L: Natural Toxins and Envenomations

TAXONOMY

Arthropoda means “joint-footed” in Latin and describes arthropods’ jointed bodies and legs connected to a chitinous exoskelelton.⁵ The majority of arthropods are benign to humans and environmentally beneficial. Some clinicians regard bites and stings as inconsequential and more of a nuisance than a threat to life. However, some spiders have toxic venoms that can produce dangerous, painful lesions or significant systemic effects. Important clinical syndromes are produced by bites or stings from animals in the phylum Arthropoda, specifically the classes Arachnida (spiders, scorpions, and ticks) and Insecta (bees, wasps, hornets, and ants) (Table 118–1). Infectious diseases transmitted by arthropods, such as the various encephalitides, Rocky Mountain spotted fever, human anaplasmosis, babesiosis, and Lyme disease, are not discussed in this chapter.

Arthropoda comprises the largest phylum in the animal kingdom. It includes more species than all other phyla combined (Fig. 118–1).⁵ At least 1.5 million species are identified, and half a million or more are yet to be classified. Araneism (pertaining to spiders) or arachnidism (spiders including other arachnids) results from the envenomation caused by a ­spider bite. “Bites” are different from “stings.” Bites are defined as creating a wound using the oral pole with the intention for either catching or envenomating prey or blood feeding,^96,195 or for the purpose of feeding such as in arthropods that have mouthparts for chewing or sucking (plant sucking). “Stings” occur from a modified ovipositor at the aboral pole that is also able to function in egg laying as in bees and wasps. In scorpions the sting is not a modified ovipositor and the “tail” is not a tail but the metasoma section of the abdomen. Stinging behavior typically is used for defense. Most spiders are venomous, and the venom weakens the prey, enabling the spider to secure and digest their prey. However, there is one family of spiders, Uloboridae, which do not have a venom gland, a venom duct, or duct opening in the fangs. Spiders in general are not aggressive toward humans unless they are provoked. The chelicerae (mouthparts comprised of basal section and hinged fang) of many species have fangs that are too short to penetrate human skin.

Spiders can be divided into categories based on whether they pursue their prey as hunters or trappers. Trappers snare their prey by spinning webs, then feed on their prey and enshrine excess victims in a cocoon silk to be eaten later. The order of spiders (Araneae) differs from other members of the class (Arachnida) because of various anatomic differences best assessed by an entomologist/arachnologist. Simplistically, the arachnids have four pairs of joined legs whereas insects have three pairs. The arachnid’s body is divided into two parts (cephalothorax and unsegmented abdomen, except for some spiders in Mesothelae and also some Mygalomorph {tarantula-type} relatives that have abdominal plates) connected by a small pedicel and two, three, or four pairs (Mesothelae contain up to six pairs) of spinnerets from which silk is spun. Two pedipalps are attached anteriorly on the cephalothorax on either side of their chelicerae and are used for sensation, manipulation of food and objects, and in males are modified for sperm transfer. Spiders have eight eyes, although there are instances when they have two, four, six, or even no eyes and are quite myopic. Prey is localized by touch as they land in the spider’s web, though not all spiders produce webs and use silk to capture prey. Most spiders use venom to kill or immobilize their prey. The spiders of medical importance in the United States include the widow spiders (Latrodectus spp), the violin spiders (Loxosceles spp), and the hobo spider (Tegenaria agrestis). Although there is some disagreement as to the extent of the danger of hobos in the United States, hobos are not considered dangerous in Europe. In Australia, the funnel web spider (Atrax robustus) and Hadronyche species can cause serious illness and death. In South America, the Brazilian Huntsmen (Phoneutria fera) and Arantia Armedeira (Phoneutria nigriventer) are threats to humans.

HISTORY AND EPIDEMIOLOGY

Since the time of Aristotle, spiders and their webs were used for medicinal purposes. Special preparations were concocted to cure a fantastic array of ailments, including earache, running of the eyes, “wounds in the joints,” warts, gout, asthma, “spasmodic complaints of females,” chronic hysteria, cough, rheumatic afflictions for the head, and stopping blood flow.²²⁷

One Latrodectus species has an infamous history of medical concern, hence the name mactans, which means “murderer” in Latin.¹⁸³ Hysteria regarding spider bites peaked during the 17th century in the Taranto region of Italy. The syndrome tarantism, which is characterized by lethargy, stupor, and a restless compulsion to walk or dance, was blamed on Lycosa tarantula, a spider that pounces on its prey like a wolf. Deaths were associated with these outbreaks. Dancing the rapid tarantella to music was the presumed remedy. The real culprit in this epidemic was Latrodectus tredecimguttatus.¹⁸³ Other epidemics of arachnidism occurred in Spain in 1833 and 1841.¹⁵⁶ In North America, there was an increase in spider exposures during the late 1920s; Rome reported large numbers in 1953; Yugoslavia reported a large number of cases between 1948 and 1953.^33,156 These epidemics may be related to actual reporting biases as well as climatic variations.¹⁸³ Spider bites are more numerous in warmer months, presumably because both spiders and humans are more active during that season.

Approximately 200 species of spiders are associated with envenomations.^192,196 Eighteen genera of North American spiders produce poisonings that require clinical intervention (Table 118–2). In one series of 600 suspected spider bites, 80% were determined to result from arthropods other than spiders, such as ticks, bugs, mites, fleas, moths, butterflies, caterpillars, flies, beetles, water bugs, and some members (ants, bees, wasps) of order Hymenoptera. Ten percent of the presumed bites actually were manifestations of other nonarthropod disorders.^194,196

From 2006 to 2007, an annual average of 14,000 spider exposures and 44,000 insect exposures were reported to US poison centers.^36,40 No more than two fatalities were reported per year. One was from the Hymenoptera category, and the other was an unknown spider exposure.³⁶ However, from 2008 to 2011 the annual average of spider and insect exposures declined to 10,900 and 39,600 exposures, respectively.^37,38,39,41 Fatalities again were low. In 2008, one death was reported as caused by scorpion exposure; in 2009, one death was reported as caused by an “other insect bite/sting”; in 2010, two deaths were reported from bee stings and one death from an “other spider bite”^37,38,39 (Chap. 136).

Most information on the clinical presentation of spider bites continues to be unreliable because it is based on case reports and case series. Frequently, the cases do not have any expert confirmation of the actual spider involved, which can lead to propagation of misinformation about different spiders, particularly with necrotic arachnidism. For example, cutaneous anthrax was mistaken for a cutaneous necrotic spider bite.¹⁹¹ Additionally, the white tail spider (Lampona spp) was suspected for more than 20 years to cause necrotic lesions. Only recently has a prospective study of confirmed spider bites refuted this myth by reporting more than 700 confirmed spider bites in Australia.^127,128,129 Because most arthropod-focused research involves characterizing the structure of spider toxins rather than verifying clinical presentations, it is important to produce clinical studies that have bites confirmed by the presence of the spider that is identified by an expert. Definite spider bites or stings are defined as the following: (1) evidence of a bite or sting soon after the incident or the creature can be seen to bite or sting, (2) collection of the particular creature, either alive or dead, with positive identification of the creature by an expert biologist/taxonomist in the field relating to the creature.^128,130

BLACK WIDOW SPIDER (LATRODECTUS MACTANS; HOURGLASS SPIDER)

Five species of widow spiders are found in the United States: Latrodectus mactans (black widow; Fig. 118–2A), Latrodectus hesperus (Western black widow), Latrodectus variolus (found in New England, Canada, south to Florida, and west to eastern Texas, Oklahoma, and Kansas), Latrodectus bishopi (red widow of the South), and Latrodectus geometricus (brown widow or brown button spider; Fig. 118–2B). They are present in every state except for Alaska. Dangerous widow spiders in other parts of the world include L. geometricus and Latrodectus tredecimguttatus (European widow spider found in southern Europe), Latrodectus hasselti (red-back widow spider found in Australia, Japan, and India; Fig. 118–2C), and Latrodectus cinctus (found in South Africa). These spiders live in temperate and tropical latitudes in stone walls, crevices, wood piles, outhouses, barns, stables, and rubbish piles. They molt multiple times and as a result can change colors. The ventral markings on the abdomen are species specific, and the classic red hourglass-shaped marking is noted in only L. mactans. Other species may have variations on their ventral surface, such as triangles and spots.

Typically, the female L. mactans is shiny, jet-black, and large (8–10 mm), with a rounded abdomen and a red hourglass mark on its ventral surface. Her larger size and ability to penetrate human skin with her fangs make her more venomous and toxic than the male spider, which resembles the immature spider in earlier stages of development and is smaller, lighter in color, and has a more elongated abdomen and fangs that usually are too short to envenomate humans (Table 118–3). Black widow females are trappers and inhabit large, untidy, irregularly shaped webs. Webs are placed in or close to the ground and in secluded, dimly lit areas that can trap flying insects, such as outdoor privies, barns, sheds, and garages.⁵

Pathophysiology

The venom is more potent on a volume-per-volume basis than the venom of a pit viper and contains six active components with molecular weights of 5000 to 130,000 Da.⁵ The six components are five latroinsectotoxins (α-, β-, γ-, δ-, ε-LITs) (insect-specific neurotoxins), and α-latrocrustatoxin (α-LCT) (crustacean-specific neurotoxin).¹⁰⁵ α-Latrotoxin binds, with nanomolar affinity, to the specific presynaptic receptors neurexin I-α and Ca²⁺-independent receptor for α-latrotoxin (CIRL), otherwise known as latro­philin.^30,114,126 The binding triggers a cascade of events: conformational change allowing pore formation by tethering the toxin to the plasma membrane; Ca²⁺ ionophore formation; translocation of the N-terminal domain of α-LTX into the presynaptic intracellular space, and intracellular activation of exocytosis of norepinephrine, dopamine, neuropeptides, acetylcholine, glutamate, and γ-aminobutyric acid (GABA), respectively. This massive release of neurotransmitters is what causes the clinical envenomation syndrome known as lactrodectism.^5,171,174

Clinical Manifestations

Widow spiders are shy and nocturnal. They usually bite when their web is disturbed or upon inadvertent exposure in shoes and clothing. A sharp pain typically described as a pinprick occurs as the victim is bitten. A pair of red spots may evolve at the site, although the bite is commonly unnoticed.^53,155 The bite mark itself tends to be limited to a small puncture wound or wheal and flare reaction that often is associated with a halo (Table 118–3). However, the bite from L. mactans may produce latrodectism, a constellation of signs and symptoms resulting from systemic toxicity. Some cases do not progress; others may show severe neuromuscular symptoms within 30 to 60 minutes. The effects from the bite spread contiguously. For example, if a person is bitten on the hand, the pain progresses up the arm to the elbow, shoulder, and then toward the trunk during systemic poisoning. Typically, a brief time to symptom onset denotes severe envenomation. One patient developed latrodectism following the intentional intravenous injection of a crushed whole black widow spider.⁴⁷

One grading system divides the severity of the envenomation into three categories.⁶⁰ Grade 1 envenomations range from no symptoms to local pain at the envenomation site with normal vital signs. Grade 2 envenomations involve muscular pain at the site with migration of the pain to the trunk, diaphoresis at the bite site, and normal vital signs. Grade 3 envenomations include the grade 2 symptoms with abnormal vital signs; diaphoresis distant from the bite site; generalized myalgias to back, chest, and abdomen; and nausea, vomiting, and headache.

The myopathic syndrome of latrodectism involves muscle cramps that usually begin 15 minutes to 1 hour after the bite. The muscle cramps initially occur at the site of the bite but later may involve rigidity of other skeletal muscles, particularly muscles of the chest, abdomen, and face. The pain increases over time and occurs in waves that may cause the patient to writhe. Large muscle groups are affected first. Classically, severe abdominal wall spasm occurs and may be confused with a surgical abdomen, especially in children who cannot relate the history with the initial bite.⁴⁴ Muscle pain often subsides within a few hours but may recur for several days. Transient muscle weakness and spasms may persist for weeks to months.

Additional clinical findings include “facies latrodectismica,” which consists of sweating, contorted, grimaced face associated with blepharitis, conjunctivitis, rhinitis, cheilitis, and trismus of the masseters.¹⁵⁵ A fear of death, pavor mortis, is described.¹⁵⁵ Nausea, vomiting, sweating, tachycardia, hypertension, muscle cramping, restlessness, compartment syndrome at the site of the bite, and, rarely, priapism are also reported.^5,61,119,214 The mechanism of compartment syndrome developing after a black widow spider envenomation is unclear, but two postulated theories include rhabdomyolysis and the venom affecting the blood vessels leading to engorgement and obstruction of the venous outflow. In one case, the compartment syndrome was treated with antivenom, and the patient recovered without the need for a fasciotomy.⁶¹ Recovery usually ensues within 24 to 48 hours, but symptoms may last several days with more severe envenomations. Life-threatening complications include severe hypertension, respiratory distress, myocardial infarction, cardiovascular failure, and gangrene.^{47,60,61,81,165,179,183} In the past 20 years, more than 40,000 presumed black widow spider bites have been reported to the American Association of Poison Control Centers. Death is rarely reported. There have been two fatalities in Madagascar from envenomation by L. geometricus, one from cardiovascular failure and the other from gangrene of the foot.¹⁸³ The most recent fatality reported from Greece resulted from myocarditis secondary to envenomation by L. tredecimguttatus,¹⁸² confirmed by a local veterinarian. The patient developed severe dyspnea, hypoxemia, cyanosis, cardiomyopathy, and global hypokinesis of the left ventricle confirmed by echocardiography, followed by death 36 hours later; antivenom was not available. On autopsy, diffuse interstitial and alveolar edema, with mononuclear infiltrate of the myocardium and degenerative changes, were noted, and toxicologic analysis for xenobiotics, as well as all blood, urine, bronchial, and serologic viral cultures, were negative. The paucity of mortalities is presumed to result from the improvement in medical care, the availability of antivenom, or the limited toxicity of the spider.

Diagnostic Testing

Laboratory data generally are not helpful in management or predicting outcome. According to one study, the most common findings include leukocytosis and increased creatine phosphokinase and lactate dehydrogenase concentrations.⁶⁰ Currently, no specific laboratory assay is capable of confirming latrodectism. However, the clinical situation may warrant the need to check laboratory tests and other studies to evaluate the sequelae of the black widow spider envenomation.

Management

Treatment involves establishing an airway and supporting respiration and circulation, if indicated. Wound evaluation and local wound care, including tetanus prophylaxis, are essential.²³⁶ The routine use of antibiotics is not recommended.

Pain management is a substantial component of patient care and depends on the degree of symptomatology. Using the grading system, grade 1 envenomations may require only cold packs and orally administered nonsteroidal antiinflammatory agents. Grade 2 and 3 envenomations probably require intravenous (IV) opioids and benzodiazepines to control pain and muscle spasm.

