Are You Confident of the Diagnosis?
What you should be alert for in the history
Patients with bug bites rarely present with the history of arthropod exposure and subsequent bites. Bites are so common that most patients easily recognize the typical symptoms and are able to self medicate with over-the-counter antihistamines and topical hydrocortisone. Typically, patients that do seek medical advice are those who are unaware that they are getting bit, are getting bites when no one else is, or who do not believe their lesions represent bites. Patients will often be exasperated by the ongoing eruption of new lesions after they have meticulously cleaned, fumigated, and otherwise “debugged” their environment.
Exaggerated bug bites are another common reason why patients are referred to dermatologists. Similarly, arthropod stings are almost always recognized by the patient as such, and result in mild and self-limited symptoms. Patients with arthropod stings commonly present with atypical or dramatic reactions including large local reactions or anaphylaxis.
Arthropod exposures typically happen during the warmer months, when outdoor activity is increased, and when insects and other arthropods are most plentiful and most active. However, travel to a more tropical location during winter months, or exposure to indoor arthropods (including fleas and bed bugs) are a few exceptions to this generalization.
The diagnosis of an arthropod reaction is straightforward when the appropriate history of an arthropod exposure is documented. However, arthropod reactions (particularly arthropod bites) can occasionally be more dramatic or atypical, or the history of an arthropod exposure is unobtainable in the face of otherwise classical lesions. This latter scenario is common and makes for a challenging office visit for busy clinicians.
Characteristic findings on physical examination
Typical arthropod bites cause pruritic edematous red to pink papules (rarely vesicles or bullae) at the site of exposure (Figure 1). These papules are typically only a few millimeters in size, although occasionally patients will have vigorous allergic reactions, causing several centimeter-sized edematous pruritic plaques (the so-called exaggerated arthropod reaction). Bites can be purpuric on the lower extremities and mimic vasculitis (Figure 2).
A few insect bites are large enough to cause pain from the bite itself, with or without an allergic response. These insects include large biting flies, gnats and assassin bugs and related wheel bugs (Figure 3).
Arthropod stings usually cause immediate pain and burning, followed by an edematous wheal and pruritus or tenderness that may last minutes or hours (Figure 4).
Most arthropod stings are caused by bees, wasps, ants, and other members of the insect order Hymenoptera. Fire ant stings characteristically cause pustules at the site of stings, which are typically multiple.
The so-called large local reaction begins similarly to an insect sting, but by definition is larger than 10 cm in diameter and can last for up to a few days. Finally, some arthropod stings can induce systemic symptoms culminating in anaphylaxis. Systemic reactions typically begin within 30 minutes of envenomation and may produce urticaria, wheezing, shortness of breath, nausea and vomiting, edema of the oropharynx, confusion or anxiety, hypotension, and respiratory arrest. It does not appear that large local reactions are a risk factor for subsequent anaphylactic reactions.
Expected results of diagnostic studies
Diagnostic studies are usually unnecessary, even in dramatic cases of arthropod reactions. The presentation of multiple, extremely pruritic pink papules and plaques, often with secondary change due to excoriation, is classic for an arthropod bite reaction. A shave biopsy or a 4-millimeter punch biopsy, at the site of a bite, can be helpful in cases where the patient needs confirmation that the lesions represent bites.
The typical biopsy shows a wedge-shaped dense perivascular lymphoid infiltrate with numerous eosinophils. Often, endothelial cells are swollen, and there is overlying acanthosis, spongiosis, and sometimes crusting (Figure 5).
Arthropod parts are rarely seen on biopsy with the exception of tick mouth parts or rarely caterpillar hairs. Exaggerated arthropod reactions show more dramatic inflammatory infiltrates, occasionally extending into the subcutis, and sometimes with flame figures (as appreciated in Wells syndrome) (Figure 6).
The differential diagnosis of arthropod bite reaction includes allergies to foods, fragrances, medications, plant substances, animal dander, and other chemicals. A thorough history is necessary to differentiate these causes. Papular urticaria can also be caused by dermatitis herpetiformis, id reactions, and folliculitis. Pruritic urticarial papules or plaques in the elderly may be incipient lesions of bullous pemphigoid. These entities may be distinguished by their characteristic distributions and by culture and/or biopsy.
