Clinical Practice Review
Journal of Veterinary Emergency and Critical Care 19(4) 2009, pp 329–336 doi:10.1111/j.1476-4431.2009.00440.x
Brown recluse spider (Loxosceles reclusa) envenomation in small animals Lonny B. Pace, DVM and Richard S. Vetter, MS
Abstract Objective – To provide a comprehensive review of relevant literature regarding the brown recluse spider (BRS) and to define those criteria that must be satisfied before making a diagnosis of brown recluse envenomation. Etiology – The complex venom of the BRS contains sphingomyelinase D, which is capable of producing all the clinical signs in the human and some animal models. Diagnosis – There is no current commercially available test. In humans there are many proposed guidelines to achieve a definitive diagnosis; however, there are no established guidelines for veterinary patients. Therapy – Currently, no consensus exists for treatment of BRS envenomation other than supportive care, which includes rest, thorough cleaning of the site, ice, compression, and elevation. Prognosis – Prognosis varies based on severity of clinical signs and response to supportive care. (J Vet Emerg Crit Care 2009; 19(4): 329–336) doi: 10.1111/j.1476-4431.2009.00440.x
Keywords: dermonecrotic, Loxosceles, matrix metalloproteinases, sphingomyelinase D
Introduction Brown recluse spiders (BRS), Loxosceles reclusa, are considered, in human and veterinary medicine, to be one of the most clinically important spiders in North America. In spite of their importance, there is a paucity of veterinary literature addressing arachnid-companion animal BRS envenomation (BRSE). Almost all available recommendations regarding the effects of BRSE in companion animals is extrapolated from bite manifestations in humans. In 1872, Caveness became the first clinician to report specific symptoms following an assumed brown recluse spider bite (BRSB) in a human. In 1928, Schmaus was the first to report symptoms following a documented BRSB and Macchiavello, in 1937, reported that dermonecrotic lesions were associated with the South American species, Loxosceles laeta. In 1957, Atkins and colleagues1 definitively identified BRS venom as a potential source of necrotic lesions. A definitive diagnosis is difficult to obtain and clinicians From the Central California Veterinary Specialty Center, Fresno, CA 93710 (Pace); the Department of Entomology, University of California, Riverside, CA 92521 and Biology Division, San Bernardino County Museum, Redlands, CA, 92373 (Vetter). The authors have declared no conflicts. Address correspondence and reprint requests to Dr. Lonny B. Pace, Central California Veterinary Specialty Center, Fresno, CA 93710, USA. Email: [email protected] & Veterinary Emergency and Critical Care Society 2009
must base their diagnosis on multiple criteria including geography, clinical signs, and preferably, authoritative identification of the spider. While Loxosceles spiders are distributed throughout the world, the endemic range of the BRS is limited, even within the United States.1 The biology, natural history, and distribution of Loxosceles spiders are poorly documented. Unfortunately, numerous clinical cases are based on presumptive bites that lead to misconceptions and misdiagnoses.2,3 BRS venom is highly complex with only some of the components described in the literature. Still, the manifestations of envenomation are highly variable and are intimately linked with the body’s immune response. Clinical signs range from minor local irritations to death.1,4–7 Diagnosis of BSRE remains problematic because there is no specific laboratory test to facilitate diagnosis and histopathology is nonspecific.1 The absence of a broadly accepted treatment protocol in human literature adds confusion,8–12 so caution must be exercised when extrapolating from human data.
The Spider Range Loxosceles spiders are indigenous in the temperate regions of the Americas, Africa, and Europe. Of the approximately 100 species, over 80% are found in the Americas. Within the United States there are 11 indig329
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enous and 2 nonindigenous species.8 Many species exist in areas devoid of human populations or are extremely rare, with few documented specimens.13 The distribution of the BRS in the United States is primarily Midwestern (see Figure 1). Other species dwell in the sparsely inhabited deserts from southeastern California through Texas.13,14 Despite the well-established range of Loxosceles spiders, medical professionals continue to diagnose BRSE in areas not endemic to the spider. In 1 study, medical professionals reported 216 BRSE within 41 months in Colorado, Washington, California, and Oregon; however, only 35 verified BRS, or Mediterranean brown spiders, have ever been found in these states.15 In a separate 6 year study, medical personnel from 3 Florida poison control centers reported 124 BRSB; however, in the past 100 years there have been only 11 Florida sites, where Loxosceles spiders have been identified by arachnologists and most of these were single specimen reports.16 In 2004, South Carolina physicians diagnosed 738 BRSE despite the fact that only 44 BRS had been verified in 6 locations since 1953.17 Skeptics argue that interstate transplantation of the spider could occur during household relocations and may account for bites out of the reported range. However, the sheer number of people moving and goods being shipped between endemic and nonendemic areas is not proportional to the very small number of BRS found outside of the range. The BRS has not shown the ability to readily expand its range. The heightened awareness of BRS outside of their range also exists for the general public. In a 4.5 year study, identifying any creature suspected to be a Loxosceles spider, 1773 arachnids were submitted to the University of California Riverside from 49 states.13 Of
Figure 1: Map of the distribution of the most widespread Loxosceles spiders in North America. Recluse spiders will be common and frequently encountered in the middle of their range but will dissipate toward the margins as the populations diminish to nonexistence.
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these, 324 BRS were submitted, with only 2 finds emanating from outside the reported range. Of the many patients from nonendemic Loxosceles areas, who were diagnosed with a BRSE and subsequently submitted a spider for identification, not one was a recluse. One Texas medical school was using non-Loxosceles spiders (Kukulcania hibernalis, Psilochorus sp.) as teaching specimens of BRS for their medical students. Pest control personnel, county health officials, and a veterinarian also made misidentifications.13 Identification The mature BRS is 8–13 mm in body length, with legs measuring 20–30 mm. They tend to be brown, but shades may vary from light or yellow-brown to graybrown. The BRS has a characteristic violin shape on its dorsal cephalothorax, which may not be evident in immature spiders. Instead of the usual 8 eyes found in most spiders, Loxosceles spiders have 6 eyes arranged in pairs called dyads positioned on both lateral aspects and anteriorally8,12 (see Figure 2). As a way of identifying a Loxosceles spider, the eye pattern is far more diagnostic and less readily misinterpreted than the violin pattern. The spider’s fangs open in a side-to-side manner placing them in the suborder, Araneomorphae. This distinguishes them from tarantulas and Australian funnel web spiders, which have parallel fangs. Their legs are long in comparison with their body and have fine recumbent hairs. Natural history The BRS is found either indoors or out and true to its name, is usually reclusive by nature preferring dark
Figure 2: Brown recluse spider, Loxosceles reclusa. Although the violin mark is conspicuous in this spider, it is not as well demarcated in other species or immatures. The 6-eye pattern is more diagnostic for identification.