Traditionally, 10 mL 10% calcium gluconate solution was given IV to decrease cramping. However, a retrospective chart review of 163 patients envenomated by the black widow concluded that calcium gluconate was ineffective for pain relief compared with a combination of IV opioids (morphine sulfate or meperidine) and benzodiazepines (diazepam or lorazepam).^60,141 Another study found greater neurotransmitter release when extracellular calcium concentrations were increased, suggesting that administration of calcium is irrational in patients suffering from latrodectism.¹⁹² The mechanism of action of calcium remains unknown, and its efficacy is anecdotal; therefore, we do not recommend calcium administration for pain management.

Although often recommended, methocarbamol (a centrally acting muscle relaxant) and dantrolene also are ineffective for treatment of latrodectism.^141,197 A benzodiazepine, such as diazepam, is more effective for controlling muscle spasms and achieves sedation, anxiolysis, and amnesia. Management should primarily emphasize supportive care, with opioids and benzodiazepines for controlling pain and muscle spasms, because the use of antivenom risks anaphylaxis and serum sickness.

Latrodectus antivenom (Wyeth) is rapidly effective and curative. In the United States, the antivenom formulation is effective for all species but is available as a crude hyperimmune horse serum that may cause anaphylaxis and serum sickness. The morbidity of latrodectism is high, with pain, cramping, and autonomic disturbances, but mortality is low. Hence controversy exists over when to administer the black widow antivenom. The antivenom can be administered for severe reactions (eg, hypertensive crisis or intractable pain), to high-risk patients (eg, pregnant women suffering from a threatened abortion), or for treatment of priapism.^141,183 Use of antivenom probably should not be considered for patients unless systemic effects are designated as grade 3.⁶¹ The usual dose is one to two vials diluted in 50 to 100 mL 5% dextrose or 0.9% sodium chloride solution, with the combination infused over 1 hour (Antidotes in Depth: A34). Skin testing may identify a highly allergic individual but does not eliminate the occurrence of hypersensitivity reactions; therefore, we do not recommend skin testing. Recently, an anaphylactoid reaction to the black widow spider antivenin was reported after a negative skin test in both a boy and a man^124,168 who subsequently died from the anaphylactoid reaction. Both were being treated for intractable pain after failing intravenous opioid management. Pretreatment with histamine H₁- or H₂-blockers, or both, and epinephrine may be beneficial in preventing histamine release and anaphylaxis. Patients with allergies to horse serum products and those who have received antivenom or horse serum products are at risk for immunoglobulin IgE-mediated hypersensitivity reactions and, though efficacy is largely unproven, may benefit from the pretreatment with antihistamines and corticosteroids.

A purified F(ab)2 fragment Latrodectus mactans antivenom, Analatro¯, is currently undergoing clinical trials (Antidotes in Depth: A34).

In Australia, a purified equine-derived IgG-F(ab)₂ fragment antivenom for the red-back spider L. hasselti (RBS-AV) is available. The RBS-AV (CSL, Melbourne, Australia) is administered intramuscularly and given as first-line therapy to patients presenting with systemic signs or symptoms in Australia. Since its introduction in 1956, no deaths are reported, and the incidence of mild allergic reactions to RBS-AV is only 0.54% in 2144 uses.²²³

However, an underpowered prospective cohort study of confirmed red-back spider bites failed to show that intramuscular antivenom was better than no treatment when all patients were followed up over one week.¹²⁹ This study did note that only 17% of patients were pain-free at 24 hours with antibody treatment. Therefore, intramuscular antivenom appears to be less effective than previously thought, and the route of administration requires review. Recently in Italy, an FM₁ Fab fragment specific for the α-latroxin has been highly effective in neutralizing the toxin in vivo in mice and shows some promise for possible use in humans.^12,45 This single monoclonal antibody shows great promise in the treatment for severe black widow envenomation. Inadvertent use of RBS-AV successfully treated envenomations from the comb-footed spider (Steatoda spp),¹³⁰ and the Steatoda venom and clinical effects are similar to the Latrodectus venom but milder in clinical presentation.¹⁰³

BROWN RECLUSE SPIDER (LOXOSCELES RECLUSA; VIOLIN OR FIDDLEBACK SPIDER)

Loxosceles reclusa was confirmed to cause necrotic arachnidism in 1957, although reports of systemic symptoms following brown spider bites have appeared since 1872.¹⁰ This spider has a brown violin-shaped mark on the dorsum of the cephalothorax, three dyads of eyes arranged in a semicircle on top of the head, and legs that are five times as long as the body. It is small (6–20 mm long) and gray to orange or reddish brown (Fig. 118–3A). Loxosceles spiders weave irregular white, flocculent adhesive webs that line their retreats.⁹² Spiders in the genus Loxosceles have a worldwide distribution. In the United States, other species of this genus, which include L. rufescens, L. deserta, L. devia, and L. arizonica, are prominent in the Southeast and Southwest.⁹ L. rufescens was inadvertently introduced in several buildings in New York City. Though it is unclear how they initially arrived there, they were most likely transported on personal belongings and cartons of materials (confirmed by Lou Sorkin BCE, arachnologist, American Museum Natural History, New York).²¹¹ They are hunter spiders that live in dark areas (wood piles, rocks, basements), and their foraging is nocturnal. They are not aggressive but will bite if antagonized (Table 118–3). These spiders live up to 2 years and maybe even longer. They are resilient and can survive up to 6 months without water or food and can tolerate temperatures from 46.4° to 109.4°F (8°–43°C).⁹⁶ Like the black widow spider, the female is more dangerous than the male. Loxosceles venom has variable toxicity, depending on the species, with Loxosceles intermedia venom causing more severe clinical effects in humans.^15,16 The peak time for envenomation is from spring to autumn, and most victims are bitten in the morning. However, the brown recluse spider is often misdiagnosed as the culprit for a necrotic wound and has been identified as the biting spider when L. rufescens was the actual species. One study examined 182 patients enrolled over 23 months who presented to the emergency department (ED) for a chief complaint of spider bite. The study found that only 3% (7/182) were ultimately confirmed by their treating physician to have the diagnosis of a spider bite, whereas 84% (152/182) had a skin and soft tissue infection (SSTI), nine patients were bitten by other animals, six patients were given other non-bite diagnoses, such as erythema multiforme, subcutaneous nodules, folliculitis from a razor cut, and eight patients had no diagnostic category recorded. Of the seven patients that had a confirmed spider bite, only one brought the spider in for identification, while the others saw a spider or witnessed a bite, and one patient did not witness or feel a bite.²¹⁷ Community-acquired MRSA was the most common cause of SSTI’s, accounting for 70% of positive wound cultures when performed. Hence the spider bite diagnosis is often frequently misused, and a diagnosis of dermatonecrotic wound of uncertain etiology would be more accurate.²¹⁷

Pathophysiology

The venom is cytotoxic. The two main constituents of the venom are sphingomyelinase-D and hyaluronidase, though other subcomponents include deoxyribonuclease, ribonuclease, collagenase, esterase, proteases, alkaline phosphatase, and lipase.^70,146,232 Hyaluronidase is a spreading factor that facilitates the penetration of the venom into tissue but does not induce lesion development.¹⁴⁶ Sphingomyelinase-D is the primary constituent of the venom that causes necrosis and red blood cell hemolysis and also causes platelets to release serotonin.¹⁴⁶ Sphingomyelinase also reacts with sphingomyelin in the red blood cell membrane to release choline and N-acylsphingosine phosphate, which triggers a chain reaction releasing inflammatory mediators, such as thromboxanes, leukotrienes, prostaglandins, and neutrophils, leading to vessel thrombosis, tissue ischemia, and skin loss.¹⁴⁶ Early perivascular collections of polymorphonuclear leukocytes with hemorrhage and edema progress to intravascular clotting. Coagulation and vascular occlusion of the microcirculation occur, ultimately leading to necrosis.²⁰⁷

Clinical Manifestations

The clinical spectrum of loxoscelism can be divided into three major categories. The first category includes bites in which very little, if any, venom is injected. A small erythematous papule may be present that becomes firm before healing and is associated with a localized urticarial response. In the second category, the bite undergoes a cytotoxic reaction. The bite initially may be painless or have a stinging sensation but then blisters and bleeds and ulcerates 2 to 8 hours later (Table 118–3). The lesion may increase in diameter, with demarcation of central hemorrhagic vesiculation, then ulcerates and develops violaceous necrosis, surrounded by ischemic blanching of skin and outer erythema and induration over 1 to 3 days. This is also known as the “red, white, and blue” reaction (Fig. 118–3B).^142,242 Necrosis of the central blister occurs in 3 to 4 days, with eschar formation between 5 and 7 days. After 7 to 14 days, the wound becomes indurated and the eschar falls off, leaving an ulceration that heals by secondary intention. Local necrosis is more extensive over fatty areas (thighs, buttocks, and abdomen).¹⁴⁶ The size of the ulcer determines the time for healing. Large lesions up to 30 cm may require months or more to heal.

Upper airway obstruction was reported in a child who was bitten on his neck and subsequently developed progressive cervical soft tissue edema with airway obstruction and dermatonecrosis 40 hours later.¹⁰⁰ Another case reported stridor and respiratory distress following a brown recluse envenomation of the ear. Although the presentation is rare, respiratory compromise should be considered when an envenomation occurs near the airway.⁹⁵

The third category consists of systemic loxoscelism, which is not predicted by the extent of cutaneous reaction, and occurs 24 to 72 hours after the bite. The young are particularly susceptible.^99,198 The clinical manifestations of systemic loxoscelism include fever, chills, weakness, edema, nausea, vomiting, arthralgias, petechial eruptions, rhabdomyolysis, disseminated intravascular coagulation, hemolysis that can lead to hemoglobinemia, hemoglobinuria, acute kidney injury, and death.^{27,49,88,99,153,202,239} However, in North America, the incidence of systemic illness is rare, and mortality is low.⁷

Diagnostic Testing

Bites from other spiders, such as Cheiracanthium (sac spider), Phidippus (jumping spider), and Argiope (orb weaver), can produce necrotic wounds. These spiders are often the actual culprits when the brown recluse is mistakenly blamed. Definitive diagnosis is achieved only when the biting spider is positively identified. No routine laboratory test for loxoscelism is available for clinical application, but several techniques are presently used for research purposes. The lymphocyte transformation test measures lymphocytes that have undergone blast transformation up to one month after exposure to Loxosceles venom. The lymphocytes incorporate thymidine into the nucleoprotein, providing a quantitative response.⁸ A passive hemagglutination inhibition test (PHAI) has been developed in guinea pigs. The PHAI assay is based on the property of certain brown recluse spider venom components to spontaneously adsorb to formalin-treated erythrocyte membranes and the ability of the brown recluse spider venom to inhibit antiserum-induced agglutination of venom-coated red blood cells.¹⁸ The test is 90% sensitive and 100% specific for 3 days postenvenomation and may prove useful for early diagnosis of brown recluse spider envenomation.¹⁸ An enzyme-linked immunoassay (ELISA) specific for Loxosceles venom in biopsied tissue can confirm the presence of venom for 4 days postenvenomation,¹⁸ and in an experimental model using rabbits, the antigen was recoverable using the ELISA assay from 14 to 21 days.¹⁵⁸ The drawbacks of using a skin biopsy are the invasive nature of the procedure, which can result in further scarring with an increased potential for infection, and the lack of proof that skin biopsy can diagnose early envenomations prior to the development of dermatonecrosis. Another ELISA utilizing serum for detection of venom antigens has been developed that correctly discriminates the mice inoculated with antigens from L. intermedia venom. The ELISA immunoassay and antivenom may become useful diagnostic tools if envenomation can be proved or disproved early.⁵⁷ A venom-specific enzyme immunoassay that uses hair, skin biopsies, or aspirated tissue near a suspected lesion to detect the presence of venom up to 7 days after injury is under investigation.^145,161 In Brazil, ELISA is used to detect the venom of Loxosceles gaucho in wounds and patient sera, but the technique is not in widespread clinical use.⁵³

Clinical laboratory data may be remarkable for hemolysis, hemoglobinuria, and hematuria. Coagulopathy may be present, with laboratory data significant for elevated fibrin split products, decreased fibrinogen concentrations, and a positive D-dimer assay. Other tests may show increased prothrombin time (PT) and partial thromboplastin time (PTT), leukocytosis (up to 20,000–30,000 cells/mm³), spherocytosis, Coombs-positive hemolytic anemia, thrombocytopenia, or abnormal kidney and liver function tests.^{5,12,92,194,196,198,237}

Treatment

Optimal local treatment of the lesion is controversial. The most prudent management of the dermatonecrotic lesion is wound care, immobilization, tetanus prophylaxis, analgesics, and antipruritics as warranted (Table 118–4).^5,92,234,237 Early excision or intralesional injection of corticosteroids appears unwarranted.¹⁸⁹ Corrective surgery can be performed several weeks after adequate tissue demarcation has occurred. In one case series the use of curettage of the lesion to remove necrotic and indurated tissue from the lesion, thus eliminating any continuing action of the lytic enzymes on the surrounding tissue, showed promising results.¹¹⁷ These patients had wound healing without further necrosis and minimal scarring. Vacuum-assisted closure, otherwise known as negative pressure wound therapy, is also described in a series of clinical cases in the surgical literature as a means to treat necrotic wounds caused by presumed brown recluse spider bites more quickly than the traditional methods, due to increased bacterial clearance and dermal perfusion, modulating the inflammatory response, extracting toxic substances, and accelerated rate of granulation tissue formation.²⁴⁰ Electric shock delivered via stun guns was not found to be useful in a guinea pig envenomation model.¹⁸ Cyproheptadine, a serotonin antagonist, was not beneficial in a rabbit model.¹⁷⁶ A randomized, controlled study evaluating the efficacy of topical nitroglycerin for envenomated rabbits showed no difference in preventing skin necrosis and suggested the possibility of increased systemic toxicity.¹⁵⁰ Antibiotics should be used to treat cutaneous or systemic infection, but they should not be used prophylactically.

Early use of dapsone (in patients who develop a central purplish bleb or vesicle within the first 6–8 hours) may inhibit local infiltration of the wound by polymorphonuclear leukocytes.¹⁴² The dosage recommended is 100 mg twice daily for 2 weeks.¹⁸⁷ However, prospective trials with large numbers of patients are lacking. One study compared the efficacy of erythromycin and dapsone therapy, erythromycin and antivenom therapy, and erythromycin, dapsone, and antivenom therapy (developed in rabbits based on a previous study).¹⁸⁶ Although the treatment groups were very small, all groups showed wound healing at approximately 20 days despite the different therapies used. This study’s biggest limitation includes the definition of a spider bite diagnosis (the study used the following criteria: a patient feeling the spider bite, seeing the spider, or having a clinically plausible necrotic lesion). The study suggests that the use of dapsone may eliminate the need for surgery following bites and that antivenom therapy was most effective clinically if the patient never developed the necrotic lesion. Hence, the use of dapsone in the management of a local lesion should be considered experimental until its use is validated by randomized, controlled clinical trials. Hepatitis,¹⁹⁰ methemoglobinemia (Chap. 127), and hemolysis are associated with dapsone use. If dapsone therapy is used, a baseline glucose-6-phosphate dehydrogenase and weekly complete blood counts should be performed.