The differential diagnosis of arthropod stings includes cellulitis, bites from other animals, traumatic puncture and foreign body. The differential for systemic reactions to stings includes allergies to medications, foods, and hereditary angioedema. Appropriate history gathering readily differentiates these conditions.
Who is at Risk for Developing this Disease?
Arthropod reactions are incredibly common. It is safe to say that most people are bitten or stung by insects each year. Most insects show no age or gender preference, although fire ant stings and caterpillar exposures may be more common in younger age groups. Adult age, male sex, and larger body size have all been shown to increase mosquito bites. Men are more frequently affected by arthropod stings, probably due to increased exposure.
Outdoor work or hobbies, such as gardening, camping, or walking, all potentially increase exposure to offensive arthropods. Living in tropical climates increases the duration of risk. Crowded living conditions, such as in large urban centers, may increase the risk of bed bugs or lice. Pet ownership increases the risk of flea exposure.
Large local sting reactions are more common in people who are frequently stung, such as apiarists. The risk of systemic reactions to arthropod stings increases with decreasing time between stings. However, persons who have numerous and frequent stings seem to develop some tolerance to sting reactions, perhaps akin to desensitization therapy.
What is the Cause of the Disease?
Typical arthropod reactions are caused by a Type-1 hypersensitivity response to arthropod saliva or arthropod mouthparts that come in contact with the patient’s tissue (Figure 7).
Exaggerated bite reactions occur in susceptible individuals who often have a history of more typical lesions of arthropod assault. However, over time these patients respond more and more vigorously to each new arthropod assault and develop the larger, more persistent plaques.
IgE-mediated inflammation appears to be involved in many insect bite and sting reactions. Little work has been done to characterize the IgE-binding proteins in most species of insects. Some insects, such as biting flies, harbor enzymes of myriad function within their saliva. Hymenoptera stings are often irritant/toxic in nature, with enzymes such as phospholipase and hyaluronidase responsible for the attendant reaction.
Components of insect venom, including phospholipase and hyaluronidase, are also major allergens in hymenoptera stings. These allergens bind to specific IgE antibodies on basophils and mast cells, causing degranulation and release of inflammatory mediators that are responsible for systemic allergic reactions and anaphylaxis.
Stinging caterpillars may harbor proteases with trypsin- or chymotrypsin-like activity, as well as phospholipase A or other chemicals. Histamine may be found within the saliva of other insects, as well as the irritating hairs of some caterpillars. Some insect reactions, including those due to flea bites and caterpillar stings, may have more than one mechanism, with evidence of both an IgE-mediated immediate response as well as a Type-IV delayed hypersensitivity reaction.
Eosinophils characteristically infiltrate the site of arthropod assault. Eosinophil granule proteins may increase vascular permeability, contributing to tissue edema. These proteins also induce basophils and mast cells to release histamine. Histamine further increases vascular permeability, allowing inflammatory cells and proteins to enter the surrounding tissues.
Systemic Implications and Complications
Bug bites are typically self-limited. Excoriation can cause secondary impetiginization and, in exceptional cases, cellulitis. Heavy excoriation can lead to ulceration, postinflammatory pigment alteration, and scarring.
Exaggerated bite reactions may be seen in myeloproliferative disorders, especially chronic lymphocytic leukemia, and in patients who are infected with HIV. Arthropod bites rarely cause life-threatening allergic reactions such as anaphylaxis or angioedema. However, insect stings may cause these life-threatening reactions, particularly stings from bees, ants, or wasps.
Large local reactions occur in 2-10% of people stung by hymenoptera, and these reactions are more common in those who are frequently stung, such as apiarists. Systemic reactions to stings, including anaphylaxis, occur in 0.4 -5% of the population. In addition to anaphylaxis, high numbers of simultaneous stings from hymenoptera can rarely cause “intoxication,” with cases of rhabdomyolysis, liver and kidney disease reported.
Many arthropods may carry and transmit serious diseases. Mosquitoes transmit numerous diseases including malaria, filariasis, yellow fever, dengue fever, West Nile virus, and Chikungunya disease. In contrast, it is felt that HIV is nearly impossible to acquire from a mosquito bite. Furuncular myiasis caused by larvae of the fly Dermatobia hominis is actually transmitted by a mosquito who serves as an unwilling vector for the fly’s ova. Biting flies carry filariasis (including onchocerciasis and loiasis), Oroya fever/Carrion’s disease, Leishmaniasis, and sleeping sickness. Reduviid bugs can carry Chagas disease in the southern U.S., Mexico, and Central and South America.