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areas. In nature, it prefers to remain beneath rocks and under tree bark. However, Loxosceles spiders easily cohabitate within human domiciles, being commonly found under clothes piles, bedding, in or under boxes, in cellars, and any other undisturbed areas. The BRS is reluctant to bite and given its shy nature, human envenomation rarely occurs. In a 6-month period, 2055 BRS were found in 1 Kansas home. Despite this infestation, none of the occupants reported a bite18 during the study or in the 5.5 years prior, although, in the 11th year of home occupancy, the first known bite did occur in this highly infested house.19 The spiders are more active in the warmer months but can withstand temperatures from 8–431C.1,20 BRSs are nocturnal, hunting spiders, are not prolific web spinners but do produce a cottony, irregular-shaped web as a retreat. They do not use webs to capture prey although the web may alert a spider to the presence of a temporarily entangled insect that they attack quickly then retreat until the venom paralyses the creature. They can live for 6–12 months without food and water.19 In the laboratory setting these spiders have lived 1755 days, with the average female living 627 days. Newly emerged spiderlings of Loxosceles intermedia lack the potentially dangerous venom components, which are not detectable until the third-instar spiderling (ie, an instar is the growth period between 2 successive molts in arthropods).12 Venom Loxosceles spider venom is a complex mixture of components creating literally a constellation of different clinical signs ranging from local to systemic. At least 8 subcomponents have been found within the venom including the 35 kDa protein sphingomyelinase D (SMase D), hyaluronidase, alkaline phosphatase, collagenase, esterase, ribonuclease, deoxyribonuclease, and several different proteases.3,4 The complex venom is remarkable when considering the amount of venom injected compared with the severity of the clinical signs. The average amount of venom injected by the Eastern diamondback rattlesnake is 200–850 mg21 compared with Loxosceles envenomation of 30–65 mg of protein.7,12 There are 4 major phospholipids in the mammalian cell membrane including sphingomyelin, which is mostly found in the membrane’s outer leaflet. Phospholipases like SMase D are common components of animal venoms. In the animal kingdom, SMase D is found only in Loxosceles spiders and close taxonomic relatives of the genus Sicarius (found in African and South America).22 The only other known source of SMase D is an exotoxin from certain Corynebacterium spp, and Arcanobacterium hemolyticum.22
A full understanding on how 30 mg of venom can cause extensive local tissue injury and sometimes develop into life-threatening systemic disease is the subject of active research. SMase D is capable of inducing all the clinical signs of whole venom.23 It will activate endogenous matrix metalloproteinases (MMPs), cleaving sphingomyelin into its 2 components, ceramide1-phosphate and choline and catalyzing the release of choline from albumin-bound lysophosphatidylcholine in the presence of Mg21.24 The hydrolysis of albuminbound lysophosphatidylcholine creates lysophosphatidic acid and choline. Lysophosphatidic acid stimulates platelet aggregation, causing endothelial hyperpermeability, and is strongly proinflammatory.24 Loxosceles spider venom activates certain MMPs. Activation of these endopeptidases is suspected to be one source of the massive neutrophilic infiltration seen in envenomation and likely has other roles in the wound propagation. SMase D changes and cleaves proteins on the surface of the erythrocyte, activating both classic and alternative complement cascades. This leads to the formation of the membrane attack complex and subsequent cellular lysis. SMase D is capable of antagonizing activation of protein C, potentially creating a procoagulatory state.25 Induction of complement, activation of MMPs, alteration of transmembrane proteins, preventing activation of protein C, and apoptosis appear to be involved in the propagation of the profound immune response leading to dermonecrosis.22,23,26–30 The female spider has a higher biological activity suggesting its venom is more toxic and likely accounting for some of the variability between bites.31 The variability of responses to BRSE in veterinary medicine Research involving BRSE in companion animals is almost nonexistent. Veterinary literature extrapolates data from the human literature without evidence that dogs and cats will follow the human model. There is tremendous variability to spider envenomation among mammalian species,9,32–34 hence, extrapolation could lead to grievous errors. As an example of the extremes that can manifest in mammals in response to a spider bite, an Australian report retrospectively documented bites from theraphosid spiders (ie, tarantulas) on humans and dogs over 23 years. The 9 human victims suffered mild effects, including pain and puncture marks, while all 7 dogs died. Two of the dogs were in the human weight range (40–50 kg) and in 2 cases, the same spider envenomated both the human and the dog with widely dichotomous outcome for the bite victims.33 Similarly, Loxosceles venom also produces differential mammalian toxicity. Rats and mice do not
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develop dermonecrotic lesions from Loxosceles spider venom while guinea pigs and rabbits do, although there appears to be variability between studies.6,8 BRS venom will lyse erythrocytes of humans and pigs, but not those of dogs, rats, or guinea pigs.10,11 The in vivo effects of BRS venom on 9 dogs demonstrated that following intravenous injection, all animals developed poor feeding, dehydration, and apathy with 2 progressing to jaundice and bleeding manifestations after 24 hours. A striking reticulocytopenia was noted in all patients within 2 hours of injection along with increased hemoglobin, and corresponding decreases in hematocrit suggesting red cell lysis and corresponding elevation of free hemoglobin. Coombs test and liver function tests were all negative with the exception of transient indirect bilirubinemia in the 2 severely affected animals. All dogs recovered fully within 72–120 hours.11 It is difficult to extrapolate too much information from this study as envenomations are usually intradermal not intravenous. A Chilean study34 rated susceptibility based on weight/dose relationships in several different animals to L. laeta venom. Rabbits, mice, guinea pigs, and dogs were rated as high susceptibility; hamsters, pigeons, chickens, and toads had moderate susceptibility; frogs were low; and rats and fish exhibited no response to the venom. Dogs (n 5 2) succumbed to the venom after the contents of 417 venom glands (8.5 spiders cumulative venom) were injected intradermally while dogs (n 5 4) injected with 1–15 glands survived with no effects. Intradermal injections of 0.75–3 venom glands/kg in these dogs caused only small local lesions while similar injections in rabbits reproduced the same dermonecrotic lesion as seen in humans.34 However, even with rabbits, there is a different response compared with humans in that rabbits heal more quickly and do not develop chronic ulceration.35
Clinical Implications of the BRSB Clinical signs Because of the paucity of primary research performed on Loxosceles venom in companion animals, the descriptions of clinical signs are based primarily on the human response to BRSE. In humans, the hallmark lesion produced by the BRS is a dermonecrotic skin lesion, although there is a great range of venom manifestation. There are 3 categories of clinical signs in loxoscelism.31,36–38 The first clinical category incorporates the majority of all bites and is characterized by no clinical signs or local irritation. The bite is usually not felt by the victim or is described as a small pinch.39 Necrotic arachnidism, gangrenous arachnidism, or cutaneous loxoscelism are used to describe the second 332
category of clinical signs.1,5,36,37 These occur in approximately 4% of the cases12 and mild to severe pain may be encountered 2–8 hours post-envenomation. Transient pruritis and erythema may be noted initially, followed at 12–24 hours by a vesicle surrounded by ischemic tissue often called a bulls-eye or red, white, and blue lesion. During the subsequent 24–48 hours, the wound may progress to a necrotic lesion of dark blue or violet. At 3–7 days an eschar may form and the following week the area will become indurated. The eschar will subsequently fall off exposing an ulcer that may take up to 6–8 weeks to heal.4,12 The third category is progression to systemic disease or viscerocutaneous loxoscelism31 and is extremely rare, occurring in o1% of all BRSE cases12,39 that progressed to the second category. Children are the most susceptible to systemic loxoscelism.39,40 Mild systemic effects include fever, malaise, pruritis, exanthema, nausea, and vomiting.3 Prolonged coagulation times (depletion of FVIII, FIX, FXI, and FXII), thrombocytopenia, hemoglobinuria, proteinuria, intravascular hemolysis, and renal failure are all manifestations of systemic loxoscelism.25,37,41 Anemia, leukocytosis, elevated liver, and renal values are not uncommon findings with the most severe envenomations progressing to shock, pulmonary edema, renal failure, and death.1,42,43 One report documents 8 deaths from 1983 to 2004. However, in all cases the BRSE was presumed, with no definitive diagnosis.1 Diagnostic testing Diagnosing the envenomation of BRS or other Loxosceles species is difficult and has presented veterinarians and physicians with serious challenges. The lack of a definitive test has led to the rampant over-diagnosis of loxoscelism and subsequent inappropriate treatment. The inability to properly diagnose BRSE has led some to suggest reporting standards for the diagnosis of loxoscelism. The following are suggested criteria for grouping envenomations in the human patient. For a case to be classified as a proven envenomation, the spider must be recovered immediately and in close proximity to the clinical reaction on the skin. It also must be identified by an experienced entomologist or arachnologist. The specimen must be kept and complete records of case details, including follow-up and resolution, should be maintained. To be classified as probable envenomation, one must find a verified Loxosceles spider in the immediate vicinity, must be in a region where loxoscelism is medically known to occur, and the lesion must be wholly typical of the spider bite as defined by clinical experts. Possible envenomations must show a lesion typical of loxoscelism and must occur in an area considered endemic to the species.