An underpowered animal study evaluated the effects on the size of skin lesions induced by Loxosceles envenomation by treatment with hyperbaric oxygen therapy, dapsone, and combined hyperbaric oxygen therapy and dapsone.¹¹⁵ The study concluded that there was no clinically significant change in necrosis or induration by these treatment modalities. Further evaluation of these interventions remains appropriate. Another study using hyperbaric oxygen for treatment of Loxosceles-induced necrotic lesions in rabbits revealed no clinical improvement in the size of the lesion; however, the histology of the lesions improved. Whether this finding is of value in humans has not been determined.^115,216 Use of 1.2 mg colchicine, a leukocyte inhibitor, followed at 2-hour intervals with 0.6 mg for 2 days, then 0.6 mg every hours for 2 additional days is sometimes recommended, but we do not advocate this treatment because of potential colchicine toxicity.¹⁹⁴ Rabbit-derived intradermal anti-Loxosceles Fab (α-Loxd) fragments attenuated the dermatonecrotic inflammation of rabbits injected with L. deserta venom in a time-dependent fashion.⁹⁷ At time 0 after envenomation, lesion development was blocked. At time 1 and 4 hours after envenomation, the α-anti-Loxd Fab antivenom continued to suppress the lesion areas, although the longer the delay in treatment, the smaller the difference in treatment and control lesion areas. At time 8 and 12 hours postenvenomation, there was no difference in lesion size. The typical 24-hour delay in lesion development makes the diagnosis difficult, and the antivenom would likely be useless if administered so late in the clinical course. Currently this antivenom is not available for commercial use.

One preclinical study shows promise for the treatment of Loxosceles envenomations using an antiloxoscelic serum that was produced from recombinant sphingomyelinase D that was derived from the sphingomyelinase of the L. intermedia and L. laeta spiders. The isolated sphingomyelinase from the respective Loxosceles species carried the full biological effects of the entire venom. This antiloxoscelic serum when administered IV into rabbits that were given intradermal injections of the loxoscelic venom from L. laeta and L. intermedia had greater neutralizing activity than when compared to the existing antiarachnid serum, which is made by hyperimmunizing horses against the venom of L. gaucho, P. nigriventer, and the scorpion Tityus serrulatus. In Brazil and South America, most of the envenomations occur with the L. laeta and L. intermedia, not L. gaucho. Knowing which species envenomated the patient could help determine which antiserum should be used.⁷³

Patients manifesting systemic loxoscelism or those with expanding necrotic lesions should be admitted to the hospital. All patients should be monitored for evidence of hemolysis, acute kidney injury, or coagulopathy. If hemoglobinuria ensues, increased IV fluids and urinary alkalinization can be used in an attempt to prevent acute kidney injury. Hemolysis, if significant, can be treated with transfusions. Patients with coagulopathy should be monitored with serial complete blood cell count, platelet count, PT, PTT, fibrin split products, and fibrinogen. Disseminated intravascular coagulopathy may require treatment, based on severity.

HOBO SPIDER (TEGENARIA AGRESTIS, NORTHWESTERN BROWN SPIDER, WALCKENAER SPIDER)

The hobo spider is native to Europe and was introduced to the northwestern United States (Washington, Oregon, Idaho) in the 1920s or 1930s.²³³ These spiders build funnel-shaped webs within wood piles, crawl spaces, basements, and moist areas close to the ground. They are brown with gray markings and 7 to 14 mm long. They are most abundant in the midsummer through the fall. They bite if provoked or threatened but otherwise retreat quickly with disturbance.²³ The medical literature is sparse in reported hobo spider bites that are verified by a specialist. There is only one confirmed Hobo spider bite resulting in a necrotic lesion.⁶³ A 42 year-old woman with a history of phlebitis who felt a burning sensation on her ankle rolled her pants and found a crushed brown spider, which was later confirmed (unpublished source cited by MMWR) to be T. agrestis. She complained of persistent pain, nausea, and dizziness, and a vesicular lesion developed within several hours. The vesicle ruptured and ulcerated the next day. The lesion initially was 2 mm, but over the next 10 weeks enlarged to 30 mm in diameter and was circumscribed with a black lesion, at which time she sought medical advice. She was given a course of antibiotics, which did not limit the progression of this ulcer. Subsequently, the patient was unable to walk, and she was found to have a deep venous thrombosis. The other cases implicating Hobo spiders as a cause for dermatonecrotic injuries are based on proximity of the Hobo spider or other large brown spiders that are unidentified. T. agrestis venom implanted into rabbit skin can produce hemorrhagic necrotic lesions dermally and systemically.^233,234

The venom from European Hobo spiders and US Hobo spiders was analyzed using liquid chromatography to address the question of variability between the two spiders. T. agrestis originating from Europe is considered medically harmless. Liquid chromatography (European Hobo T. agrestis from the United Kingdom and American Hobo T. agrestis from Washington State, United States) found little variability between the two venoms to account for their differential necrotic effects.²⁸ The authors suggest four possibilities for the discrepancy between the European Hobo and American Hobo spiders: (1) an evolutionary change may have accounted for the novel necrotic effects; (2) venom chemistry may be similar but the habitat might account for the difference in behavior; (3) venom chemistry and habitat may be similar but an extrinsic factor such as a bacterium found in the US Hobo spider might be the cause for the necrotic effects; (4) T. agrestis do not directly or indirectly cause necrotic arachnidism and have been falsely accused.²⁸ The authors suggest that either a bacterium such as Mycobacterium ulcerans, known to cause slow-developing ulcers on human skin, might coexist on the chelicerae of the T. agrestis, which is highly unlikely because of the presence of antibacterial peptides in the venom,^113,241 or the more likely circumstance that T. agrestis has been falsely accused as being a cause for necrotic arachnidism. Further evidence to suggest that the T. agrestis is not likely to be a culprit for necrotic arachnidism is based on a study that evaluates the possibility of the spider’s ability to carry and transfer pathogenic bacteria including the methicillin-resistant Staphylococcus aureus (MRSA) and analyzes the venom’s hemolytic properties.⁹¹ One hundred two T. agrestis adult spiders were collected, and a bacterial diversity assay was conducted to find a total of six Gram-positive and four Gram-negative bacteria genera identified which was consistent with the bacteria found in the fauna of the natural environment of the Pacific Northwest and several occurring on human and animal skin. Spiders were then exposed to MRSA on polyethylene disks since the tissue lesions caused by this bacterium is often confounded with a necrotic arachnism. No MRSA was found on either the spiders or the surfaces to which the MRSA exposed spiders were subjected, although the MRSA was found to persist on the polyethylene disks. Finally, the Hobo Spider venom was analyzed to determine its hemolytic activity in vertebrate blood. Compared to the known Loxoceles reclusa hemolytic activity of 37%, the potential of T. agrestis venom hemolysis activity was negligible at 0.62 and 0.93% for male (n = 5) and female (n = 7) spiders, respectively. Misdiagnosis of spider bites is common. Wounds can be misleading and can occur from the reaction of other organisms such as ticks and other arthropods, superinfection with anthrax, or underlying medical conditions like diabetes and leukemia or bacterial infections. The need to revisit the Hobo spider toxicity syndrome with further studies that show direct evidence of T. agrestis causing necrotic arachnidism in humans is warranted before one can conclude that any necrotic arachnidism in the Pacific Northwest is caused by T. agrestis.

Pathophysiology

The toxin has been fractionated, with three peptides identified as having potent insecticidal activity and no discernible effects in mammalian in vivo assays.¹³⁴ The peptide toxins TaITX-1, TaITX-2, and TaITX-3 exhibit potent insecticidal properties by acting directly in the insect central nervous system and not at the neuromuscular junction.¹³⁴ Insects envenomated with T. agrestis venom and the insecticidal toxins purified from the venom developed a slowly evolving spastic paralysis. Currently, little is known about the toxin and its mechanism of action in humans.

Clinical Manifestations

The toxicity of Hobo spider venom is questionable; however, it occasionally causes necrosis secondary to infection. Other causes of dermatonecrotic lesions should be considered. The most common symptom associated with the spider bite is a headache that may persist for one week.⁶³ Other symptoms, including nausea, vomiting, fatigue, memory loss, visual impairment, weakness, and lethargy, are reported.^63,234

Diagnostic Testing

No specific laboratory assay confirms envenomation with T. agrestis spider.

Treatment

Treatment emphasizes local wound care and tetanus prophylaxis, although systemic corticosteroids for hematologic complications may be of value. Surgical graft repair for severe ulcerative lesions may be warranted when there is no additional progression of necrosis.⁶³

TARANTULAS

Tarantulas are primitive mygalomorph spiders that belong to the family Theraphosidae, a subgroup of Mygalomorphae (Greek word mygale for field mouse).^58,200 There are more than 1500 species, with 54 species found in the deserts of the western United States.¹⁷⁸ Because of their great size and reputation, tarantulas are often feared. They are the largest and hairiest spiders, popular as pets, and can be found throughout the United States as well as in tropical and subtropical areas (Fig. 118–4). The lifespan of the female can exceed 15 to 20 years. They have poor eyesight and usually detect their victims by touch and vibrations. Their defense lies in either their painful bite with erect fangs or by barraging their victim with urticating hairs that are released on provocation.⁵⁸ Only the New World tarantulas (tarantulas indigenous to the Americas) have and use the urticating hairs to defend themselves.⁵⁸

Tarantulas may bite when provoked or roughly handled. Based on the few case reports, their venom has relatively minor effects in humans but can be deadly for canines and other small animals, such as rats, mice, cats, and birds.^44,131 Small prey might actually be killed by the physical nature of having fangs impaled many times through their bodies. A study from Australia covering a 25 year span reported only nine confirmed bites by Theraphosid spiders in humans and seven confirmed bites in canines—in two cases the owner was bitten after the dog.^19,131 At least four genera of tarantulas (Lasiodora, Grammostola, Acanthoscurria, and Brachypelma) possess urticating hairs that are released in self-defense when the tarantulas rub their hind legs against their abdomen rapidly to create a small cloud.⁹⁶ There are seven different types of urticating hairs. Type 1 hairs are found on tarantulas in the United States and are the only hairs that do not penetrate human skin. Type 2 hairs are incorporated into the silk web retreat but are not thrown off by the spider. Type 3 hairs can penetrate up to 2 mm into human skin. Type 4 hairs belong to the South American Grammostola spider and can cause severe respiratory inflammation. Urticarial hairs or setae are composed of chitin, lipoproteins, and mucopolysaccharides, which are recognized as foreign bodies triggering a humoral response in the mammalian immune system. Chitin is proinflammatory and activates T helper cells to stimulate activated macrophages to produce chitanases, which will break down the chitin but also trigger inflammation. Besides cell-mediated inflammation, spider setae can also trigger immunoglobulin E-mediated hypersensitivity.^19,55

Pathophysiology

Tarantula venom, specifically the venoms of Aphonopelma hentzi (synonym of Dugesiella hentzi {Arkansas tarantula}) and other members of the genus Aphonopelma (Arizona or Texas brown tarantula), contains hyaluronidase, nucleotides (adenosine triphosphate {ATP}, adenosine diphosphate, and adenosine monophosphate), and polyamines (spermine, spermidine, putrescine, and cadaverine) that are used for digesting their prey.^48,139,200 The role of spermine is unclear, but hyaluronidase is a spreading factor that allows more rapid entrance of venom toxin by destruction of connective tissue and intercellular matrix. ATP potentiates death in mice exposed to the A. hentzi venom and lowers the LD₅₀ in comparison to venom without ATP.^56,155 Both venoms cause skeletal muscle necrosis when injected intraperitoneally into mice.⁹⁰ The primary injury results in rupture of the plasma membrane, followed by the inability of mitochondria and sarcoplasmic reticulum to maintain normal concentrations of calcium in the cytoplasm leading to cell death. Aphonopelma venom is similar to scorpion venom in composition and clinical effects. Novel toxins have been discovered in the venom that can act on potassium channels, calcium channels, and the recently discovered acid-sensing ion channels that may elucidate the molecular mechanism of voltage-dependent channel gating and their respective physiologic roles.^82,83

Clinical Manifestations

Although relatively infrequent in occurrence, bites present with puncture or fang marks. They range from being painless to a deep throbbing pain that may last several hours without any inflammatory component.¹³¹ Fever occurs in the absence of infection, suggesting a direct pyrexic action of the venom. Rarely, bites create a local histamine response with resultant itching, and hypersensitive individuals could have a more severe reaction and, less commonly, mild systemic effects such as nausea and vomiting.^96,131 Contact reactions from the urticating hairs are more likely to be the health hazard than the spider bite. The urticating hairs provoke local histamine reactions in humans and are especially irritating to the eyes, skin, and respiratory tract. Tarantula urticating hairs cause intense inflammation that may remain pruritic for weeks. Inflammation can occur at all levels from conjunctiva to retina. An allergic rhinitis can develop if the hairs are inhaled.¹³⁹ Tarantula hairs resemble sensory setae of caterpillars: both are type 3 that can migrate relentlessly and cause multiple foci of inflammation at all levels of the eye.¹²¹ Ophthalmia nodosa, a granulomatous nodular reaction to vegetable or insect hairs, is reported with casual handling of tarantulas.^22,26 Other eye findings include setae in the corneal stroma, anterior chamber inflammation, migration into the retina, and secondary glaucoma and cataracts.³¹

Treatment

Treatment is largely supportive. Cool compresses and analgesics should be given as needed. All bites should receive local wound care, including tetanus prophylaxis if necessary. If the hairs are barbed, as in some species, they can be removed by using adhesive such as duct tape or cellophane tape followed by compresses or irrigation with 0.9% sodium chloride solution. If the hairs are located in the eye, then surgical removal may be required, followed by medical management of inflammation. If the hairs are difficult to remove and the patient has persistent ocular pain and discomfort, then a therapeutic pars plana vitrectomy may be necessary to reduce the antigenic load and to improve clinical symptomatology.¹¹⁸ Urticarial reactions should be treated with oral antihistamines and topical or systemic corticosteroids.