Treatment options for arthropod bite reactions and sting reactions are summarized in Table I and Table II.
|Tape stripping (for insects with irritating hairs or setae)|
|Topical antipruritics and anesthetics|
|Stinger removal (if still embedded)|
|Topical antipruritics and anesthetics|
Optimal Therapeutic Approach for this Disease
The best approach to arthropod bites and stings is avoidance. This begins with making the proper diagnosis and educating the patient about modes of exposure. Outdoor activity should be minimized in areas where biting or stinging insects may be found. Protective clothing. including long sleeves, pants, hats with mosquito nets, and gloves may be warranted for extended outdoor activity. If outdoor activity is unavoidable, DEET-containing repellants are very effective (see below). In sensitized individuals, even brief outdoor activity, such as a neighborhood walk, may be enough to provide opportunity for bites.
If indoor arthropod assault is suspected, prompt evaluation by a reputable exterminator is necessary. Often, patients will protest that their house is clean or that they have used home extermination regimens. In this author’s opinion, this is inadequate.
The most commonly used insect repellant is a chemical called N, N- diethyl-3-methylbenzamide (DEET). DEET works well against mosquitoes, biting flies, chiggers, fleas, ticks, and other arthropods. Products with higher concentrations of DEET last longer, and 10 to 35% concentration is usually effective for 4-6 hours.
Extended formulations of DEET are now available that last up to 12 hours. However, moderate exercise, warm weather, or rain may dramatically decrease the efficacy and longevity of topical DEET preparations. DEET is safe to use on clothing made of cotton, wool, and nylon, but it can damage spandex, rayon, and leather products. Furthermore, it can damage plastics found in eyeglass frames or tool handles as well as vinyl products.
Permethrin is another chemical that is often used on clothing to prevent mosquitoes, ticks, and other insects. It is more effective against ticks than DEET. When a 0.5% permethrin-containing product is used on clothing, it is effective for up to 5 washings. A randomized trial found that canvas tents sprayed with 0.4% permethrin can reduce the burden of mosquito bites in campers.
Picaridin (KBR 3023) is a newer chemical that is widely used in Europe. There are a few US products that also use it. It is probably as effective as DEET for mosquitoes, biting flies, and ticks. Some people prefer picaridin-products because it has no smell and does not damage plastics or fabrics. In Europe, a 20% picaridin product has been shown to last for about 8 to 10 hours.
All insect repellants should be applied evenly to a dry surface such as exposed skin or clothing. Care should be taken to avoid eye or mouth contact with the repellant. It is ok to use sunscreen in addition to the insect repellant. As with sunscreen, the repellant should be reapplied after toweling off. Some products need to be reapplied after several hours of use; the product label can be very helpful in this regard. In addition, all insect repellants should be washed off before eating or going to bed.
Arthropod reactions are usually mild and self limited. Medical treatment is not necessary when the diagnosis is obvious and symptoms are not bothersome. However, many patients are quite bothered by their itchy lesions, some to the point of being overwhelmed. In these cases, I suggest the following therapeutic ladder. Topical antipruritic agents, such as camphor and menthol 0.5%, or topical anesthetics like pramoxine 1% can be used several times a day for rapid relief. These medications are available over the counter at most pharmacies.
Topical steroids such as hydrocortisone 2.5% can be used once a day for persistent itchy bites. Stronger steroids such as triamcinolone 0.1% or fluocinonide 0.05% are available in generic formulations and are very inexpensive. For exaggerated bite reactions, superpotent topical steroids such as clobetasol 0.05% can be used, with or without occlusion, for up to 2 weeks at a time. Oral antihistamines, such as fexofenadine 180mg or cetirizine 10mg, can be taken once or twice daily to help relieve itching.
Double blind, placebo-controlled trials have shown that cetirizine, levocetirizine, and loratadine decrease wheal diameter and pruritus scores due to mosquito bites. Another double-blinded study found that cetirizine 10 mg was more effective than loratadine 10 mg, but was also more sedating. Sedating antihistamines such as diphenhydramine or hydroxyzine can be taken orally in doses of 10-25mg at night. If sedation is not a problem and symptoms persist, higher doses can be used.