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Focal necrosis of the skin is suggested as a diagnostic category when the region has no or few Loxosceles spiders, proven loxoscelism is uncommon and no Loxosceles spiders are recovered in the immediate vicinity of the patient. Recommended laboratory tests for suspected loxoscelism include baseline hemoglobin, hematocrit, and platelet counts as well as urinalysis for hemoglobinuria, hematuria, or proteinuria. Other testing recommended in higher risk patients should include full serum chemistries, including liver and renal screening, and lactate dehydrogenase. Full coagulation testing including prothrombin time, partial thromboplastin time, bleeding time, fibrinogen, and D-dimers are indicated if systemic disease is suspected.4,41 Biopsies are currently not recommended in human patients due to risk of scarring and lack of microscopic findings exclusive to loxoscelism. Histopathologic findings from rabbits injected with the venom are nonspecific. Early stages include edema, hemorrhage, degeneration of blood vessel walls, plasma exudation, thrombosis, neutrophil accumulation, and intensive diapedesis.1,12,44,45 As the disease progresses, the major changes noted are massive neutrophil infiltration into the tissues, hemorrhage, and subsequent myonecrosis.12,44–46 At the time of writing there are no commercially available tests for loxoscelism. A passive hemagglutinin inhibition test exhibited 90% specificity for diagnosing venom in guinea pigs 3 days after envenomation.47 An ELISA has shown the ability to detect venom in wound aspirates, hair follicles, and punch biopsies in rabbits 7 days post-envenomation.47 Cross-reactivity to other North American arthropod venoms was observed when higher venom amounts were assayed.47–50 In 2006, Missouri physicians diagnosed a BRSE by properly identifying the offending spider and submitting a swab sample for ELISA in which 34.4 pg of Loxosceles venom was recovered.50 Securing an accurate diagnosis is vital for properly treating the patient because large numbers of disease processes produce dermonecrotic lesions. If inaccurately diagnosed as loxoscelism, severe consequences can result. There are at least 50 differential diagnoses in the human patient (see Table 1). Lyme disease, cutaneous anthrax, chemical burns, and bacterial infections have all been initially misdiagnosed as BRSE in the human patient.1,8,14,39,51
Treatment Currently, no consensus exists for treatment of BRSE other than supportive care, which includes rest, thorough cleaning of the site, ice, compression, and elevation. Most treatment protocols attempt to attenuate the dramatic influx of neutrophils, activation of comple-
Table 1: A list of medical conditions that have been or could be misdiagnosed as loxoscelism Infections Atypical mycobacteria Streptococcus Staphylococcus (especially MRSA) Lyme borreliosis Cutaneous anthrax Syphilis Gonococcemia Ricketsial disease Tularemia Deep Fungal Sporotrichosis Aspergillosis Cryptococcosis Ecthyma gangrenosum (Pseudomonas aeruginosa) Parasitic (Leishmaniasis) Viral (herpes simplex, herpes zoster [shingles]) Vascular occlusive or venous disease Antiphospholipid-antibody syndrome Livedoid vasculopathy Small-vessel occlusive arterial disease Venous statis ulcer Necrotising vasculitis Leukocytoclastic vaculitis Polyarteritis nodosa Takayasu’s arteritis Wegeners granulomatosis Neoplastic disease Leukemia cutis Lymphoma (eg, mycosis fungoides) Primary skin neoplasms (basal cell carcinoma, malignant melanoma, squamous cell carcinoma) Lymphomatoid papulosis Topical and exogenous causes Burns (chemical, thermal) Toxic plant dermatitis (poison ivy, poison oak) Factitious injury (ie, self-induced) Pressure ulcers (ie, bed sores) Other arthropod bites Radiotherapy Other conditions Calcific uremic arteriolopathy Cryoglobulinemia Diabetic ulcer Langerhans’-cell histiocytosis Pemphigus vegetans Pyoderma gangrenosum Septic embolism Adapted from Swanson MD, Vetter RS. N Engl J Med 2005;352:700–707.