FUNNEL WEB SPIDERS

Australian funnel web spiders are a group of large Hexathelidae mygalomorphs that can cause a severe neurotoxic envenomation syndrome in humans. The fang positions of funnel web spiders (as well as the tarantulas) are vertical relative to their body, which requires the spider to rear back and lift the body to attack. The length of fangs can reach up to 5 mm. This spider can bite tenaciously and may require extraction from the victim.¹⁶³ Atrax and Hadronyche species are found along the eastern seaboard of Australia. A. robustus, also called the Sydney funnel web spider, is the best known and is located around the center of Sydney, Australia.¹⁶³ Funnel web spiders tend to prefer moist, temperate environments.¹⁶³ They are primarily ground dwellers and live in burrows, crevices in rocks, and around foundations of houses. They build tubular or funnel-shaped webs.⁹⁶ At night, the spiders ascend the tubular web and wait for their prey. The Sydney funnel web spider is considered one of the most poisonous spiders. It was responsible for 14 deaths between 1927 and 1980, at which time the antivenom was introduced.^220,221

Pathophysiology

Originally called robustotoxin from A. robustus spider and versutoxin from the Hadronyche versuta spider, the toxin which is now referred to as atracotoxin or atraxin (δ-ACTX –Arl and δ-ACTX-Hvla, respectively) is the lethal protein component of A. robustus venom and is unique in its toxicity affecting primates and newborn mice in biological doses, although other mammals are susceptible in higher doses.^{163,219,221,238} δ-ACTX is a 42 amino acid peptide that targets mammals by increasing the ion conductance at voltage-gated sodium channels via trapping the channel’s voltage sensor domain IV S4 segment in an inward conformational change, preventing the closure of the ion channel, thereby evoking a fulminant neurotransmitter release at the autonomic and/or somatic synapses.^151,172 Hence δ-ACTX produces an autonomic storm, releasing acetylcholine, noradrenaline, and adrenaline. In monkeys, a 5 μg/kg intravenous infusion dose of robustotoxin from male A. robustus spiders causes dyspnea, blood pressure fluctuations leading to severe hypotension, lacrimation, salivation, skeletal muscle fasciculation, and death within 3 to 4 hours.¹⁶⁹ Versutoxin, a toxin from the Blue Mountain funnel web spider, is closely related to robustotoxin and has demonstrated voltage-dependent slowing of sodium channel inactivation.¹⁷³

Clinical Manifestations

A biphasic envenomation syndrome is described in humans and monkeys.^220,221 Phase 1 consists of localized pain at the bite site, perioral tingling, piloerection, and regional fasciculations (most prominent in the face, tongue, and intercostals). Fasciculations may progress to more overt muscle spasm; masseter and laryngeal involvement may threaten the airway.²¹⁹ Other features include tachycardia, hypertension, cardiac dysrhythmias, nausea, vomiting, abdominal pain, diaphoresis, lacrimation, salivation, and acute respiratory distress syndrome (ARDS), which often is the cause of death in phase 1.²³⁸ Phase 2 consists of resolution of the overt cholinergic and adrenergic crisis; secretions dry up, and fasciculations, spasms, and hypertension resolve. This apparent improvement can be followed by the gradual onset of refractory hypotension, apnea, and cardiac arrest.²²¹

Treatment

Pressure immobilization using the crepe bandage to limit lymphatic flow and immobilization of the bitten extremity may inactivate the venom and should be applied if symptoms of envenomation are present. Funnel web venom is one of the few animal toxins known to undergo local inactivation. Monkey studies and a human case report support the utility of pressure immobilization.^101,222 After injecting A. robustus venom subcutaneously in monkeys, pressure-immobilization technique increased survival by retarding the venom movement and also by allowing the local peripheral enzymes inactivating the venom.^220,222

The patient should be transferred to the nearest hospital with the bandage in place and then stabilized and placed in a resuscitation facility with adequate ampules of antivenom readily available before the bandage is removed; otherwise, a precipitous envenomation may occur during the removal of the pressure bandage. A purified IgG antivenom protective against Atrax envenomations was developed in rabbits.²²⁰ One ampule of the antivenom contains 100 mg purified rabbit IgG or 125 units of neutralizing capacity per ampule.²³⁸ It has been effective for more than 40 humans bitten by the Atrax species.²²² The starting dose is two ampules if systemic signs of envenomations are present, and four ampules if the patient develops ARDS or decreased mental status. Doses are repeated every 15 minutes until clinical improvement occurs.²³⁸ Up to eight ampules is common in a severe envenomation. Since anaphylaxis has not been reported,²²² the manufacturer no longer recommends premedication. Serum sickness is rare after funnel web antivenom administration, with only one reported case in a patient who received five ampules of antivenom.¹⁶²

SCORPIONS

Scorpions are invertebrate arthropods that have existed for more than 400 million years.⁶² Of the 650 known living species, most of the lethal species are in the family Buthidae (Table 118–5). The genera of the family Buthidae include Centruroides, Tityus, Leiurus, Androctonus, Buthus, and Parabuthus.⁶² Scorpions envenomate humans by stinging rather than biting. Their five-segmented metasoma (“tail”) contains a terminal bulbous segment called the telson that contains the venom apparatus (Fig. 118–5). More than 100,000 medically significant stings likely occur annually worldwide, predominantly in the tropics and North Africa.^{1,25,73,106,132,144} According to American Association of Poison Control Centers data from 1995 to 2011, approximately 11,000 to 19,000 scorpion annual exposures occurred in the United States, mostly in the southwestern region, but no deaths have been reported. These members of the class Arachnida rarely cause mortality in victims older than 6 years.¹⁸⁹ The venomous scorpions in the United States are Centruroides exilicauda and Centruroides vittatus. The most important is C. exilicauda, previously called Centruroides sculpturatus Ewing and Centruroides gertschii (bark scorpion; Table 118–6).⁸⁶

Pathophysiology

Components of scorpion venom are complex and species specific.^{109,181,189,190} Buthidae venom is thermostable and consists of phospholipase, acetylcholinesterase, hyaluronidase, serotonin, and neurotoxins. Four neurotoxins, designated toxins I to IV, have been isolated from C. exilicauda. Some of the toxins target excitable membranes,^{71,85,107,159,199} especially at the neuromuscular junction, by opening sodium channels. The results are repetitive depolarization of nerves in both sympathetic and parasympathetic nervous systems causing catecholamine and acetylcholine release, respectively, and associated cardiac hypoxia, and action at the juxtaglomerular apparatus, causing increased renin secretion.^68,189 The clinical effects of Tityus scorpion sting are related to elevated concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, kinins,⁸⁹ and tumor necrosis factor (TNF)-α, which correlate with the severity of envenomation and hyperamylasemia.^67,90

Clinical Manifestations

Scorpion stings produce a local reaction consisting of intense local pain, erythema, tingling or burning, and occasionally discoloration and necrosis without tissue sloughing (Table 118-6). Depending on the scorpion species involved, systemic effects may occur, including autonomic storm consisting of cholinergic and adrenergic effects. Cardiotoxic effects include myocarditis, dysrhythmias, and myocardial infarction.^{71,85,107,159,199} Electrocardiographic (ECG) abnormalities may persist for several days and include sinus tachycardia, sinus bradycardia, bizarre broad notched biphasic T-wave changes with additional ST elevation or depression in the limb and precordial leads, appearance of tiny Q waves in the limb leads consistent with an acute myocardial infarction pattern, occasional electrical alternans, and prolonged QT interval.^107,109 Other reported effects include pancreatitis, coagulation disorders, acute respiratory distress syndrome (ARDS), massive hemoptysis, cerebral infarctions in children, seizures, and a shock syndrome that may precede but usually follows the hypertensive phase.^{24,76,85,107,108,199,209}

In the United States, C. exilicauda stings produce local paresthesias and pain that can be accentuated by tapping over the envenomated area (tap test) without local skin evidence of envenomation.^62,189 Symptoms begin immediately after envenomation, progress to maximum severity in 5 hours, and may persist for up to 30 hours.^62,189 Autonomic findings include hypertension, tachycardia, diaphoresis, emesis, and bronchoconstriction. The somatic motor symptoms reported include ataxia, muscular fasciculations, restlessness, thrashing, and opsoclonus; rarely, children require respiratory support (Table 118–6).^68,181

Treatment

Because most envenomations do not produce severe effects, local wound care, including tetanus prophylaxis and pain management, usually is all that is warranted. In young children or patients who manifest severe toxicity, hospitalization may be required. Treatment emphasizes support of the airway, breathing, and circulation. Corticosteroids, antihistamines, and calcium have been administered without any known benefit.⁶⁷ Continuous IV midazolam infusion is often used for C. exilicauda scorpion envenomation until resolution of the abnormal motor activity and agitation occurs.⁹⁴

The severity of envenomation dictates the need to use antivenom, with antivenom indicated for grade III and grade IV envenomations. (Table 118–6).⁶⁷ When an equine-derived F(ab')₂ product called Alacramyn, developed in Mexico against the Centruroides limpidus venom, was administered to critically ill US children with neurotoxicity from scorpion stings, there was a rapid resolution of symptoms, decreased need for sedation, and reduced concentrations of circulating unbound venom.³⁴ This antivenom was subsequently approved in the United States in 2011 and called Anascorp (Bioclon, Mexico)⁷³ (Antidotes in Depth: A35). Because the neurotoxic syndrome occurs almost exclusively in children < 10 years of age, antivenom use is most likely to be considered in children. However, intractable pain in adults not responding to reasonable doses of opioids or other systemic effects that may pose a danger to the patient or a fetus should be considered potential indications for antivenom therapy.

Atropine has been used to reverse the excessive oral secretions in C. exilicauda scorpion envenomation, with some success in healthy children.²¹⁸ Routine use is not recommended and should be limited to species such as such as Parabuthus transvaalicus in southern Africa,²¹⁸ whose envenomations cause a prominent cholinergic crisis. Potentiation of the adrenergic effects causing cardiopulmonary toxicity is reported.²¹ Atropine use to reverse the effects of stings from scorpions from India, South America, the Middle East, and Asia is contraindicated because these scorpions cause an “autonomic storm” with transient cholinergic stimulation followed by sustained adrenergic hyperactivity.^20,218

TICKS

In 1912, Todd described a progressive ascending flaccid paralysis after bites from ticks.²²⁹ Three families of ticks are recognized: (1) Ixodidae (hard ticks), (2) Argasidae (soft ticks), and (3) Nuttalliellidae (a group that has characteristics of both hard and soft ticks and not thought to be parasitic compared to ixodids and argasids). The terms hard and soft refer to a dorsal scutum or “plate” that is present in the Ixodidae but absent in the Argasidae. Both types are characteristically soft and leathery, and both have clinical importance. Ixodidae females are capable of enormous expansion up to 50 times their weight in fluid and blood.⁹³ The paralytic syndrome can be induced following envenomation during the larva, nymph, and adult stages and is related to the tick obtaining a blood meal. The following discussion focuses only on tick paralysis (TP) or tick toxicosis and not on any of the infectious diseases associated with tick bites. Most of the major tick-borne diseases in North America are transmitted by Ixodid ticks except for relapsing fever, which is spread by the soft tick of the genus Ornithodorus or Pediculus humanus (human louse).

In North America, Dermacentor andersoni (Rocky Mountain wood tick) and Dermacentor variabilis (American dog tick), and Amblyomma americanum (Lone Star tick) are the most commonly implicated causes of TP.^99,229 Typically, tick toxicosis occurs in the Southeast, Rocky Mountain, and Pacific Northwest regions of the United States, but cases are also reported in the Northeast.⁷² In Australia, the Ixodes holocyclus or Australian marsupial tick is the most common offender.^99,229 I. holocyclus also seems to be the most potent of the world’s paralyzing ticks and has been known to paralyze dogs, cats, sheep, mice, foals, pigs, chickens, and humans.¹⁵⁴

Pathophysiology

Venom secreted from the salivary glands during the blood meal is absorbed by the host and systemically distributed. To allow successful feeding over several days, ticks need to overcome the host’s hemostatic, inflammatory, and immune mechanisms by producing anticoagulants, fibrinolytic enzymes, antiplatelet and vasodilator substances.^140,188 The saliva also contains some cement to anchor the tick to the host, the hypostome of the I. holocyclus reaches up to 980 microns into the host’s skin and does not need cement support.⁶ Paralysis results from the neurotoxin “ixobotoxin,”¹⁶⁷ which inhibits the release of acetylcholine at the neuromuscular junction and autonomic ganglia, very similar to botulinum toxin.^102,167 Both botulinum toxin and ixobotoxin demonstrate temperature dependence in rat models and show increased muscular twitching activity as the temperature is reduced.^64,154 The salivary toxin of I. holocyclus directly affects vascular and cardiac potassium channels by blockade, and this action differed from the respiratory distress caused by progressive muscle paralysis.¹¹ Cardiovascular function was decreased in dogs with TP. The dogs developed acute left-sided congestive heart failure and prolonged QT intervals were noted.⁵¹

Clinical Manifestations

Usually the tick must remain on the person for 5 to 6 days in order to result in systemic effects. Several days must pass before tick salivary glands begin to secrete significant quantities of toxin. Once secreted, the toxin does not act immediately and may undergo binding and internalization, in a similar sequence to botulinum toxin.^18,64,136 Ticks typically attach to the scalp but can be found on any part of the body, including the ear canals and anus. Children, particularly girls, and adult men in tick-infested areas are predominantly affected. One large series of 305 cases in Canada reported that 21% were adults older than 16 years.²⁰⁴ Among the children, 67% were girls; in adults, 83% were male. The distribution was attributed to the difficulty of detecting ticks in long hair and the possible greater exposure of adult men to tick-infested environments. Children may appear listless, weak, ataxic, and irritable for several days before they develop an ascending paralysis that begins in the lower limbs. Fever usually is absent. Other manifestations include sensory symptoms such as paresthesias, numbness, and mild diarrhea. These symptoms are followed by absent or decreased deep-tendon reflexes and an ascending generalized weakness that can progress to bulbar structures involving speech, swallowing, and facial expression within 24 to 48 hours, as well as fixed, dilated pupils and disturbances of extraocular movements.^102,204 Other atypical presentations are reported and include the following: a child presenting with double vision and being unable to see before the neuromuscular changes occurred, and a healthy elderly man presenting with unilateral weakness and numbness in the left arm for 2 days. Both patients fully recovered after the removal of the tick.⁷² If the tick is not removed, respiratory weakness can lead to hypoventilation, lethargy, coma, and death. Unlike the Dermacentor spp of North America, removal of the I. holocyclus tick does not result in dramatic improvement for several days to weeks. The maximal weakness may not be reached until 48 hours after the tick has been removed or drops off.¹⁰² It is imperative to closely observe patients for possible deterioration. A recent 60-year meta-analysis of TP in the United States reviewed 50 well-documented cases from 1946 to 2006 supporting the above findings.⁷⁸ The demographics were analyzed and the following remained the same: (1) TP is highly predictable regional disease found in the US Pacific Northwest (WA), the West (CA, CO), and the Southeast (GA, MS, NC, SC, VA), and very few cases occurred outside those areas; (2) TP remains a highly predictable seasonal disease occurring during the spring to summer seasons; (3) TP remains more common in females of all ages (80% female/male 4.9:1); (4) Tick attachment sites on the head and scalp continued to predominate over all other attachment sites, representing 48% of the reported attachment sites, 20% occur behind the ear; (5) The Rocky Mountain wood tick (D. Andersoni) was the only TP vector in the western United States (CA, WA, CO) when reported, and D. variabilis, the American dog tick, was the only TP vector from the southeastern United States (GA, NC) when reported.