Intradermal injection of corticosteroid may be the best treatment for exaggerated bite reactions. Triamcinolone at concentrations of 2.5-10mg/ml can be injected directly into particularly bothersome lesions at doses of 0.1ml or more, depending on the size of the lesion being treated. Enough steroid should be injected intradermally to blanch the lesion. Higher concentrations of injectable steroid increase the risk of local lipoatrophy, although lipoatrophy usually self-corrects after months or years. In widespread or dramatic cases of bug bites, short courses of oral corticosteroids (such as prednisone) can be rapidly effective. Dosing should start at 0.5 -.0mg/kg and tapered down over 7-14 days. No effective immunotherapy exists for allergic reactions to bug bites.
For insect stings, application of ice for 15-minute intervals with a cloth between the ice and the skin can be helpful. Immediate removal of the stinger, if still present, is advised. Topical anesthetics such as pramoxine 1% lotion and oral analgesics (acetaminophen or ibuprofen) can be helpful. Severe pain may require short-term narcotic analgesia. For large local reactions, especially those than involve the distal limbs or the face/lips, oral antihistamines and systemic corticosteroids, dosed similarly as for arthropod bites, is recommended.
For anaphylactic reactions, intramuscular epinephrine (0.3-0.5ml of 1:1000 epinephrine) can be given, and doses may be repeated at 10-minute intervals as needed. Immediate consultation with critical care is also recommended. Systemic corticosteroids may be administered to prevent delayed or recurrent anaphylaxis.
Unlike insect bite reactions, there is good evidence for desensitization procedures in patients with systemic reactions to arthropod stings. Although effective, desensitization is not generally recommended for large local reactions due to the low incidence of subsequent systemic reactions. Skin testing and venom-specific IgE tests for various hymenoptera are available.
Venom-specific immunotherapy is indicated in those patients with a history of systemic reactions to insect stings in combination with either positive skin testing or positive venom-specific IgE testing. Immunotherapy should be administered by qualified medical providers with access to resuscitation equipment and emergency facilities in the unlikely event of a systemic allergic reaction during immunotherapy. Immunotherapy is 75-95% protective in preventing further systemic reactions. So far, sublingual immunotherapy has not been proven effective for systemic reactions to arthropod stings. Patients with a history of anaphylaxis should be offered auto-injectable epinephrine.
Arthropod bite reactions can be frustrating to treat, especially when they are chronic. Patients often opine that they have not seen any insects, or that others around them are not suffering from bites. When the physical examination and/or biopsy shows a bite reaction, the patient should be told in no uncertain terms that his or her lesions are bites.
Patients should be encouraged to look for potential sources of exposure, including even brief time outdoors, exposure to pets or animals, foreign or domestic travel, or visiting a friend’s home. Having an exterminator visit the home is of utmost importance. When this is suggested, patients will sometimes protest that their house is clean or that they have used home extermination regimens. In this author’s opinion, this is inadequate. For instance, it is well known that bed bugs can evade home foggers and many pesticides by hiding within the walls of the house or within other protected areas while the chemicals dissipate.
If indoor arthropod assault is suspected, prompt evaluation by a reputable exterminator is necessary. Patients should also be told that examination, clinically or pathologically, of arthropod reactions does not tell you the source of the bites, as these bites are a reactionary pattern that is similar no matter what the inciting antigen is. Only a thorough history and examination of the patient’s environment can pinpoint the source of bites.
Not everyone gets an allergic response to bug bites. When one member of a household has bite reactions and others do not, it may mean that some members are not reacting to the bites. A recent study showed that up to 25% of those bitten by bed bugs do not have a visible bite reaction. All members of the household are likely being bitten, but only some have the reaction.
Patients with arthropod stings do not require dermatologic follow up once the diagnosis is made unless there is a history of anaphylactic reactions. Long-term management of patients with large local reactions is somewhat controversial; it is estimated that these patients have a 5-10% chance of developing a systemic reaction if re-stung. Although opinions vary, most experts recommend that patients with a history of large local reactions carry auto-injectable epinephrine.
Unusual Clinical Scenarios to Consider in Patient Management
Systemic allergic reactions to insect stings tend to be more severe in patients with mastocytosis, and patients with mastocytosis may have a higher risk of anaphylaxis after insect stings: studies show between 6 and 27% of adult patients with mastocytosis will experience anaphylaxis to hymenoptera stings. The most severe allergic reactions occur in those with systemic mastocytosis, rather than purely cutaneous mastocytosis.