ment, and subsequent tissue destruction. Steroids, dapsone, antihistamines, colchicine, surgical excision, vasodilators, hyperbaric oxygen, antibiotics, anticoagulants, shock therapy, topical nitroglycerine, high doses of vitamin C, and meat tenderizer have all been proposed. To date, none of these have been consistently effective and in some cases have proven to be
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detrimental.1,8,46,51–53 Surgical excision, once widely recommended, has also fallen out of favor.8,46 Treatment of secondary manifestations such as demonstrated coagulopathies or bacterial infections should be considered when appropriate. Dapsone The use of dapsone is controversial due to mixed reports of efficacy but has been recommended as a potential therapy for the small animal veterinary patient by one author.4,8,20,37,39,40 Dapsone or diamino-diphenyl sulphone is an antimycobacterial used for the treatment of leprosy in both humans and felines as well as an alternative treatment for pemphigus in the small animal veterinary patient.54 It inhibits influx of neutrophils; however, adverse effects of dapsone can be severe and are similar to BRSE. Reported adverse effects include hepatotoxicity, anemia, thrombocytopenia, neutropenias, gastrointestinal signs, neuropathies, and cutaneous drug eruptions in the small animal veterinary patient.55 In humans who are deficient in glucose6-dehydrogenase, the hemolytic adverse effects can be catastrophic.8 Dapsone is ineffective if not given within hours of a bite.46,51,52 Because of severe adverse effects and lack of conclusive evidence, its administration is not recommended.1,8,12,36,52 Antivenin Specific antivenin has shown some success in animal studies when given within 1 hour of envenomation. Antigen binding fragments specific for anti-Loxosceles attenuate the lesion if given within 4 hours of the bite.5,56 In Brazil, loxoscelism is commonly diagnosed and treated with antivenins. The efficacy of antivenins in human retrospective studies suggests that a benefit may exist but there is no empirical evidence to support this.5,20,35 Tetracyclines Tetracycline protects against dermonecrosis in rabbits when topically applied as a lanolin cream but not when injected.57 Doxycycline was less effective than tetracycline but was still capable of preventing an increase in size of the lesion and oral administration of both tetracycline or doxycycline was much less effective possibly due to the level of concentration achieved.57 Tetracyclines have the ability to inhibit protein synthesis by binding the bacterial ribosomal subunit 30S, but they also have the ability to bind metal ions including calcium (Ca21) and zinc (Zn21). MMPs are a major group of enzymes regulating cell-matrix composition and are integral in normal and pathological processes
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including wound healing, inflammation, neovascularization, neoplasia, and embryogenesis. SMase D, the major component of Loxosceles venom, binds to the cell surface and activates MMPs including MMP-9, which plays a crucial role in diapedesis of neutrophils, lymphocytes, and eosinophils. Ca21 and Zn21 ions are required to maintain the correct conformation and hydrolytic activity of MMPs. In vivo studies report topical treatment with tetracycline considerably decreases MMP-2 and MMP-9 activity presumably by binding the metal ion.
Conclusion While the BRS is commonly associated with dermonecrotic lesions in the small animal veterinary patient, a diagnosis of BRSE should be made with extreme caution. These authors were unable to find any clinical research to support the belief that dermonecrotic lesions occur in canine or feline patients. In fact, only 2 in vivo studies were found that evaluated the effects of BRS venom in dogs.11,34 No similar studies using cats as subjects were found. Detection of venom from a hair shaft or from a properly prepared swab appears to have promise, but at the time of publication, these tests were not commercially available. Until the ELISA becomes commercially available, adhering strictly to the criteria for a documented bite, as proposed in the human literature, appears to be the most prudent course. Misdiagnosis of wounds leads to poor patient care and proliferates the distribution of misinformation about the BRS.
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Brown recluse spider envenomation 9. Morgan PN. Preliminary studies on venom from the brown recluse spider Loxosceles reclusa. Toxicon 1969; 6:161–165. 10. Futrell JM, Morgan BB, Morgan PN, et al. An in vitro model for studying hemolysis associated with venom from the brown recluse spider (Loxosceles reclusa). Toxicon 1979; 17:355–362. 11. Denny WF, Dillaha CJ, Morgan PN, et al. Hemotoxic effect of Loxosceles reclusa venom: in vivo and in vitro studies. J Lab Clin Med 1964; 64:291–298. 12. da Silva PH, da Silveira RB, Appel MH, et al. Brown spiders and loxoscelism. Toxicon 2004; 44:693–709. 13. Vetter RS. Arachnids submitted as suspected brown recluse spiders (Araneae: Sicariidae): Loxosceles spiders are virtually restricted to their known distributions but are perceived to exist throughout the United States. J Med Entomol 2005; 42: 512–521. 14. Vetter RS, Bush SP. Reports of presumptive brown recluse spider bites reinforce improbable diagnosis in regions of North America where the spider is not endemic. Clin Infect Dis 2002; 35:442–445. 15. Vetter RS, Cushing PE, Crawford RL, et al. Diagnoses of brown recluse spider bites (loxoscelism) greatly outnumber actual verifications of the spider in four western American states. Toxicon 2003; 42:413–418. 16. Vetter RS, Edwards GB, James LF. Reports of envenomation by brown recluse spiders (Araneae: Sicariidae) outnumber verifications of Loxosceles spiders in Florida. J Med Entomol 2004; 41: 593–597. 17. Frithsen IL, Vetter RS, Stocks IC. Reports of envenomation by brown recluse spiders exceed verified specimens of Loxosceles spiders in South Carolina. J Am Board Fam Med 2007; 20: 483–488. 18. Vetter RS, Barger DK. An infestation of 2,055 brown recluse spiders (Araneae:Sicariidae) and no envenomations in a Kansas home: implications for bite diagnoses in nonendemic areas. J Med Entomol 2002; 39:948–951. 19. Vetter RS. Spiders of the genus Loxosceles (Araneae, Sicariidae): a review of biological, medical and psychological aspects regarding envenomations. J Arachnol 2008; 36:150–163. 20. Gendron BP. Loxosceles reclusa envenomation. Am J Vet Med 1990; 8:51–54. 21. Russell FE. Snake Venom Poisoning. Philadelphia: J. Lippincott Company; 1980, 154pp. 22. Binford GJ, Cordes MHJ, Wells MA. Sphingomyelinase D from venoms of Loxosceles spiders: evolutionary insights from cDNA sequences and gene structure. Toxicon 2005; 45:547–560. 23. Tambourgi DV, Magnoli FC, van den Berg CW, et al. Sphingomyelinases in the venom of the spider Loxosceles intermedia are responsible for both dermonecrosis and complementdependent hemolysis. Biomed Biophys Res Commun 1998; 251: 366–373. 24. van Meeteren LA, Giepmans BNG, Pedrosa MFF, et al. Spider and bacterial sphingomyelinases D target cellular lysophosphatidic acid receptors by hydrolyzing lysophosphatidylcholine. J Biol Chem 2004; 279:10833–10836. 25. Van Den Berg CW, Goncalves de Anrade RM, et al. Loxosceles spider venom induces the release of thrombomodulin and endothelial protein C receptor: implications for the pathogenesis of intravascular coagulation as observed in loxoscelism. Clin Appl Thromb Hemost 2007; 5:989–995. 26. Tambourgi DV, da Silva MS, Billington SJ, et al. Mechanism of induction of complement susceptibility of erythrocytes by spider and bacterial sphingomyelinases. Immunology 2002; 107: 93–101. 27. Tambourgi DV, Fernandes Pedrosa MF, Concalves de Andrade RM, et al. Sphingomyelinases D induce direct association of C1q to the erythrocyte membrane causing complement mediated autologous haemolysis. Mol Immunol 2007; 44:576–582. 28. de Andrade SA, Murakami MT, Cavalcante DP, et al. Kinetic and mechanistic characterization of the sphingomyelinases D from Loxosceles intermedia spider venom. Toxicon 2006; 47:380–386.