The differential diagnosis is extensive and includes Guillain-Barré syndrome (GBS), the Miller-Fisher variant of Guillain-Barré, poliomyelitis, botulism, transverse myelitis, myasthenia gravis, periodic paralysis, elapid snakebites, marine neurotoxin poisoning, acute cerebellar ataxia, and spinal cord lesions. The cerebrospinal fluid remains normal, and the rate of progression is rapid, unlike GBS and poliomyelitis.^78,84,201 The edrophonium test is negative. Nerve conduction studies in patients with TP may resemble those of patients with early stages of GBS: findings in both conditions include prolonged latency of the distal motor nerves, diminished nerve conduction velocity, and reduction in the amplitudes of muscle and sensory-nerve action potentials.⁸⁴ With GBS, there is a prolongation of the F wave, however, which does not occur with TP, reflecting the more proximal demyelination of the nerve root.¹⁰⁴ The other causes for acute ascending flaccid paralysis should be eliminated by a complete history, including environmental exposure, hobbies, workplace, travel, ingestions, obtaining appropriate laboratory testing, psychiatric evaluations if needed, and of course a thorough physical examination.

Treatment

Other than removal of the entire tick, which is curative, treatment is entirely supportive. Proper removal of the tick is very important, otherwise infection or incomplete tick removal may occur. The tick should be grasped as close to the skin surface as possible with blunt curved forceps, tweezers, or gloved hands. Steady pressure without crushing the body should be used; otherwise, expressed fluid may infect the patient and lead to inoculating the patient with a higher dose of toxin or infectious agent. After tick removal, the site should be disinfected. Traditional methods of tick removal using petroleum jelly, topical lidocaine, fingernail polish, isopropyl alcohol, or a hot match head are ineffective and may induce the tick to salivate or regurgitate into the wound.¹⁷⁰ It should be remembered that the very same vectors responsible for tick toxicosis can also cause infectious illnesses such as babesiosis, Rocky Mountain spotted fever, anaplasmosis, tularemia, Colorado tick fever, tick-borne relapsing fever, and Lyme disease. Since I. holocyclus of Australia is considerably more toxic and patients are more likely to deteriorate before they improve, close observation is required for several days until improvement is certain.⁸⁴ A hyperimmune serum prepared from dogs is the usual treatment for paralyzed animals, but it has been used sparingly in severely ill humans because of the risk of acute reactions and serum sickness.⁸⁴

HYMENOPTERA: BEES, WASPS, HORNETS, YELLOW JACKETS, AND ANTS

Within the order Hymenoptera are three families of clinical significance: Apidae (honeybees and bumblebees), Vespidae (yellowjackets, hornets, and wasps), and Formicidae (ants, specifically fire ants). These insects (Fig. 118–6) are of great medical importance because their stings are the most commonly reported and can cause acute toxic and fatal allergic reactions. In the 1960s and 1970s, an estimated 40 deaths per year were attributed to anaphylaxis secondary to hymenoptera stings in the United States.^17,208 However, from 2008 to 2011 there have been only two deaths related to envenomations from bees, wasps, and hornets reported to the National Data Poisons System, probably due to increased public awareness of allergic reactions and easier access to medical care.^37,38,39,41

Apis and Bombus species (honeybees and bumblebees) generally build nests away from humans and are passive unless disturbed, but nests of both the honeybees and bumblebees have been found in walls and rodent burrows near homes. Honeybee workers can only sting once because their stinger is a modified ovipositor that resides in the abdomen and its shaft is barbed and has a venom sac attached. Once the stinger embeds into the skin, the stinger disembowels the bee. Bumblebees, however, can sting multiple times. Vespids, on the other hand, are more aggressive and build nests in human living areas, such as in trees and under awnings; yellow jackets inhabit shrubs, trees, and the ground. They, too, are able to sting multiple times.⁹⁶ The introduction of the Africanized honeybee in Brazil (because originally they were thought to be a more efficient honey producer) has caused significant economic and health issues. The bees have migrated toward the southern border of the United States and pose a greater threat to humans. Africanized honeybees are characterized by large populations, can make nonstop flights of at least 20 km, and have a tendency toward mass attack with little provocation.¹⁶⁴

Pathophysiology

Several allergens (Table 118–7) and pharmacologically active compounds are found in honeybee venom. The three major venom proteins are found in the honeybee: melittin, phospholipase A₂, and hyaluronidase.¹⁴⁹ Other proteins include apamin, acid phosphatase, and other unidentified proteins. Phospholipase A₂ is the major antigen/allergen in bee venom.³²

Melittin is the principal component of honeybee venom. It acts as a detergent to disrupt the cell membrane and liberate potassium and biogenic amines.¹⁴ Histamine release by bee venom appears to be largely mediated by mast cell degranulation peptide. Apamin is a neurotoxin that acts on the spinal cord. Apamin binds to the Ca⁺²-triggered K⁺ channel and depresses delayed hyperpolarization to cause its toxicity, which is seen in the mouse model as uncoordinated movements leading to spasms, jerks, and convulsions of a spinal origin.¹¹² Adolapin inhibits prostaglandin synthase and has antiinflammatory properties that may account for its use in arthritic therapy.²⁰⁶ Phospholipase A₂ and hyaluronidase are the chief enzymes in bee venom.

The three major proteins in vespid venoms serve as allergens and are accompanied by a wide array of vasoactive peptides and amines.¹⁴⁹ The intense pain following vespid stings is largely caused by serotonin, acetylcholine, and wasp kinins. Antigen 5 is the major allergen in vespid venom.¹⁶⁵ Its biologic function is unknown. Mastoparans have action similar to mast cell degranulation peptide, but weaker.¹⁴ Phospholipase A₂ may be responsible for inducing coagulation abnormalities.¹⁷⁵

Clinical Manifestations

Normally, the honeybee sting is manifested as immediate pain, a wheal-and-flare reaction, and localized edema without a systemic reaction. Vomiting, diarrhea, and syncope can occur with a higher dose of venom resulting from multiple stings.³⁵ Rarely, a sting in the oropharynx produces airway compromise.²⁰⁸

Toxic reactions occur with multiple stings (more than 500 stings are described as possibly fatal and occur with Africanized honeybees)⁹⁶ and include gastrointestinal (GI) symptoms, headache, fever, syncope and, rarely, rhabdomyolysis, acute kidney injury, and seizures.³⁵ Other rare complications include idiopathic intracranial hypertension,²²⁶ cerebral infarction, and ischemic optic neuropathy²⁰³ and Parkinsonism¹⁴⁸ and are thought to occur because of the proximity of the sting near the head and neck. Bronchospasm and urticaria are typically absent.

This type of toxic reaction is different from the hypersensitivity reactions or anaphylactic reactions because it is not an IgE-mediated response, but rather a direct effect from the venom itself. Hypersensitivity reactions, including anaphylaxis, occur from Hymenoptera stings. These reactions are IgE mediated. The IgE antibodies attach to tissue mast cells and basophils in individuals who have been previously sensitized to the venom. These cells are activated, allowing for progression of the cascade reaction of increased vasoactive substances, such as leukotrienes, eosinophil chemotactic factor-A, and histamine. An anaphylactic reaction is not dependent on the number of stings. Patients who are allergic to hymenoptera venom develop a wheal-and-flare reaction at the site of the inoculum. The shorter the interval between the sting and symptom onset, the more likely the reaction will be severe. Fatalities can occur within several minutes; even initially mild symptoms may be followed by a fulminant course. Generalized urticaria, throat and chest tightness, stridor, fever, chills, and cardiovascular collapse can ensue.

Treatment

Application of ice at the site usually is sufficient to halt discomfort. Stingers from honeybees should be removed by scraping with a credit card or scalpel, as opposed to pulling, which may release additional retained venom. Since the stinger in other bee species typically stays within the insect, this removal technique would not be necessary if other bee species are involved. Therapy is aimed at supportive care that includes standard therapy for anaphylaxis with epinephrine, diphenhydramine, and corticosteroids.

FIRE ANTS

There are native fire ants in the United States, but the imported fire ants Solenopsis invicta and Solenopsis richteri are significant pests that have no natural enemies. They are native to Brazil, Paraguay, Uruguay, and Argentina but were introduced into Alabama in the 1930s. They have spread rapidly throughout the southern United States, damaging crops, reducing biologic diversity, and inflicting severe stings to humans.²²⁴ S. invicta, the most aggressive species, now infests 13 southern states and has been introduced into Australia.^210,213 Allergic reactions to ant stings were limited to the jumper ant (Myrmecia pilosula, other Myrmecia spp) and the greenhead ant (Rhytidoponera metallica; Odontomachus, Cerapachys, and Brachyponera spp) in Australia until February 2001, when the imported red fire ant was identified at two sites in Brisbane.²¹⁰ The mode of introduction is unknown but may have originated from the transport of infested cargo. Fire ants range from 2 to 6 mm in size. They live in grassy areas, garden sites, and near sources of water. The nests are largely subterranean and have large, conspicuous, dome-shaped above-ground mounds (up to 45 cm above the ground), with many openings for traffic. The mounds can contain 80,000 to 250,000 workers and one or more queens that live for 2 to 6 years and produce 1500 eggs daily.²³⁵ Fire ants are named for the burning pain inflicted after exposure, and necrosis can result at the site. The imported fire ant attacks with little warning. By firmly grasping the skin with their mandibles, both the fire ant and the jumper ant can repeatedly inject venom from a retractile stinger at the end of the abdomen. Pivoting at the head, the fire ant injects an average of seven or eight stings in a circular pattern.²¹³

Pathophysiology

The venom inhibits sodium and potassium adenosine triphosphatases, reduces mitochondrial respiration, uncouples oxidative phosphorylation, adversely affects neutrophil and platelet function, inhibits nitric oxide synthetase, and perhaps activates coagulation.^133,135 Unlike the venoms of wasps, bees, and hornets that contain mostly aqueous-containing proteins, the imported fire ant venom is 95% alkaloid, with a small aqueous fraction that contains soluble proteins.¹⁵² Of the alkaloids, 99% is a 2,6-disubstituted piperidine that has hemolytic, antibacterial, insecticidal, and cytoxic properties.⁷⁴ There is also some in vivo evidence that the Solenopsin alkaloids can inhibit nitric oxide synthetase activity and has direct cardiotoxic, convulsant, and respiratory depressant activities.^123,243 These alkaloids do not cause allergic reactions, but they produce a pustule and pain. The aqueous portion of the venom contains the allergenic activity of fire ant venom, Sol i I to IV.^116,213 The proteins identified in the venom include a phospholipase, a hyaluronidase, and the enzyme N-acetyl-β-glucosaminidase.^75,213

Clinical Manifestations

In the United States, residents of health care facilities who are immobile or cognitively impaired are at risk for fire ant attacks, especially when the facility lacks pest control techniques for fire ants.⁷⁵ Three categories are suggested based on the reactions to the imported fire ant: local, large local, and systemic.²¹³ Local reactions occur in nonallergic individuals. Large local reactions are defined as painful, pruritic swelling at least 5 cm in diameter and contiguous with the sting site. Systemic reactions involve signs and symptoms remote from the sting site. The sting initially forms a wheal that is described as a burning itch at the site, followed by the development of sterile pustules. In 24 hours, the pustules umbilicate on an erythematous base. Pustules may last 1 to 2 weeks.⁹⁶ Late cutaneous allergic reactions can occur in some persons who experience indurated pruritic lumps at the site of subsequent stings.⁷⁴ Large reactions may lead to tissue edema sufficient to compromise blood flow to an extremity. Anaphylaxis occurs in 0.6% to 6% of persons who have been stung.²¹³ Often, healing occurs with scarring in 10 to 14 days.

The majority of individuals who die after fire ant attacks succumbed to heart failure.⁷⁵ These individuals came from nursing homes primarily; however, the solenopsins were found to strongly inhibit myocardial contractility which might explain the heart failure that occurred after massive envenomations.^75,123

Diagnosis

Clinical clues such as pustule development at the sting site after 24 hours, species identification, and history may help to identify fire ant exposure. No laboratory assays to determine exposure are available. Fire ant allergy can be determined by correlating the clinical manifestation of fire ant sting reactions with imported fire ant–specific IgE determined by skin testing or radioallergosorbent test.

Treatment

Local reactions require cold compresses and cleansing with soap and water. Some authors recommend topical or injected lidocaine with or without 1:100,000 epinephrine, and topical vinegar and salt mixtures to decrease pain at the site of the bite and sting.^{43,120,157,193}

Large local reactions can be treated with oral corticosteroids, antihistamines, and analgesics. Secondary infections should be treated with antibiotics. Systemic reactions should be treated with subcutaneous or intravenous epinephrine

BUTTERFLIES, MOTHS, AND CATERPILLARS

Butterflies and moths are insects of the order Lepidoptera. Several moth and butterfly families have species whose caterpillars are clinically important, that is, they contain spines or urticating hairs that secrete a poison that is irritating to humans on contact. Lepidopterism is a general term that describes the systemic adverse effects such as generalized urticaria, headache, pharyngitis, conjunctivitis, nausea, vomiting, bronchospasm, wheezing, and dyspnea that occur when humans are exposed to moths and butterflies.¹⁶⁶ Erucism is the term used when a cutaneous dermatitis results from contact with urticating caterpillars, the larval forms of the insect order Lepidoptera (moths and butterflies).⁷⁹ Caterpillar species from about 12 families of moths and rarely butterflies worldwide can inflict serious human injuries, including urticarial dermatitis, allergic reactions, consumptive coagulopathy, acute kidney injury, intracerebral hemorrhage, arthritis, joint deformity, and even altered mental status, ataxia, and dysarthria.^79,122

Caterpillar, which means hairy cat in Latin, is the larval stage for moths and butterflies. In the United States, several significant stinging caterpillars are of note. Often the puss caterpillar (Megalopyge opercularis) is considered one of the most important and toxic of the caterpillars in the United States because of the frequency with which reactions have been reported, especially in Texas.²¹⁵ Other names for the puss caterpillar are woolly/hairy worm, wooly slug, opossum bug, tree asp, Italian asp, and “el perrito” in Spanish.²¹⁵ The caterpillars look furry and are covered in silky tan to brownish hairs that hide short spines containing an urticarial toxin. The spines are yellowish with black tips, and the hairs vary in color ranging from pale yellow and gray to brown.²⁹ Other significant stinging caterpillars in the United States are the flannel moth caterpillar (Megalopyge crispata), the Io moth (Automeris io), the saddleback caterpillar (Sibine stimulata), and the hickory tussock caterpillar (Lophocampa caryae).¹⁴⁷ In South America, especially Brazil, Lonomia obliqua caterpillars are notorious for causing severe pain and a hemorrhagic syndrome.^52,69 In Australia, several caterpillars are of medical importance: mistletoe brown tail moth (Euproctis edwardsi), processionary caterpillars (Ochrogaster lunifer), cup moths (Doratifera spp), and the white-stemmed gum moth (Chelepteryx collesi).¹³ Pine processionary caterpillars (Thaumetopoea pityocampa) are the most important defoliator of pine forests in the Mediterranean and central European countries, with significant consequential economic and occupational repercussions for workers who frequent these pine forests.²³⁰ In Nigeria, the Anaphe venata caterpillar is an important resource for protein that can cause thiamine deficiency syndrome similar to dry beriberi. Finally, the dendrolimus caterpillars of China and the Preolis semirufa caterpillars in Brazil cause significant joint disease.