Amongst patients with anaphylaxis, the prevalence of mast cell disease may be as high as 7.9%. Serum tryptase is an inexpensive and useful test in patients with a history of anaphylaxis for the presence of mast cell disease. Patients with a serum tryptase of more than 20ug/L (some authors propose an upper limit of 11.4ug/L) should undergo complete evaluation for the presence of an underlying mast cell disorder, which may require bone marrow biopsy. Venom immunotherapy can be effective in these patients.
All patients with mastocytosis and a history of anaphylaxis should carry autoinjectable epinephrine. Of note, insect stings appear to be an exceedingly rare cause of anaphylaxis in children with mastocytosis, even though these children do have an increased overall risk of anaphylaxis. Most cases of anaphylaxis in these patients are due to medications, foods, or other triggers.
Exaggerated bite-like reactions have been reported in patients with hematologic malignancies, particularly (but not exclusively) chronic lymphocytic leukemia. Approximately 50 cases have been reported to date. Some cases have been refractory to conventional therapy, including systemic corticosteroids. The histopathology ranges from a typical bite-like reaction to massive dermal edema and eosinophil degranulation with flame figures (Wells syndrome). Patients often, but not always, report a history of arthropod exposure.
Whether these lesions in patients with hematologic malignancies are truly arthropod related or not is unclear. Cases not related to arthropod bites may be related to immunodeficiency combined with various immunologic stimuli such as medications or infections. Regardless of the etiology, the possibility of underlying hematologic malignancy should be considered in elderly patients with exaggerated arthropod bite or bite-like reactions.
What is the Evidence?
Hoffman, DR. “Biting insect allergens”. Clin Allergy Immunol. vol. 21. 2008. pp. 251-60. (This recent review covers the known allergenic extracts from many common biting insects, including mosquitoes, flies, ticks, and bed bugs.)
Steen, CJ, Carbonaro, PA, Schwartz, RA. “Arthropods in dermatology”. J Am Acad Dermatol. vol. 50. 2004 Jun. pp. 819-42. (Excellent review of papular urticaria and most of the major arthropods of medical importance. Includes preventative and treatment measures.)
Severino, M, Bonadonna, P, Passalacqua, G. “Large local reactions from stinging insects: from epidemiology to management”. Curr Opin Allergy Clin Immunol. vol. 9. 2009 Aug. pp. 334-7. (Thorough review of large local reactions to insect stings, including treatment measures.)
Przybilla, B, Ruëff, F. “Hymenoptera venom allergy”. J Dtsch Dermatol Ges. vol. 8. 2010 Feb. pp. 114-27. (Recent, thorough review on the diagnosis and management of various reactions to hymenoptera stings.)
Karppinen, A, Kautiainen, H, Petman, L, Burri, P, Reunala, T. “Comparison of cetirizine, ebastine and loratadine in the treatment of immediate mosquito-bite allergy”. Allergy. vol. 57. 2002 Jun. pp. 534-7. (This double-blind, placebo controlled trial found that cetirizine 10mg and ebastine 10mg were more effective than loratadine 10mg at reducing whealing and itching from mosquito bites.)
Barzilai, A, Shpiro, D, Goldberg, I, Yacob-Hirsch, Y, Diaz-Cascajo, C, Meytes, D. “Insect bite-like reaction in patients with hematologic malignant neoplasms”. Arch Dermatol. vol. 135. 1999 Dec. pp. 1503-7. (Review of exaggerated bite-like reactions in patients with hematologic malignancies, including some theories as to the pathogenesis of these reactions.)
Bonadonna, P, Zanotti, R, Müller, U. “Mastocytosis and insect venom allergy”. Curr Opin Allergy Clin Immunol. vol. 10. 2010 Aug. pp. 347-53. (Review of the relationship between mastocytosis and systemic allergic reactions, proposed pathogenesis, testing, and treatment.)
Brockow, K, Jofer, C, Behrendt, H, Ring, J. “Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients”. Allergy. vol. 63. 2008 Feb. pp. 226-32. (This study of patients with known mastocytosis showed that hymenoptera stings (particularly wasps) were the most common cause of anaphylaxis in adults with mastocytosis. Twenty-seven percent of their adult cohort reported anaphylaxis to hymenoptera stings. In contrast, hymenoptera stings were not found to cause any cases of anaphylaxis in children.)
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