29. Tambourgi DV, Paixao-Cavalcante D, Concalves de Andrade RM, et al. Loxosceles sphingomyelinase induces complement-dependent dermonecrosis, neutrophil infiltration, and endogenous gelatinase expression. J Invest Dermatol 2005; 124:725–731. 30. Paixao-Cavalcante D, van den Berg CW, Fernandes-Pedrosa MF, et al. Role of matrix metalloproteinases in HaCaT keratinocytes apoptosis induced by Loxosceles venom sphingomyelinase D. J Invest Dermatol 2006; 126:61–68. 31. de Oliveira KC, de Andrade RM, Piazza RMF, et al. Variations in Loxosceles spider venom composition and toxicity contribute to the severity of envenomation. Toxicon 2005; 45:421–429. 32. Davidson JM. Animal models for wound repair. Arch Dermatol Res 1998; 290(14):S1–S11. 33. Isbister GK, Seymour JE, Gray MR, et al. Bites by spiders of the family Theraphosidae in humans and canines. Toxicon 2003; 41:519–524. 34. Schenone H, Letonja T, Knierim F. Algunos datos sobre el aparato venenoso de Loxosceles laeta y toxicidad de su veneno sobre diversas especies animales (esp). Bol Chil Parasitol 1975; 30: 37–42. 35. Pauli I, Puka J, Gubert IC, et al. The efficacy of antivenom in loxoscelism treatment. Toxicon 2006; 48:123–137. 36. Dyachenko P, Ziv M, Rozenman D. Epidemiological and clinical manifestations of patients hospitalized with brown recluse spider bite. J Eur Acad Dermatol Venereol 2006; 20:1121–1125. 37. Malaque CM, Castro-Valencia JE, Cardoso JLC, et al. Clinical and epidemiological features of definitive and presumed loxoscelism in Sao Paulo, Brazil. Rev Inst Med Trop Sao Paulo 2002; 44:139–143. 38. Gomez HF, Greenfield DM, Miller MJ, et al. Direct correlation between diffusion of Loxosceles reclusa venom and extent of dermal inflammation. Acad Emerg Med 2001; 8:309–314. 39. Wendell RP. Brown recluse spiders: a review to help guide physicians in non-endemic areas. South Med J 2003; 98: 486–490. 40. Glenn JB, Lane JE, Clark EK. Arachnid envenomation from the brown recluse spider. Clin Pediatr 2003; 42:567–570. 41. Chaim OM, Sade YB, da Silveira RB, et al. Brown spider dermonecrotic toxin directly induces nephrotoxicity. Toxicol Appl Pharmacol 2006; 211:64–77. 42. de Oliveira Christoff A, de Oliveira A, Chaim OM, et al. Effects of the venom and the dermonecrotic toxin LiRecDT1 of Loxosceles intermedia in the rat liver. Toxicon 2008; 52:695–704. 43. Bey TA, Walter FG, Lober W, et al. Loxosceles arizonica bite associated with shock. Ann Emerg Med 1997; 30:701–703. 44. Zanetti VC, da Silveira, Dreyfuss JL, et al. Morphological and biochemical evidence of blood vessel damage and fibrinogenolysis triggered by brown spider venom. Blood Coagul Fibrinolysis 2002; 13:135–148. 45. Schwartz RA. Brown recluse spider bite. Available at: http://emedicine.medscape.com/article/1088714-overview. Accessed October 6, 2009. 46. Ospedal KZ, et al. Histopathological findings in rabbits after experimental acute exposure to the Loxosceles intermedia (brown spider) venom. Int J Exp Pathol 2002; 84:287–294. 47. Krywko DM, Gomez HF. Detection of Loxosceles venom in dermal lesions: a comparison of 4 venom recovery methods. Ann Emerg Med 2002; 39:475–480. 48. Barrett SM, Romine-Jenkins M, Blick KE, et al. Passive hemagglutination inhibition test for diagnosis of brown recluse spider bite envenomation. Clin Chem 1993; 39:2104–2107. 49. Gomez HF, Krywko DM, Stoecker WV. A new assay for the detection of Loxosceles species (brown recluse) spider venom. Ann Emerg Med 2002; 39:469–474. 50. Stoecker WV, Green JA, Gomez HF. Diagnosis of loxoscelism in a child confirmed with an enzyme-linked immunosorbent assay and noninvasive tissue sampling. J Am Acad Dermatol 2006; 55:888– 890. 51. Osterhoudt KC, Zaoutis T, Zorc JJ. Lyme disease masquerading as brown recluse spider bite. Ann Emerg Med 2002; 39:558–561.
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55. Plumb DC. Dapsone in: Plumb’s Veterinary Drug Handbook, 6th ed. Ames: Blackwell Publishing, pp. 338–340. 56. Gomez HF, Miller MJ, Trachy JW, et al. Intradermal anti-Loxosceles Fab fragments attenuate dermonecrotic arachnidism. Acad Emerg Med 1999; 6:1195–1202. 57. Paixao-Cavalcante D, van den Berg CW, Concalves de Andrade RM, et al. Tetracycline protects against dermonecrosis induced by Loxosceles spider venom. J Invest Dermatol 2007; 127:1410–1418.
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Journal of Veterinary Emergency and Critical Care 19(4) 2009, pp 329–336 doi:10.1111/j.1476-4431.2009.00440.x
Brown recluse spider (Loxosceles reclusa) envenomation in small animals Lonny B. Pace, DVM and Richard S. Vetter, MS
Abstract Objective – To provide a comprehensive review of relevant literature regarding the brown recluse spider (BRS) and to define those criteria that must be satisfied before making a diagnosis of brown recluse envenomation. Etiology – The complex venom of the BRS contains sphingomyelinase D, which is capable of producing all the clinical signs in the human and some animal models. Diagnosis – There is no current commercially available test. In humans there are many proposed guidelines to achieve a definitive diagnosis; however, there are no established guidelines for veterinary patients. Therapy – Currently, no consensus exists for treatment of BRS envenomation other than supportive care, which includes rest, thorough cleaning of the site, ice, compression, and elevation. Prognosis – Prognosis varies based on severity of clinical signs and response to supportive care. (J Vet Emerg Crit Care 2009; 19(4): 329–336) doi: 10.1111/j.1476-4431.2009.00440.x
Keywords: dermonecrotic, Loxosceles, matrix metalloproteinases, sphingomyelinase D
Introduction Brown recluse spiders (BRS), Loxosceles reclusa, are considered, in human and veterinary medicine, to be one of the most clinically important spiders in North America. In spite of their importance, there is a paucity of veterinary literature addressing arachnid-companion animal BRS envenomation (BRSE). Almost all available recommendations regarding the effects of BRSE in companion animals is extrapolated from bite manifestations in humans. In 1872, Caveness became the first clinician to report specific symptoms following an assumed brown recluse spider bite (BRSB) in a human. In 1928, Schmaus was the first to report symptoms following a documented BRSB and Macchiavello, in 1937, reported that dermonecrotic lesions were associated with the South American species, Loxosceles laeta. In 1957, Atkins and colleagues1 definitively identified BRS venom as a potential source of necrotic lesions. A definitive diagnosis is difficult to obtain and clinicians From the Central California Veterinary Specialty Center, Fresno, CA 93710 (Pace); the Department of Entomology, University of California, Riverside, CA 92521 and Biology Division, San Bernardino County Museum, Redlands, CA, 92373 (Vetter). The authors have declared no conflicts. Address correspondence and reprint requests to Dr. Lonny B. Pace, Central California Veterinary Specialty Center, Fresno, CA 93710, USA. Email: [email protected] & Veterinary Emergency and Critical Care Society 2009
must base their diagnosis on multiple criteria including geography, clinical signs, and preferably, authoritative identification of the spider. While Loxosceles spiders are distributed throughout the world, the endemic range of the BRS is limited, even within the United States.1 The biology, natural history, and distribution of Loxosceles spiders are poorly documented. Unfortunately, numerous clinical cases are based on presumptive bites that lead to misconceptions and misdiagnoses.2,3 BRS venom is highly complex with only some of the components described in the literature. Still, the manifestations of envenomation are highly variable and are intimately linked with the body’s immune response. Clinical signs range from minor local irritations to death.1,4–7 Diagnosis of BSRE remains problematic because there is no specific laboratory test to facilitate diagnosis and histopathology is nonspecific.1 The absence of a broadly accepted treatment protocol in human literature adds confusion,8–12 so caution must be exercised when extrapolating from human data.