Pathophysiology

The pathophysiology of dendrolimiasis is not understood, but the tegument-produced venom contains formaldehyde and several uncharacterized histamine analogs with a tropism for receptors in bone, joints, and cartilage and during the acute phase may result from IgE-mediated allergy to foreign proteins, and the chronic bone and joint disease may be autoimmune mediated.¹²⁵ The composition of the venom varies according to the different caterpillar species. Some toxins contain proteins that cause histamine release, such as thaumetopoien isolated from T. pityocampa or pine processionary caterpillar.^230,231 Another protein isolated from the L. obliqua caterpillar causes coagulopathy. It is called lonomin V and is a proteolytic enzyme, which is isolated in the hairs, spines, and hemolymph of the L. achelous.¹¹¹ Its mechanism of action is not fully known, but it somehow activates factors X and II, and there is some evidence that collagen degradation might be responsible for platelet inhibition.^80,110,138 The venom and hair structure of Lagoa crispata, which has often been confused with the southern Texas puss caterpillar, has been characterized.¹⁴⁷ The venom is stored at the base of the hollow setae (spines) where the poison sac and nervous tissue are located. Upon contact with these spines, the toxin is released. The toxin may be a protein or a substance that conjugates with proteins.⁸⁷ The varying differences of caterpillar venom and their clinical effects emphasize the importance of positive identification of caterpillars.

Clinical Manifestations

The pathophysiologic effects of venomous caterpillar exposures can be classified into seven distinct clinical syndromes to guide clinicians in making earlier, more species-specific diagnoses to direct therapies, including: (1) erucism, (2) lepidopterism, (3) dendrolimiasis, (4) ophthalmia nodosa, (5) consumptive coagulopathy with secondary fibrinolysis,⁷⁹ (6) seasonal ataxia, and (7) pararamose.¹²² Erucism is the preferred term for caterpillar dermatitis caused by contact with caterpillar urticating hairs, spines, or toxic hemolymph. Lepidopterism is a systemic illness caused by a constellation of adverse effects resulting from direct or aerosol contact with caterpillar, cocoon, or moth urticating hairs, spines or body fluids and is characterized by generalized urticaria, headache, conjuctivitis, pharyngitis, nausea, vomiting, bronchospasm, wheezing, and, rarely, dyspnea. Dendrolimiasis is a chronic form of lepidopterism caused by direct contact with urticating hairs, spines, or hemolymph of living or dead central Asian pine-tree lappet moth caterpillars or their cocoons and is characterized by urticating maculopapular dermatitis, migratory inflammatory polyarthritis, migratory inflammatory polychondritis, chronic osteoarthritis, and, rarely, acute scleritis.¹²⁵ Ophthalmia nodosa is a chronic ocular condition characterized by initial conjunctivitis with subsequent panuveitis caused by corneal penetration and subsequent intraocular migration of urticating hairs from lymantriid caterpillars and moths and therapsid spiders (tarantulas).

The South American Lonomia saturniid moth caterpillars range from Venezuela to northern Argentina and pose a threat in Brazil due to the high fatality rates from venom-induced consumptive coagulopathy, intracerebral hemorrhage, and acute renal failure, possibly due to a combination of venom nephrotoxicity and microcirculatory fibrin deposition.⁴⁶ The hemorrhagic syndrome can present as a disseminating intravascular coagulopathy and as a secondary fibrinolysis with skin, mucosal, and visceral bleeding, acute kidney injury, and intracerebral hemorrhage.^52,138

Seasonal ataxia is a syndrome of of unsteady gait and dysarthria, which occurs after the ingestion of the caterpillar of Anaphe venata. This occurs in areas of Nigeria where they are a source of protein.^3,4 Ingestion of the roasted larvae causes nausea and vomiting and progresses to dizziness, ataxia, and unsteady gait in more than 90% of victims. These symptoms may take weeks to months for resolution. Dysarthria and impaired consciousness have also been reported. The pathogenesis is related to thiamine deficiency induced by the caterpillars.

Pararamose is similar to dendrolimiasis with pruritic or painful dermatitis associated with arthritis and joint deformity, arising from contact with the caterpillar of Premolis semirufa, which are found in the Brazilian Amazon rain forests. Rubber tree plantation workers are particularly at risk even when wearing protective gloves.^66,77

The clinical effects of caterpillar exposure can generally be separated into two types—stinging reaction and pruritic reaction—although overlap may occur. Stinging caterpillars, such as M. opercularis, envenomate by contact with their hollow spines containing venom. The reaction is characterized as a painful, burning sensation with local effects and, less commonly, systemic effects. The area may become erythematous and swollen, and papules and vesicles may appear. The classic gridlike pattern develops within 2 to 3 hours of contact. Reported symptoms include nausea, vomiting, fever, headache, restlessness, tachycardia, hypotension, urticaria, seizures, and even radiating lymphadenitis and regional adenopathy.¹⁷⁷ Pruritic reactions occur upon exposure to the itchy caterpillars that have nonvenomous urticating hairs, which can produce a mechanical irritation, allergic reaction, or a granulomatous reaction from the chronic presence of the hairs. Several species that cause allergic reactions are the white-stemmed moth (C. collesi), Douglas fir tussock moth (Orgyria pseudotsugata), and gypsy moth caterpillar (Lymantria dispar).¹⁶⁶ Caterpillar hairs can cause ocular trauma, otherwise known as ophthalmia nodosa.²¹² The range of ocular pathology depends on the penetration factor and the effect of the released urticating toxins.⁵⁰ The ocular spectrum has been classified into five types.⁵⁰

Type 1: Brief exposure time of 15 minutes. Symptoms of chemosis, inflammation, epiphora, and foreign body sensation may last for weeks.

Type 2: Chronic mechanical keratoconjunctivitis (hairs in bulbar/palpebral conjunctivitis). Foreign body sensation is relieved by removal of hairs. Corneal abrasions may be present.

Type 3: Gray-yellow nodules or asymptomatic granulomas.

Type 4: Severe iritis with or without iritis nodules; hairs are in the anterior chamber and possible intralenticular foreign body.

Type 5: Vitreoretinal involvement. Hairs may enter through the anterior chamber or iris lens or by transscleral migration. May cause vitreitis, cystoid macular edema, papillitis, or endophthalmitis.

Treatment

Management for most dermal caterpillar envenomations is entirely supportive and includes washing the area with soap and water; “no touch” drying of the sting site with a hair dryer; gentle stripping of the bite site with cellophane or adhesive duct tape; and application of ice packs with cooling enhanced by initial topical swabbing with isopropyl alcohol. Rings should be removed in anticipation for potential swelling of the extremity, and tetanus prophylaxis should be updated accordingly.⁷⁹

Treatment of ocular lesions depends upon the exposure classification and should be managed by the ophthalmologist. Most patients can be classified as type 1 or 2. Irrigation with 0.9% sodium chloride solution should be followed by meticulous removal of setae, followed by topical steroids and antibiotics. Type 3 requires surgical excision of the nodules. Type 4 requires topical steroids with or without iridectomy for nodules or operative removal of setae. Type 5 requires local treatment with or without systemic steroids. Resistant cases may require vitrectomy with removal of setae.

Opioids may be necessary, if minor analgesics do not provide relief. If muscle cramps develop, benzodiazepines should be administered. One study recommended the use of 10 mL 10% calcium gluconate administered IV, which provided pain relief.¹⁶⁰ Topical corticosteroids can be used to decrease local inflammation. Antihistamines such as diphenhydramine (25–50 mg for adults and 1 mg/kg, maximum 50 mg, in children) can be used to relieve pruritus and urticaria.^160,177 Nebulized β-agonists and epinephrine administered subcutaneously may be required for more severe respiratory symptoms and anaphylactoid/anaphylactic-type reactions. Dendrolimiasis treatment consists of mostly supportive care with early surgical intervention recommended to excise draining sinus tracts and infected cartilage and to prevent permanent bone and joint deformities.¹²⁵ For hemorrhagic syndrome resulting from exposure to L. obliqua caterpillar, besides restoration of clotting factors, platelet, and cryoprecipitate infusions, an antidote called the antilonomic serum (SALon) is available and is used for treatment of the hemorrhagic syndrome in Brazil.⁶⁹ It is important to involve an experienced hematologist for suspected Lonomia envenomation and very important to distinguish Lonomia obliqua from Lonomia achelous because the cryoprecipitate, purified fibrinogen, and antifibrinolytic drugs, such as aprotinin and ε-aminocaproic acid, have been successfully used in Lonomia achelous but may exacerbate the hemorrhagic symptoms in Lonomia obliqua with fatal consequences.^59,98 Patients exposed to either species should neither receive whole blood nor fresh plasma or they may worsen clinical symptoms. Treatment for the seasonal ataxia includes supportive care with the administration of thiamine 100 mg orally every 8 hours, which found reversal of symptoms within 48 hours without long term sequelae in a double blinded placebo controlled trial.²

BLISTER BEETLES

Blister beetles are plant-eating insects that exude a blistering agent for protection. They can be found in the eastern United States, southern Europe, Africa, and Asia. Most are from the order Coleoptera, family Meloidae. Epicauta vittata is the most common of more than 200 blister beetles identified in the United States.¹³⁷ When the beetles sense danger, they exude cantharidin by filling their breathing tubes with air, closing their breathing pores, and building up body fluid pressure until fluid is pushed out through one or more leg joints.⁹⁶ Cantharidin is a potent blistering agent found throughout all 10 stages of life of the blister beetle.⁵⁴ Cantharidin is produced only by the male blister beetle and is stored until mating. In the wild, the female repeatedly acquires cantharidin as copulatory gifts from her mates. However, the female blister beetle loses most of her reserves as she matures.⁵⁴ Cantharidin, also known popularly as Spanish fly, takes its name from the Mediterranean beetle Cantharis vesicatoria. It has been ingested as a sexual stimulant for millennia. The aphrodisiac properties are related to the ability of cantharidin to cause vascular engorgement and inflammation of the genitourinary tract upon elimination, hence the reports of priapism and pelvic organ engorgement.²²⁸ Cantharidin was once used for treatment of bladder and kidney infections, stones, stranguria (bladder spasm), and various venereal diseases.¹³⁷ In the last century, cantharidin was commonly used for treatment of pleurisy, pneumonia, arthritis, neuralgias, and various dermatitides. A topical 1% commercial preparation can be used for removal of warts and molluscum contagiosum.^65,205 Cantharidin poisoning is reported by cutaneous exposure,⁴² unintentional inoculation,¹⁸⁰ and inadvertent ingestion of the beetle itself.²²⁵ There is one case report of a child being treated for molluscum contagiosum with cantharidin preparation that included podophyllin and salicylic acid, also called Canthacur PS or Canthacur Plus.²⁰⁵ The child developed varicelliform vesicular dermatitis in the distribution of the application of petrolatum. It is thought that the petrolatum used by the parents to moisturize her skin spread the lipophillic cantharidin preparation to the nearby areas causing the blistering reaction. Canthacur PS should not be used for molluscum contagiosum but is reserved for verrucae vulgaris on acral areas. Canthacur or Cantharone contains plain cantharidin and can be used for the treatment of molluscum contagiosum. Fewer than 30 cases of Spanish fly poisoning have been reported since 1900.¹³⁷

Pathophysiology

Cantharidin is a natural, defensive, highly toxic terpenoid (lethal dose for humans 0.5 mg/kg) produced by blister beetles and shares a structural similarity with the herbicide Endothall.¹⁴⁹ Endothall causes corrosive effects to the GI tract; cardiomyopathy and vascular permeability lead to shock. A single case report of lethal poisoning with 7 to 8 g of endothall has been reported, and the healthy young male died of hemorrhage of the GI tract and lung, which is clinically similar to the cantharidin exposures. Although the mechanism of action has not been elucidated, one mechanism based on an in vitro study suggests that cantharidin inhibits the activity of protein phosphatases type 1 and 2A. This inhibition alters endothelial permeability by enhancing the phosphorylation state of endothelial regulatory proteins and results in elevated albumin flux and dysfunction of the barrier.¹⁴³ Enhanced permeability of albumin may be responsible for the systemic effects of cantharidin, which lead to diffuse injury of the vascular endothelium and resultant blistering, hemorrhage, and inflammation.

Clinical Manifestations

The clinical effects can mostly be attributed to the irritative effects on the exposed organ systems. The secretions of cantharidin from the beetle’s leg joints cause an urticarial dermatitis that is manifested several hours later by burns, blisters, or vesiculobullae.⁴² Symptoms may be immediate or delayed over several hours. In addition to the local effects, cantharidin can be absorbed through the lipid bilayer of the epidermis and cause systemic toxicity, with diaphoresis, tachycardia, hematuria, and oliguria from extensive dermal exposure.²²⁸ If the periorbital region is contaminated, edema and blistering can evolve. Ocular findings from direct contact with the beetle or hand contamination include decreased vision, pain, lacrimation, corneal ulcerations, filamentary keratitis, and anterior uveitis.¹⁸⁰ Most human exposures involve inadvertent contact with the beetle or its secretions, resulting in dermatitis, keratoconjunctivitis, and periorbital edema secondary to hand-eye involvement, also called the Nairobi eye.¹⁸⁰

When cantharidin is ingested, severe GI disturbances and hematuria can occur. Initial patient complaints may include burning of the oropharynx, dysphagia, abdominal cramping, vomiting, hematemesis followed by lower GI tract hematochezia, and tenesmus. An inadvertent blister beetle ingestion by a child who thought it was the edible Eulepida mashona or white grub resulted in hematuria and abdominal cramping.²²⁵ Genitourinary effects include dysuria, urinary frequency, hematuria, proteinuria, and renal impairment. Most symptoms resolved over several weeks. However, death from renal failure with acute tubular necrosis is reported.²²⁸

Diagnostic Testing

Cantharidin toxicosis has been identified for equine and ruminant exposures by screening urine and gastric contents with high-performance liquid chromatography and gas chromatography-mass spectrometry.^184,185 This method has not been used in clinical practice.

