take interfered with bio-chemistry lab (my major), so instead I tookgraduate courses in immunology. Aftermedical school and a general surgery resi-dency, I did a fellowship in and then prac-ticed transplant surgery. So while I learnedand practiced more immunology (by trans-planting foreign organs), my personalexperience with bee stings was still lack-ing. After my fellowship, I married anexperienced intensive care nurse, who isnow a certified pulmonary-allergy nurse.Then, I finally became a beekeeper and amnow a Master Beekeeper in NorthCarolina. I have large local reactions to beestings and have experienced quite a fewof those! Being concerned about my risk ofmore serious reactions, I went back to theimmunology and allergy journals. Then,last year, I had an anaphylactic reaction(fortunately not to bee stings, but to salmon which I had eaten many times before)!Thus, I am a doctor, a beekeeper, and apatient. In addition to all the photo credits,Id also like to thank two excellent aller-gists for their review of this article: Aneysa

Sane, MD from Wake Forest UniversityMedical Center, and Larry Williams, MDfrom Duke University Medical Center.

Selected BibliographyAnnila IT, Annila PA, and P Morsky.

1997. Risk assessment in determiningsystemic reactivity to honeybee stings inbeekeepers. Annals of Allergy, Asthma,and Immunology. 78(5):473-477.

Annila IT, Karjalainen ES, Annila PA,and PA Kuusisto. 1996. Bee and waspsting reactions in current beekeepers.Annals of Allergy, Asthma, andImmunology. 77(5):423-427.

Annila I, Saarinen JV, Nieminen MM,Moilanen E, Hahtola P, and ITHarvim. 2000. Bee venom induces highhistamine or high leukotriene C4 releasein skin of sensitized beekeepers. Journalof Investigational Allergology andClinical Immunology. 10(4):223-228.

Arcieri ES, Franca ET, de Oliveria HB,De Abreu Ferreira L, Ferreira MA,and FJ Rocha. 2002. Ocular lesionsarising after stings by hymenopteraninsects. Cornea. 21(3):238-330.

Bousquet J, Menardo J-L, Aznar R,Robinet-Levy M, and F-B Michel.1984. Clinical and immunologic surveyin beekeepers in relation to their sensiti-zation. Journal of Allergy and ClinicalImmunology. 73(3):332-340.

Davis CF. 2004. The Honey Bee InsideOut. Bee Craft Limited, Stoneleigh, UK.

Eich-Wanger C, and UR Muller. 1998.Bee sting allergy in beekeepers. Clinicaland Experimental Allergy. 28(10):1292-1298.

Golden DBK, Kagey-Sobotka A, and LMLichtenstein. 2000. Survey of patientsafter discontinuing venom immunothera-py. Journal of Allergy and ClinicalImmunology. 105(2 Pt 1):385-390.

Golden DBK, Kagey-Sobotka A,Norman PS, Hamilton RG, and LMLichtenstein. 2004. Outcomes of aller-

gy to insect stings in children, with andwithout venom immunotherapy. TheNew England Journal of Medicine.351(7):668-674.

Golden DBK, Kwiterovich KA, Kagey-Sobotka A, Valentine MD, and LMLichtenstein. 1996. Discontinuingvenom immunotherapy: Outcome afterfive years. Journal of Allergy andClinical Immunology. 97(2):579-587.

Goodman L. 2003. Form and Function inthe Honey Bee. International BeeResearch Association, Cardiff, UK.

Lerch E, and UR Muller. 1998. Long-Term protection after stopping venomimmunotherapy: Results of re-stings in200 patients. Journal of Allergy andClinical Immunology. 101(5):606-612.

Levine MI, Lockey RF, eds. 2003.Monograph on Insect Allergy, 4th ed,American Academy of Asthma, Allergyand Immunology, Pittsburgh, PA: DavidLambert Associates.

Reisman RE. 1992. Natural history ofinsect sting allergy: Relation to severityof symptoms of initial sting anaphylaxisto re-sting reactions. Journal of Allergyand Clinical Immunology. 90(3 Pt1):335-339.

Schmidt, JO. 1992. Allergy to VenomousInsects. In The Hive and the Honey Bee.JM Graham, ed. Dadant & Sons,Hamilton, IL, pp.1209-1269.

van Halteren HK, van der Linden P-WG, Burgers SA, and AKMBartelink. 1996. Hymenoptera stingchallenge of 348 patients: Relation tosubsequent field stings. Journal ofAllergy and Clinical Immunology.97(5):1058-1063.

Vetter RS, Visscher PK, and SCamazine. 1999. Mass envenomationsby honey bees and wasps. WesternJournal of Medicine. 170(4):223-227.

Winston ML. 1987. The Biology of theHoney Bee. Harvard University Press,Cambridge, MA.


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