The Spider Range Loxosceles spiders are indigenous in the temperate regions of the Americas, Africa, and Europe. Of the approximately 100 species, over 80% are found in the Americas. Within the United States there are 11 indig329
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enous and 2 nonindigenous species.8 Many species exist in areas devoid of human populations or are extremely rare, with few documented specimens.13 The distribution of the BRS in the United States is primarily Midwestern (see Figure 1). Other species dwell in the sparsely inhabited deserts from southeastern California through Texas.13,14 Despite the well-established range of Loxosceles spiders, medical professionals continue to diagnose BRSE in areas not endemic to the spider. In 1 study, medical professionals reported 216 BRSE within 41 months in Colorado, Washington, California, and Oregon; however, only 35 verified BRS, or Mediterranean brown spiders, have ever been found in these states.15 In a separate 6 year study, medical personnel from 3 Florida poison control centers reported 124 BRSB; however, in the past 100 years there have been only 11 Florida sites, where Loxosceles spiders have been identified by arachnologists and most of these were single specimen reports.16 In 2004, South Carolina physicians diagnosed 738 BRSE despite the fact that only 44 BRS had been verified in 6 locations since 1953.17 Skeptics argue that interstate transplantation of the spider could occur during household relocations and may account for bites out of the reported range. However, the sheer number of people moving and goods being shipped between endemic and nonendemic areas is not proportional to the very small number of BRS found outside of the range. The BRS has not shown the ability to readily expand its range. The heightened awareness of BRS outside of their range also exists for the general public. In a 4.5 year study, identifying any creature suspected to be a Loxosceles spider, 1773 arachnids were submitted to the University of California Riverside from 49 states.13 Of
Figure 1: Map of the distribution of the most widespread Loxosceles spiders in North America. Recluse spiders will be common and frequently encountered in the middle of their range but will dissipate toward the margins as the populations diminish to nonexistence.
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these, 324 BRS were submitted, with only 2 finds emanating from outside the reported range. Of the many patients from nonendemic Loxosceles areas, who were diagnosed with a BRSE and subsequently submitted a spider for identification, not one was a recluse. One Texas medical school was using non-Loxosceles spiders (Kukulcania hibernalis, Psilochorus sp.) as teaching specimens of BRS for their medical students. Pest control personnel, county health officials, and a veterinarian also made misidentifications.13 Identification The mature BRS is 8–13 mm in body length, with legs measuring 20–30 mm. They tend to be brown, but shades may vary from light or yellow-brown to graybrown. The BRS has a characteristic violin shape on its dorsal cephalothorax, which may not be evident in immature spiders. Instead of the usual 8 eyes found in most spiders, Loxosceles spiders have 6 eyes arranged in pairs called dyads positioned on both lateral aspects and anteriorally8,12 (see Figure 2). As a way of identifying a Loxosceles spider, the eye pattern is far more diagnostic and less readily misinterpreted than the violin pattern. The spider’s fangs open in a side-to-side manner placing them in the suborder, Araneomorphae. This distinguishes them from tarantulas and Australian funnel web spiders, which have parallel fangs. Their legs are long in comparison with their body and have fine recumbent hairs. Natural history The BRS is found either indoors or out and true to its name, is usually reclusive by nature preferring dark
Figure 2: Brown recluse spider, Loxosceles reclusa. Although the violin mark is conspicuous in this spider, it is not as well demarcated in other species or immatures. The 6-eye pattern is more diagnostic for identification.
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areas. In nature, it prefers to remain beneath rocks and under tree bark. However, Loxosceles spiders easily cohabitate within human domiciles, being commonly found under clothes piles, bedding, in or under boxes, in cellars, and any other undisturbed areas. The BRS is reluctant to bite and given its shy nature, human envenomation rarely occurs. In a 6-month period, 2055 BRS were found in 1 Kansas home. Despite this infestation, none of the occupants reported a bite18 during the study or in the 5.5 years prior, although, in the 11th year of home occupancy, the first known bite did occur in this highly infested house.19 The spiders are more active in the warmer months but can withstand temperatures from 8–431C.1,20 BRSs are nocturnal, hunting spiders, are not prolific web spinners but do produce a cottony, irregular-shaped web as a retreat. They do not use webs to capture prey although the web may alert a spider to the presence of a temporarily entangled insect that they attack quickly then retreat until the venom paralyses the creature. They can live for 6–12 months without food and water.19 In the laboratory setting these spiders have lived 1755 days, with the average female living 627 days. Newly emerged spiderlings of Loxosceles intermedia lack the potentially dangerous venom components, which are not detectable until the third-instar spiderling (ie, an instar is the growth period between 2 successive molts in arthropods).12 Venom Loxosceles spider venom is a complex mixture of components creating literally a constellation of different clinical signs ranging from local to systemic. At least 8 subcomponents have been found within the venom including the 35 kDa protein sphingomyelinase D (SMase D), hyaluronidase, alkaline phosphatase, collagenase, esterase, ribonuclease, deoxyribonuclease, and several different proteases.3,4 The complex venom is remarkable when considering the amount of venom injected compared with the severity of the clinical signs. The average amount of venom injected by the Eastern diamondback rattlesnake is 200–850 mg21 compared with Loxosceles envenomation of 30–65 mg of protein.7,12 There are 4 major phospholipids in the mammalian cell membrane including sphingomyelin, which is mostly found in the membrane’s outer leaflet. Phospholipases like SMase D are common components of animal venoms. In the animal kingdom, SMase D is found only in Loxosceles spiders and close taxonomic relatives of the genus Sicarius (found in African and South America).22 The only other known source of SMase D is an exotoxin from certain Corynebacterium spp, and Arcanobacterium hemolyticum.22