Treatment

Treatment is largely supportive. Wound care and tetanus status should be assessed. For keratoconjunctivitis, an ophthalmologist should be consulted early in the clinical course and the patient treated with topical corticosteroids (prednisolone 0.125%), mydriatics (cyclopentolate 1%), and antibiotics (ciprofloxacin 0.3%).

SUMMARY

• Health care providers should have an extensive knowledge regarding the identification of arthropods and their bites and stings so they can provide optimal care to their patients.

• Black widow: Lactrodectism is a painful neurotoxic condition best known for causing intense muscle spasms associated with short term autonomic and central nervous system dysfunction.

• Brown recluse: Loxoscelism is manifested by necrotic tissue loss, which is less often accompanied by systemic reactions such as hemolysis, coagulopathy, renal failure, and death.

• Scorpions: Envenomation releases a neurotoxin that opens the sodium channels to cause an array of effects the envenomation leads to local as well as systemic effects that activate the sympathetic and parasympathetic branches of the nervous system leading to intense pain, edema, and erythema as well as severe hypertension and tachy- or brady-dysrhythmias.

• Ticks: Ticks are vectors that are commonly known to transmit disease but in the setting of envenomations, one must remember tick toxicosis in the differential as a cause of progressive ascending flaccid paralysis that can be fatal if the tick is not removed.

• Caterpillars: Lepidopterism is another cause of common human envenomations that typically cause dermal and ocular symptoms.

Acknowledgment

Neal A. Lewin, MD, contributed to this chapter in previous editions.

References

INTRODUCTION

The terms “antivenom” and “antivenin” often are used interchangeably. Although the origin of the term “antivenom” is obvious, “venin” is French for venom and “antivenin” is traditionally used in certain parts of the world. Wyeth Pharmaceuticals, the maker of Crotaline and Micrurus antivenom, and Merck & Co., Inc., the maker of Latrodectus antivenom, adopted “antivenin” in the brand names for their products. Brand name recognition has largely been responsible for the use of the term “antivenin” in place of “antivenom”. In 1981, the World Health Organization determined the preferred terms for the English language to be “venom” and “antivenom.”

HISTORY

Of the species of spiders of medical importance in the United States, two of the most notable are Latrodectus (L. mactans, L. geometricus, L. vaiolus, L. hesperus, and L. bihopi are native, while L. geometricus was introduced) and Loxosceles. Although commercially available antivenom exists in the United States for treatment of Loxosceles envenomation, antivenom produced for South American Loxosceles spiders demonstrates cross-reactivity with North American species like L. reclusa.¹² Currently, one commercially available Latrodectus antivenom exists in the United States. Black widow spider antivenin (Merck & Co., Inc.) (Merck BW-AV) has been available in the United States since its U.S. Food and Drug Administration (FDA) approval in 1936.³ The use of this antivenom in the treatment of Latrodectus envenomations remains controversial, as mortality from these bites is low in the United States,^7,8,30,32 and complications including death following antivenom administration are rarely reported.^7,20,31 Most recently, severe production shortages have necessitated emergency release of the product by the manufacturer within 24 hours of notification of a patient with symptoms from a presumed envenomation.¹ Ongoing research and development of an F(ab′)₂ antivenom may ameliorate concerns and limitations related to potential adverse events resulting from administration of the Merck antivenom and production shortages limiting availability.¹¹

PHARMACOLOGY

Chemistry, Preparation, and Mechanism of Action

Antivenom for spiders is prepared in a similar manner as other antivenom products by first immunizing animals with non-toxic amounts of venom.^5,25 Monkeys, horses, goats, sheep, chicken, camels, and rabbits have been used historically to source antivenom.²⁸ The animals are placed on an inoculation schedule to allow gradual production of immunoglobulins, most importantly IgG. Sufficient antibody production usually requires up to 6 weeks. Animal choice for immune serum production is more often dictated by the species availability, financial considerations, and tradition rather than scientific modeling. Horses are used by the majority of antivenom producers, since they are relatively easy to maintain, and large volumes of serum can be obtained at one time without harm. Varying efforts are made during antivenom production to remove animal proteins such as albumin. Antivenoms target, bind, neutralize, and promote elimination or redistribution of toxins from body tissues. To date, no studies have compared immune sera of different animals for human compatibility or tolerance.

The antidotal fraction of an antivenom exists as either whole IgG, Fab, or F(ab′)₂. The IgG molecule is composed of two antigen-binding fragments (Fab fragments) that are fused together and attached to the larger complement binding fragment (Fc fragment). It is the larger Fc portion that is generally considered to be the most responsible for immune mediated reactions. Digestion of the disulfide bonds of an IgG molecule with the enzyme pepsin will cleave the Fc fragment, allowing isolation of pure F(ab′)₂ fragments (two fused Fab fragments). In contrast, digestion with papain cleaves the molecule more distally such that a larger Fc portion is removed from two separate Fab fragments. Both Fab and F(ab′)₂ molecules can be isolated with affinity chromatography, and the highly antigenic Fc portion discarded. Although Fab and F(ab′)₂ are more expensive to produce than their whole immunoglobin counterparts, they are generally regarded as less allergenic and therefore safer products.

Whole IgG antivenom is the easiest and least expensive to produce. It has a molecular weight of approximately 150 kDa, and is the largest of the three antivenom types. Because of its size, it is the least filterable at the glomerulus and has the smallest volume of distribution. IgG has a longer elimination half-life than either Fab or F(ab′)₂.¹⁷

F(ab′)₂ has an intermediate size (∼100 kDa) and elimination half-life. While lowering the risk of anaphylaxis compared to whole IgG, the F(ab)₂ portion retains much of the allosteric configuration of the original IgG molecule that is lost in when Fab are formed. This configuration theoretically allows for tighter binding to venom. Fab is the smallest (∼50 kDa) antivenom molecule in size and is eliminated by the kidneys. It has the largest volume of distribution and a greater ability to reach extravascular compartments. Arachnid venoms that affect the central nervous system have low molecular weights and large volumes of distribution. Fab and F(ab)₂ based antivenoms may therefore be best suited for this function.¹⁷

Immunoglobulin based antivenoms can be given by the intramuscular (IM), intravenous, or subcutaneous route. Intravenous administration achieves rapid peak serum concentrations, and the infusion can be stopped in the event of an allergic reaction.¹⁸ Intramuscular injection has been used when intravenous access is unobtainable.

Pharmacokinetics and Pharmacodynamics

Currently, there is no published pharmacokinetic or pharmacodynamic information available on Merck BW-AV in humans or animals. Graudins and colleagues demonstrated western blot binding of L. hasselti (Red Back Spider) Antivenom (RBS-AV) to purified α-latrotoxin and similar protein bands derived from multiple widow spiders (L. mactans, L. hesperus, L. lugubris, L. tredecimguttatus, and L. hasselti). When co-mixed with the venoms from these species prior to administration, RBS-AV prevented the development of a reproducible and rapid muscle contracture of an in vitro chicken nerve-muscle preparation. A dose-response relationship was observed with varying doses of RBS-AV administration.¹⁶ This confirms a direct in vitro binding effect of RBS-AV against widow spider venoms.

Previous animal studies have demonstrated that intramuscular administration of antivenom demonstrated very low serum venom concentrations.^35,36 In these rabbit studies of intramuscular administration, F(ab′)₂ and IgG had poor bioavailability (36%–42%) and delayed time to peak concentrations of 48 to 96 hours.

Pharmacokinetic and pharmacodynamic characteristics of equine derived antivenoms may differ between species studied. Equine derived antivenom maximum concentrations were greater in cows than in horses, and steady state distribution volumes were higher in cows than in horses in one study. Similar results were observed in rabbit models.³⁷ Pharmacokinetic and pharmacodynamic parameters observed in animal models should therefore be interpreted with caution with regard to behavior of antivenoms in humans.

RBS-AV has been administered intramuscularly to treat human envenomations and clinical effectiveness equivalent to intravenous administration was previously reported.²¹ Subsequent studies, however, demonstrated the absence of RBS-AV in circulating serum up to 5 hours following intramuscular administration. Serum concentrations of RBS-AV were detected within 30 minutes of administration following intravenous administration.²⁴ These results are consistent with animal studies demonstrating little if any effect on circulating venom when antivenoms are given intramuscularly. Additional studies on the pharmacokinetic and pharmacodynamic properties of RBS-AV, Merck Black Widow Antivenom, and F(ab′)₂ black widow antivenom (in development) are needed.

ROLE IN LATRODECTUS SPECIES (L. MACTANS, L. HESPERUS, L. BISHOPI, L. GEOMETRICUS, L. VARIOLUS, L. INDISTINCTUS)

Although black widow bites are associated with severe muscle pain, cramping, and autonomic disturbances, mortality remains low.^7,8,30,33 Symptomatic treatment with muscle relaxants and opioid analgesics is generally effective, although the duration of symptoms following severe envenomation may necessitate hospitalization for 1 to 2 days or more.

The use of Merck Black Widow antivenom may shorten the length of symptoms dramatically, allowing outpatient care in some cases.^{7,30,32,33,39} Studies of reported Latrodectus envenomated patients in Australia, however, have demonstrated little clinical difference between Latrodectus antivenom and placebo.²¹ In addition, anaphylaxis and other adverse events following the administration of Latrodectus antivenom are reported.^7,20,30,31

Because of low mortality and potential for adverse events following administration, some authors question the use of black widow antivenom.³⁶ Many toxicologists still believe Latrodectus antivenom is safe and effective when used appropriately, and it is generally indicated in cases of severe envenomation where muscle cramping, hypertension, diaphoresis, nausea, vomiting, and respiratory difficulty are present.⁸

Latrodectus antivenom is also reported to successfully treat priapism complicating severe envenomation.¹⁹ Although the safety of antivenom is not clearly established in the developing fetus, pregnancy is suggested as a consideration for Latrodectus antivenom administration, as the stress of severe pain and muscle cramps may have adverse fetal effects.^4,38

Antivenoms for a number of Latrodectus spiders are available worldwide (Table A34–1). A shortage of Merck antivenom prompted the finding that antivenom against L. hasseltii (RBS-AV) also neutralizes venom of L. mactans in a mouse model.¹⁰ Analatro, a polyvalent F(ab)₂, is an equine-derived antivenom created for L. mactans in both Argentina and Mexico that is currently undergoing multi-center clinical trials in Latrodectus envenomated patients in the United States.

In a review of 163 cases of presumed L. hesperus and mactans envenomations, antivenom reduced the mean duration of symptoms from 22 to 9 hours. Symptoms usually subsided within 1 to 3 hours of antivenom administration. The hospital admission rate fell from 52% in those who were managed with opioids and muscle relaxants to 12% in those patients receiving antivenom.⁷ A more recent review demonstrated pain relief in all patients receiving antivenom following symptomatic black widow envenomation.³²

ROLE IN FUNNEL-WEB SPECIES (ATRAX AND HADRONYCHE)

A rabbit IgG based funnel-web spider (Atrax robustus and others) antivenom is available in Australia. Since the introduction of the antivenom, no deaths have been reported.²³ Complete response following administration of antivenom was reported in 97% of envenomations in one series.²²

ROLE IN LOXOSCELES SPECIES (L. RECLUSA, L. LAETA, L. RUFESCENS, L. ARIZONICA, L. UNICOLOR)

Envenomation by the brown recluse spider Loxosceles reclusa is associated with low, but significant morbidity, particularly in the southeast United States. Anti-Loxosceles Fab blocked dermonecrosis in a rabbit model, but only if provided within 24 to 48 hours of envenomation.^15,34 Although no commercially available antivenom exists in North America for treatment of Loxosceles envenomation, antivenom produced against South American Loxosceles spiders has cross-reactivity with North American species like L. reclusa.¹² The usual late presentation of patients with necrotic lesions from spider bites make antivenom use for Loxosceles difficult to study. National laboratories in Brazil and Argentina produce antivenoms for L. reclusa, L. boneti, and L. rufescens.^5,12

ADVERSE EFFECTS AND SAFETY ISSUES

Despite the apparent efficacy of antivenom, the decision to give horse serum for a disease with limited mortality should be considered. Death from bronchospasm and anaphylaxis is a rarely reported complication of whole IgG antivenom (Merck) administration,^7,20,31 as is serum sickness.⁸ Serum sickness is dose-dependent and is less likely when only 1 to 2 vials are typically administered. A detailed review of one case of death following antivenom administration⁷ demonstrates that the antivenom was inappropriately prepared (not diluted) and inappropriately administered (intravenous push rather than slow infusion) to a patient with multiple drug allergies, atopy, and asthma. Resuscitation was further complicated by the development of a pneumothorax. A second death³¹ was reported in a 37 year-old man with history of asthma who received antivenom as an infusion and developed cardiac arrest as a complication of severe anaphylaxis. He died 40 hours after presentation.³¹

In Australia, antivenom to the red-back spider (L. hasseltii, CSL Ltd.) is made by immunizing horses for production of F(ab)₂. Horse-derived F(ab′)₂ has a lower reported incidence of allergic reactions, with early allergic reactions as low as 0.5% to 0.8%. The incidence of serum sickness is reported at less than 5%.^40,41 Analatro (under evaluation) is a similar F(ab′)₂ product which would be anticipated to be a safer antivenom than the currently available Merck whole IgG product.

A review of the US National Poison Data System (NPDS) demonstrated a 3.4% rate of adverse drug reactions (ADRs) following administration of the Merck Latrodectus antivenom.³⁰ This is consistent with previously reported rates of ADRs following black widow antivenom administration.⁸ Directly attributing these complications to administration of antivenom is difficult as these patients received multiple therapies including opioids, benzodiazepines, and calcium salts preceding antivenom administration, and NPDS does not attribute an ADR to a specific therapy. Similarly, the nature of these ADRs is not described in NPDS. However, it is noteworthy that no deaths occurred in 374 instances of use and only five patients received antihistamines, suggesting acute hypersensitivity reactions to the Merck black widow antivenom to be uncommon and that this antivenom is generally safe. Similarly, a review of 96 assessable instances of black widow antivenom administration over a 10 year period in a single state similarly demonstrated a low rate of adverse reactions. Four (4%) patients in the series had adverse effects ascribed to antivenom administration. These reactions were generally mild and included myalgias, fatigue, generalized paresthesias, flushing, and urticarial rash. There were no cases of dyspnea, angioedema, bronchospasm, hypotension, or death.³² This low rate of severe adverse reactions and lack of death suggests that Merck black widow antivenom is a safe product when prepared and administered correctly to patients without underlying atopy, asthma, or drug allergies.