A full understanding on how 30 mg of venom can cause extensive local tissue injury and sometimes develop into life-threatening systemic disease is the subject of active research. SMase D is capable of inducing all the clinical signs of whole venom.23 It will activate endogenous matrix metalloproteinases (MMPs), cleaving sphingomyelin into its 2 components, ceramide1-phosphate and choline and catalyzing the release of choline from albumin-bound lysophosphatidylcholine in the presence of Mg21.24 The hydrolysis of albuminbound lysophosphatidylcholine creates lysophosphatidic acid and choline. Lysophosphatidic acid stimulates platelet aggregation, causing endothelial hyperpermeability, and is strongly proinflammatory.24 Loxosceles spider venom activates certain MMPs. Activation of these endopeptidases is suspected to be one source of the massive neutrophilic infiltration seen in envenomation and likely has other roles in the wound propagation. SMase D changes and cleaves proteins on the surface of the erythrocyte, activating both classic and alternative complement cascades. This leads to the formation of the membrane attack complex and subsequent cellular lysis. SMase D is capable of antagonizing activation of protein C, potentially creating a procoagulatory state.25 Induction of complement, activation of MMPs, alteration of transmembrane proteins, preventing activation of protein C, and apoptosis appear to be involved in the propagation of the profound immune response leading to dermonecrosis.22,23,26–30 The female spider has a higher biological activity suggesting its venom is more toxic and likely accounting for some of the variability between bites.31 The variability of responses to BRSE in veterinary medicine Research involving BRSE in companion animals is almost nonexistent. Veterinary literature extrapolates data from the human literature without evidence that dogs and cats will follow the human model. There is tremendous variability to spider envenomation among mammalian species,9,32–34 hence, extrapolation could lead to grievous errors. As an example of the extremes that can manifest in mammals in response to a spider bite, an Australian report retrospectively documented bites from theraphosid spiders (ie, tarantulas) on humans and dogs over 23 years. The 9 human victims suffered mild effects, including pain and puncture marks, while all 7 dogs died. Two of the dogs were in the human weight range (40–50 kg) and in 2 cases, the same spider envenomated both the human and the dog with widely dichotomous outcome for the bite victims.33 Similarly, Loxosceles venom also produces differential mammalian toxicity. Rats and mice do not
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develop dermonecrotic lesions from Loxosceles spider venom while guinea pigs and rabbits do, although there appears to be variability between studies.6,8 BRS venom will lyse erythrocytes of humans and pigs, but not those of dogs, rats, or guinea pigs.10,11 The in vivo effects of BRS venom on 9 dogs demonstrated that following intravenous injection, all animals developed poor feeding, dehydration, and apathy with 2 progressing to jaundice and bleeding manifestations after 24 hours. A striking reticulocytopenia was noted in all patients within 2 hours of injection along with increased hemoglobin, and corresponding decreases in hematocrit suggesting red cell lysis and corresponding elevation of free hemoglobin. Coombs test and liver function tests were all negative with the exception of transient indirect bilirubinemia in the 2 severely affected animals. All dogs recovered fully within 72–120 hours.11 It is difficult to extrapolate too much information from this study as envenomations are usually intradermal not intravenous. A Chilean study34 rated susceptibility based on weight/dose relationships in several different animals to L. laeta venom. Rabbits, mice, guinea pigs, and dogs were rated as high susceptibility; hamsters, pigeons, chickens, and toads had moderate susceptibility; frogs were low; and rats and fish exhibited no response to the venom. Dogs (n 5 2) succumbed to the venom after the contents of 417 venom glands (8.5 spiders cumulative venom) were injected intradermally while dogs (n 5 4) injected with 1–15 glands survived with no effects. Intradermal injections of 0.75–3 venom glands/kg in these dogs caused only small local lesions while similar injections in rabbits reproduced the same dermonecrotic lesion as seen in humans.34 However, even with rabbits, there is a different response compared with humans in that rabbits heal more quickly and do not develop chronic ulceration.35
Clinical Implications of the BRSB Clinical signs Because of the paucity of primary research performed on Loxosceles venom in companion animals, the descriptions of clinical signs are based primarily on the human response to BRSE. In humans, the hallmark lesion produced by the BRS is a dermonecrotic skin lesion, although there is a great range of venom manifestation. There are 3 categories of clinical signs in loxoscelism.31,36–38 The first clinical category incorporates the majority of all bites and is characterized by no clinical signs or local irritation. The bite is usually not felt by the victim or is described as a small pinch.39 Necrotic arachnidism, gangrenous arachnidism, or cutaneous loxoscelism are used to describe the second 332
category of clinical signs.1,5,36,37 These occur in approximately 4% of the cases12 and mild to severe pain may be encountered 2–8 hours post-envenomation. Transient pruritis and erythema may be noted initially, followed at 12–24 hours by a vesicle surrounded by ischemic tissue often called a bulls-eye or red, white, and blue lesion. During the subsequent 24–48 hours, the wound may progress to a necrotic lesion of dark blue or violet. At 3–7 days an eschar may form and the following week the area will become indurated. The eschar will subsequently fall off exposing an ulcer that may take up to 6–8 weeks to heal.4,12 The third category is progression to systemic disease or viscerocutaneous loxoscelism31 and is extremely rare, occurring in o1% of all BRSE cases12,39 that progressed to the second category. Children are the most susceptible to systemic loxoscelism.39,40 Mild systemic effects include fever, malaise, pruritis, exanthema, nausea, and vomiting.3 Prolonged coagulation times (depletion of FVIII, FIX, FXI, and FXII), thrombocytopenia, hemoglobinuria, proteinuria, intravascular hemolysis, and renal failure are all manifestations of systemic loxoscelism.25,37,41 Anemia, leukocytosis, elevated liver, and renal values are not uncommon findings with the most severe envenomations progressing to shock, pulmonary edema, renal failure, and death.1,42,43 One report documents 8 deaths from 1983 to 2004. However, in all cases the BRSE was presumed, with no definitive diagnosis.1 Diagnostic testing Diagnosing the envenomation of BRS or other Loxosceles species is difficult and has presented veterinarians and physicians with serious challenges. The lack of a definitive test has led to the rampant over-diagnosis of loxoscelism and subsequent inappropriate treatment. The inability to properly diagnose BRSE has led some to suggest reporting standards for the diagnosis of loxoscelism. The following are suggested criteria for grouping envenomations in the human patient. For a case to be classified as a proven envenomation, the spider must be recovered immediately and in close proximity to the clinical reaction on the skin. It also must be identified by an experienced entomologist or arachnologist. The specimen must be kept and complete records of case details, including follow-up and resolution, should be maintained. To be classified as probable envenomation, one must find a verified Loxosceles spider in the immediate vicinity, must be in a region where loxoscelism is medically known to occur, and the lesion must be wholly typical of the spider bite as defined by clinical experts. Possible envenomations must show a lesion typical of loxoscelism and must occur in an area considered endemic to the species.