PREGNANCY AND LACTATION

Black widow envenomations during pregnancy are relatively rare. Of 12,640 patients envenomated by a blackwidow spider, 97 (3%) were pregnant. When compared with nonpregnant women, no significant differences were observed in recommended or administered treatments including the use of antivenom.⁶ There are six reported cases of Loxosceles envenomations in pregnant women. They were all managed with supportive therapy including analgesics, antihistamines, and short course low dose steroids. Pregnancy outcomes were favorable in all reported cases.^2,14 Merck black widow antivenom is Pregnancy Category C. It is not known whether antivenom is excreted in human milk.

DOSING AND ADMINISTRATION

The starting dose of the Merck antivenom is one vial (2.5 mL) diluted in 50 mL of saline for intravenous administration. Although black widow spider antivenom can also be given IM, this route carries the disadvantage of slower, more erratic absorption, less control over the rate of administration, and the inability to stop the administration should an allergic reaction occur. In addition, recent studies suggest IM injection of antivenom may not yield significant serum concentrations.²⁴ For these reasons, the intramuscular route is not routinely recommended.

The initial dose of antivenom in funnel-web spider envenomation is two vials in patients with any signs or symptoms of envenomation. Patients with acute respiratory distress syndrome or decreased consciousness should receive four vials.²⁹ For severe cases, the following protocol has been suggested.²⁹ Two vials (each containing 100 mg of rabbit IgG) of antivenom are administered very slowly intravenously. The dose can be repeated in 15 minutes if no improvement occurs. The dose should be doubled for severe cases. A rapid response should occur. Administration of antivenom should be repeated until symptoms are completely reversed.¹³Atrax robustus envenomations may require multiple infusions of antivenom. The recommended dosage for children is the same as for adults.

FORMULATION AND ACQUISITION

Each vial of the Merck product contains 6000 antivenom units standardized by biologic mouse assay. Because Latrodectus venoms are virtually identical by immunologic and electrophoretic mechanisms, antivenom created for L. mactans is presumed to be effective in other species of Latrodectus as well.²⁷

Latrodectus antivenin is supplied as a white to gray crystalline powder in vials containing not less than 6000 antivenin units with thimerosal 1:10,000 added as a preservative, along with a 2.5 vial of sterile diluent for reconstitution. The antivenin must be stored and shipped at 2 to 8°C (36–46°F), but never frozen. The reconstituted antivenin color ranges from light straw to very dark iced tea, although color has no effect on potency.^2a

Emergency supplies of Lactrodectus antivenin are available for patients with symptoms due to a bite by the black widow spider within 24 hours of contacting Merck. The Antivenom Index, maintained by the Association of Zoos and Aquariums (https://www.aza.org/antivenom-index/) and accesible by the nation’s Poison Control Centers, might also serve as a resource.

SUMMARY

• The decision to use spider antivenom must be individualized to the patient and clinical manifestations.

• Because mortality following black widow envenomation is low, antivenom is reserved for cases where symptoms are severe or do not respond to other therapies, and after a frank discussion with the patient of possible adverse effects.

• Although a large body of literature suggests that Merck black widow antivenom is safe when properly prepared and administered to patients without asthma. Adverse effects including severe anaphylaxis and death are reported.

• A new, purified F(ab)₂ black widow spider antivenom is in clinical development, but is currently unavailable.

References

INTRODUCTION

Centruroides exilicauda (formerly known as Centruroides sculpturatus) is the only scorpion of medical importance in the United States. It is indigenous to the deserts of Arizona but also can be found in Texas, New Mexico, California, and Nevada.¹¹ Occasionally, envenomations occur in nonindigenous areas of the country from “stowaway” scorpions in travelers’ luggage.³²

HISTORY

Arizona poison centers receive several thousand calls annually for scorpion stings. Although the incidence of morbidity with these envenomations is significant, no deaths associated with the toxic effects of scorpion venom have been reported in the United States for almost 50 years. However, deaths are associated with anaphylactic reactions to scorpion venom.⁷ Antivenom for the Centruroides spp. was produced in horses in Mexico as early as the 1930s.¹¹ In 1947, antivenom was produced from rabbits and cats immunized with C. sculpturatus and Centruroides gertschi.²⁹ The Antivenom Production Laboratory at Arizona State University (APL-ASU) began producing antivenom to C. sculpturatus in goats in 1965. This antivenom was used for treatment of scorpion stings in Arizona until 2004, when production ceased and stockpiles expired. In June 2000, Silanes Laboratory received orphan drug status for a Centruroides scorpion antivenom, an equine-derived F(ab′)₂ from Centruroides limpidus, Centruroides noxius, Centruroides suffusus suffusus, and Centruroides meisei (formerly known as Centruroides elegans) manufactured by Instituto Bioclon of Mexico, and referred to as Anascorp. In August 2011, Anascorp was approved by the US Food and Drug Administration (FDA) for the treatment of Centruroides exilicauda envenomations.¹⁵

PHARMACOLOGY

Antivenom for scorpions is prepared in the same manner as other anti­venom products (Antidotes in Depth: A34 and A37).

Pharmacokinetics and Pharmacodynamics

In a study of 8 healthy patients (6 males and 2 females, age 17–26 years) without prior scorpion envenomation, a bolus intravenous dose of 47.5 mg of Anascorp was administered. Serial blood samples were collected over 21 days. Measured pharmacokinetic parameters (mean ± standard deviation) included: area under the curve (AUC), 706 ± 352 μh/mL; clearance, 83.5 ± 38.4 mL/h; half-life, 159 ± 57 hours; and steady state volume of distribution (Vd_ss), 13.6 ± 5.4 L.³³

ROLE IN CENTRUROIDES SPECIES

One vial of Anascorp antivenom contains sufficient F(ab′)₂ to neutralize 150 mouse LD₅₀ of Centruroides venom.²⁵ Safety and efficacy are documented in both animals and humans.^1,8,9,10 In the FDA review and subsequent approval of Anascorp, six trials were submitted for consideration. Only one study was prospective, randomized, double-blinded, and controlled and demonstrated a clear benefit in reduction of signs and symptoms of scorpion envenomation by 4 hours postadministration (8/8 vs. 1/7), reduction in quantity of sedative administered (mean midazolam dose of 0.1 mg/kg (0.0–0.2 mg/kg) versus 4.6 mg/kg (0.1–16.7 mg/kg), and absence of free serum venom concentrations at one hour after administration (mean 0.0 vs. 2.65 ng/mL).⁸

One retrospective trial using historical controls was included as representative of clinical outcomes in the absence of antivenom administration. This trial demonstrated the need for exceedingly large dose of sedatives to treat the inability to walk and respiratory distress due to envenomation with a mean time to discharge of 12.6 hours without administration of scorpion antivenom.¹¹

One large (n = 1534), unpublished and open label study was also included for review. The majority (1204/1534) of patients were children (0.7 months–18 years) and male (52.3%). In 1396/1425 patients, the mean time to resolution of clinically important signs of envenomation following Anascorp administration was 1.42 hours (0.2–20.5 hours). Children reportedly improved slightly faster than adults (1.28 ± 0.8 hours vs. 1.91 ± 1.4 hours). Of the 1534 patients included in the study, 95% had relief of systemic signs associated with Centruroides envenomation within 4 hours of Anascorp administration.^9,14

Three additional open label trials (AL-02/04-adult patients, AL-02/05-pediatric patients, and AL-02/06-pediatric patients) with the use of the Instituto Bioclon of Mexico product Alacramyn (Alacramyn is the Mexican equivalent of Anascorp) were reported by the study sponsors to demonstrate 100% resolution of symptoms by 4 hours following administration of antivenom.¹⁴

ROLE IN LEIURUS SPECIES

The Leiurus quinquestriatus scorpion is indigenous to Africa, Asia, and the Middle East, including Egypt, Israel, Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, Syria, and Turkey. Antivenom to L. quinquestriatus is currently made in France, Germany, Israel, Saudi Arabia, Egypt, Tunisia, and Turkey (Table A35–1).

In observational studies, an intravenous infusion of 5 to 20 mL of Leiurus antivenom was needed to control venom effects, and only patients given antivenom within the first several hours demonstrated significant benefit.^2,20 The rate of allergic reactions for the Turkish antiscorpion antivenom is reported to be 1.6% to 6.6%.²⁰ The recommended dose of the Israeli L. quinquestriatus antivenom is 5 to 15 mL for intravenous use, although several authors report lack of clinical efficacy of this particular antivenom.^5,16,30

L. quinquestriatus antivenom was successfully used to treat a 2 year-old boy with envenomation by Androctonus crassicauda. Symptoms resolved 2 hours after antivenom administration.²⁸

ROLE IN TITYUS SPECIES

Tityus species of scorpions are endemic to South America, particularly Brazil. An F(ab)₂ antivenom for Tityus serrulatus is available from Fundação Ezequiel Dias (FUNED), in Belo Horizonte, Brazil. The usual dose of the antivenom is 20 mL as an intravenous infusion.¹³

In a series of 18 patients with T. serrulatus envenomation treated with antivenom, vomiting and local pain decreased within 1 hour, and cardiorespiratory manifestations disappeared within 6 to 24 hours in all patients except the two presenting with acute respiratory distress syndrome.¹³­Sixteen patients recovered completely by 24 hours. The Instituto Buntantan in Brazil also produces Soro antiarachnidico and Soro antiscorpionico for treatment of Tityus spp.

Role in Androctonus Species

Scorpion antivenom in South Africa is an equine-derived antivenom available from the South African Vaccine Producers, formerly South African Institute for Medical Research (SAIMR), Johannesburg, South Africa. ScorpiFAV, produced by Aventis Pasteur, is produced for treatment of Androctonus spp, B. occitanus, and L. quinquestriatus.

Buthus tamulus monovalent red scorpion antivenom serum produced by Central Research Institute of India is an equine-derived lyophilized antivenom for the venom of Mesobuthus tamulus. The manufacturer recommends a dosage of one vial, although a dose of five vials decreased mortality significantly in one study.^22,31

In Pakistan, the treatment of scorpion stings was modified in 1991 to include the administration of five vials of antivenom. A retrospective case series of 950 patients treated with and without antivenom was compared to 968 cases treated after the five vial protocol was initiated. A statistically significant decrease in mortality was demonstrated. The last recorded death in Pakistan resulting from a scorpion sting occurred in 1991 in a patient who did not receive antivenom.³¹

Parabuthus spp antivenom from South African Vaccine Producers is an equine-derived antivenom to Parabuthus spp. In one study, anti­venom was unavailable for a period of time allowing for a unique design of matched pair of patients. Patients who received antivenom had a significant decrease in hospital stay after receiving one (5 mL) vial. Pain, hypersalivation, fasciculations, tremor, and bladder distension responded best to antivenom, whereas dysphagia, ptosis, and local swelling were more resistant.⁶ More recent studies from India show equivocal results for scorpion envenomation treated with antivenom when compared to treatment with prazocin.^4,26

The unavailability of specific antivenoms often necessitates symptomatic treatment or use of a comparable foreign antivenom. In a study of 72 moderate scorpion stings in Para, Brazil, 33% who met criteria for antivenom administration did not receive treatment because of unavailability of the antivenom.²⁷

ADVERSE EFFECTS AND SAFETY ISSUES

Hypersensitivity reactions to Anascorp and other equine derived anti­venoms may occur following administration. Patients with known equine protein allergies or previous exposure to Anascorp or other equine derived antivenoms or antitoxins may be at increased risk due to previous sensitization. No deaths were reported in clinical trials of Anascorp. Adverse effects reported from cumulative clinical trial data revealed that 2.2% of patients experienced severe adverse reactions (respiratory distress, aspiration, hypoxia, ataxia, pneumonia, and eye swelling) following Anascorp administration. However, these symptoms occurred in the setting of acute Centruroides envenomation, limiting the direct attribution of symptoms to antivenom administration alone. The most common adverse effects reported included vomiting (4.7%), pyrexia (4.1%), rash (2.7%), nausea (2.1%), and pruritus (2%).¹⁴ The presence of cresol as an injectable excipient may increase localized reactions and generalized myalgias following administration. No drug interaction studies have been conducted with Anascorp.

PREGNANCY AND LACTATION

Anascorp is Pregnancy Category C. Animal reproduction studies have not been conducted, and it is unknown whether Anascorp may cause fetal harm when administered to pregnant women. Reproductive capability postadministration similarly has not been assessed. Anascorp should only be administered in pregnant women if clearly needed for alleviation of symptoms and after other therapies have been utilized. It is unknown whether Anascorp is excreted in human breast milk.¹⁴

DOSING AND ADMINISTRATION

Anascorp is the only US FDA approved treatment for the clinical signs and symptoms of Centruroides scorpion envenomation. These include, but are not limited to, loss of motor control, roving or abnormal eye movements, slurred speech, respiratory depression, and excessive oral secretions. Package insert dosing recommendations (FDA) are three vials administered intravenously over 10 minutes after reconstitution (5 mL sterile 0.9% sodium chloride solution/vial) and dilution to a total volume of 50 mL. Additional vials may be administered every 30 to 60 minutes as needed for symptom control. The price of Anascorp may vary from hospital to hospital. In one survey of Phoenix, Arizona hospitals, the charge per vial was between $7900 and $15,120.³

FORMULATION AND ACQUISITION

Anascorp is supplied as a sterile lyophilized preparation in a single-use vial. When reconstituted, each vial contains not more than 24 milligrams per milliliter of protein, and not less than 150 mouse LD50 neutralizing units. Anascorp should not be frozen, but stored at room temperature up to 25°C (77°F).¹⁴

The Antivenom Index, maintained by the Association of Zoos and Aquariums (https://www.aza.org/antivenom-index/) and accessible by the nation’s Poison Control Centers, may serve as a resource in the event of difficulty obtaining antivenom. The World Health Organization’s World Directory of Poison Centres (http://www.who.int/gho/phe/chemical_safety/poisons_centres/en/) might assist those outside of the U.S. to source more exotic antivenoms.

SUMMARY

• The indications for antivenom administration following scorpion stings remain controversial.

• The decision to use antivenom should be individualized to the patient, weighing the risk of giving an immune serum, the level of available supportive care, the risks and costs of supportive care alone, and the cost of obtaining or importing antivenom.

• Scorpion antivenom administration for some species may not improve outcome.

• The preferred route of administration of these products is intravenous. One to two vials is the recommended dose for most scorpion antivenoms; higher doses may be needed to alleviate symptoms in some cases.

References