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Focal necrosis of the skin is suggested as a diagnostic category when the region has no or few Loxosceles spiders, proven loxoscelism is uncommon and no Loxosceles spiders are recovered in the immediate vicinity of the patient. Recommended laboratory tests for suspected loxoscelism include baseline hemoglobin, hematocrit, and platelet counts as well as urinalysis for hemoglobinuria, hematuria, or proteinuria. Other testing recommended in higher risk patients should include full serum chemistries, including liver and renal screening, and lactate dehydrogenase. Full coagulation testing including prothrombin time, partial thromboplastin time, bleeding time, fibrinogen, and D-dimers are indicated if systemic disease is suspected.4,41 Biopsies are currently not recommended in human patients due to risk of scarring and lack of microscopic findings exclusive to loxoscelism. Histopathologic findings from rabbits injected with the venom are nonspecific. Early stages include edema, hemorrhage, degeneration of blood vessel walls, plasma exudation, thrombosis, neutrophil accumulation, and intensive diapedesis.1,12,44,45 As the disease progresses, the major changes noted are massive neutrophil infiltration into the tissues, hemorrhage, and subsequent myonecrosis.12,44–46 At the time of writing there are no commercially available tests for loxoscelism. A passive hemagglutinin inhibition test exhibited 90% specificity for diagnosing venom in guinea pigs 3 days after envenomation.47 An ELISA has shown the ability to detect venom in wound aspirates, hair follicles, and punch biopsies in rabbits 7 days post-envenomation.47 Cross-reactivity to other North American arthropod venoms was observed when higher venom amounts were assayed.47–50 In 2006, Missouri physicians diagnosed a BRSE by properly identifying the offending spider and submitting a swab sample for ELISA in which 34.4 pg of Loxosceles venom was recovered.50 Securing an accurate diagnosis is vital for properly treating the patient because large numbers of disease processes produce dermonecrotic lesions. If inaccurately diagnosed as loxoscelism, severe consequences can result. There are at least 50 differential diagnoses in the human patient (see Table 1). Lyme disease, cutaneous anthrax, chemical burns, and bacterial infections have all been initially misdiagnosed as BRSE in the human patient.1,8,14,39,51
Treatment Currently, no consensus exists for treatment of BRSE other than supportive care, which includes rest, thorough cleaning of the site, ice, compression, and elevation. Most treatment protocols attempt to attenuate the dramatic influx of neutrophils, activation of comple-
Table 1: A list of medical conditions that have been or could be misdiagnosed as loxoscelism Infections Atypical mycobacteria Streptococcus Staphylococcus (especially MRSA) Lyme borreliosis Cutaneous anthrax Syphilis Gonococcemia Ricketsial disease Tularemia Deep Fungal Sporotrichosis Aspergillosis Cryptococcosis Ecthyma gangrenosum (Pseudomonas aeruginosa) Parasitic (Leishmaniasis) Viral (herpes simplex, herpes zoster [shingles]) Vascular occlusive or venous disease Antiphospholipid-antibody syndrome Livedoid vasculopathy Small-vessel occlusive arterial disease Venous statis ulcer Necrotising vasculitis Leukocytoclastic vaculitis Polyarteritis nodosa Takayasu’s arteritis Wegeners granulomatosis Neoplastic disease Leukemia cutis Lymphoma (eg, mycosis fungoides) Primary skin neoplasms (basal cell carcinoma, malignant melanoma, squamous cell carcinoma) Lymphomatoid papulosis Topical and exogenous causes Burns (chemical, thermal) Toxic plant dermatitis (poison ivy, poison oak) Factitious injury (ie, self-induced) Pressure ulcers (ie, bed sores) Other arthropod bites Radiotherapy Other conditions Calcific uremic arteriolopathy Cryoglobulinemia Diabetic ulcer Langerhans’-cell histiocytosis Pemphigus vegetans Pyoderma gangrenosum Septic embolism Adapted from Swanson MD, Vetter RS. N Engl J Med 2005;352:700–707.
ment, and subsequent tissue destruction. Steroids, dapsone, antihistamines, colchicine, surgical excision, vasodilators, hyperbaric oxygen, antibiotics, anticoagulants, shock therapy, topical nitroglycerine, high doses of vitamin C, and meat tenderizer have all been proposed. To date, none of these have been consistently effective and in some cases have proven to be
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detrimental.1,8,46,51–53 Surgical excision, once widely recommended, has also fallen out of favor.8,46 Treatment of secondary manifestations such as demonstrated coagulopathies or bacterial infections should be considered when appropriate. Dapsone The use of dapsone is controversial due to mixed reports of efficacy but has been recommended as a potential therapy for the small animal veterinary patient by one author.4,8,20,37,39,40 Dapsone or diamino-diphenyl sulphone is an antimycobacterial used for the treatment of leprosy in both humans and felines as well as an alternative treatment for pemphigus in the small animal veterinary patient.54 It inhibits influx of neutrophils; however, adverse effects of dapsone can be severe and are similar to BRSE. Reported adverse effects include hepatotoxicity, anemia, thrombocytopenia, neutropenias, gastrointestinal signs, neuropathies, and cutaneous drug eruptions in the small animal veterinary patient.55 In humans who are deficient in glucose6-dehydrogenase, the hemolytic adverse effects can be catastrophic.8 Dapsone is ineffective if not given within hours of a bite.46,51,52 Because of severe adverse effects and lack of conclusive evidence, its administration is not recommended.1,8,12,36,52 Antivenin Specific antivenin has shown some success in animal studies when given within 1 hour of envenomation. Antigen binding fragments specific for anti-Loxosceles attenuate the lesion if given within 4 hours of the bite.5,56 In Brazil, loxoscelism is commonly diagnosed and treated with antivenins. The efficacy of antivenins in human retrospective studies suggests that a benefit may exist but there is no empirical evidence to support this.5,20,35 Tetracyclines Tetracycline protects against dermonecrosis in rabbits when topically applied as a lanolin cream but not when injected.57 Doxycycline was less effective than tetracycline but was still capable of preventing an increase in size of the lesion and oral administration of both tetracycline or doxycycline was much less effective possibly due to the level of concentration achieved.57 Tetracyclines have the ability to inhibit protein synthesis by binding the bacterial ribosomal subunit 30S, but they also have the ability to bind metal ions including calcium (Ca21) and zinc (Zn21). MMPs are a major group of enzymes regulating cell-matrix composition and are integral in normal and pathological processes
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including wound healing, inflammation, neovascularization, neoplasia, and embryogenesis. SMase D, the major component of Loxosceles venom, binds to the cell surface and activates MMPs including MMP-9, which plays a crucial role in diapedesis of neutrophils, lymphocytes, and eosinophils. Ca21 and Zn21 ions are required to maintain the correct conformation and hydrolytic activity of MMPs. In vivo studies report topical treatment with tetracycline considerably decreases MMP-2 and MMP-9 activity presumably by binding the metal ion.
Conclusion While the BRS is commonly associated with dermonecrotic lesions in the small animal veterinary patient, a diagnosis of BRSE should be made with extreme caution. These authors were unable to find any clinical research to support the belief that dermonecrotic lesions occur in canine or feline patients. In fact, only 2 in vivo studies were found that evaluated the effects of BRS venom in dogs.11,34 No similar studies using cats as subjects were found. Detection of venom from a hair shaft or from a properly prepared swab appears to have promise, but at the time of publication, these tests were not commercially available. Until the ELISA becomes commercially available, adhering strictly to the criteria for a documented bite, as proposed in the human literature, appears to be the most prudent course. Misdiagnosis of wounds leads to poor patient care and proliferates the distribution of misinformation about the BRS.
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