Scorpion envenomation causing skin necrosis, hemolysis, DIC, and acute kidney injury (Middle East)

INTRODUCTION — This topic will discuss the clinical manifestations, diagnosis, and treatment of envenomation by Hemiscorpius lepturus, the stings of which cause skin and tissue necrosis, hemolysis, disseminated intravascular coagulation (DIC), acute kidney injury, and noninfectious hemolytic-uremic syndrome (HUS). H. lepturus is primarily found in the Middle East.

The clinical manifestations, diagnosis, and treatment of scorpion stings that cause neuromuscular toxicity or autonomic dysfunction with cardiotoxicity in other parts of the world are discussed in detail separately.

●(See "Scorpion envenomation causing neuromuscular toxicity (United States, Mexico, Central America, and Southern Africa)".)

●(See "Scorpion envenomation causing autonomic dysfunction (North Africa, Middle East, Asia, South America, and the Republic of Trinidad and Tobago)".)

ENTOMOLOGY — Scorpions, which are grouped in the phylum Arthropoda, have a lobster-like body shape with seven sets of paired appendages: the chelicerae, the pedipalps (claws), four sets of legs, and the pectines (a pair of comb-like structures on the ventral surface) (figure 1). The segmented tail curves upward dorsally, ending in a terminal bulbous segment called the telson, which contains paired venom glands and the stinger. Scorpions fluoresce when illuminated by ultraviolet light, as from a black light or a medical Wood's lamp (picture 1). This physical property is used to collect scorpions and for pest control. Additional entomology of scorpions is discussed separately. (See "Scorpion envenomation causing neuromuscular toxicity (United States, Mexico, Central America, and Southern Africa)", section on 'Entomology'.)

APPEARANCE AND VENOM PROPERTIES — H. lepturus is a translucent to yellow, thin-tailed scorpion that is 5 to 8 cm in length (picture 2) [1,2]. It has a bead-shaped and jointed tail and displays sexual dimorphism with the adult male scorpion being larger and having a longer tail [3].

Unlike venom from other scorpion species, H. lepturus venom contains lytic enzymes (including lysophospholipase D, which lyses ester bonds in cell membranes); its venom toxins are morphologically similar to brown recluse spider toxins, and the toxic manifestations of H. lepturus envenomation in humans bears resemblance to loxoscelism [4-6]. In animal models, these toxins cause severe tissue and organ necrosis and can induce intravascular hemolysis with disseminated intravascular coagulation [4,7-10]. Animal models indicate that acute kidney injury is also related to PGC-1 alpha overexpression in response to glutathione depletion [11]. This finding suggests a potential role for PGC-1 alpha as a therapeutic target or glutathione for H. lepturus-induced acute kidney injury prevention and restoring of mitochondrial mass.

Cardiotoxicity of the crude venom from H. lepturus scorpion and its isolated fractions, F-I to F-VI, has been described in rats. Elevations of troponin and decreased ejection fraction were noted [12]. However, cardiotoxicity is generally not seen in humans with H. lepturus envenomation.

H. lepturus venom also has the ability to cause autonomic dysfunction with cardiotoxicity similar to other medically important species in the region such as Androctonus, Buthus, and Hottentotta (formerly Mesobuthus), although this is an uncommon clinical finding. (See "Scorpion envenomation causing autonomic dysfunction (North Africa, Middle East, Asia, South America, and the Republic of Trinidad and Tobago)", section on 'Venom properties'.)

EPIDEMIOLOGY — H. lepturus has been found in hot and humid regions of the Middle East including south and southwest Iran, eastern Iraq, Yemen, West Pakistan, Oman, United Arab Emirates, and Saudi Arabia. About 50,000 cases of scorpion stings are recorded in Iran annually with a majority in the southwest [2]. Clinical and laboratory symptoms of envenomation following Hemiscorpius stings are clearly different from those reported for other medically important scorpion species.

In Iran, it accounts for over 10,000 scorpion stings annually or approximately 20 to 25 percent of all reported scorpion stings in the region [1]. Stings are most common at night while the victim is sleeping and are most prevalent during the spring and summer months [1,3,8]. Children younger than five years of age and adolescents are most commonly affected [3,8,13,14]. In Iran, H. lepturus is responsible for a majority of the approximately 20 deaths per year caused by scorpion stings [1]. Mortality among pediatric patients requiring acute care approaches 8 percent in some series [8]. Thus, H. lepturus is regarded as more dangerous than other medically important scorpions in this region, including Androctonus and Buthus species.

CLINICAL MANIFESTATIONS

Presentation — Stings most commonly involve the lower extremities. Patients come to medical attention because of cutaneous findings or, in those with hemolysis or kidney injury, signs of hemoglobinuria or hematuria [2].

In marked contrast to scorpions capable of causing autonomic storm and cardiotoxicity, H. lepturus causes a relatively painless sting that may go unnoticed and may not produce a skin mark because of its small stinger size (about 1 mm long). The initial symptoms typically consist of minor itching at the sting site and mild pain. The sting frequently occurs at night while the patient is sleeping and is often not noticed until the morning [1,3,7,8,13]. Local skin manifestations are frequently negligible within the first 24 hours. Thus, medical care is not sought until systemic toxicity has been established.

Skin findings — Within the first few hours after the sting, skin findings typically consist of a sting site with a central puncta and an erythematous or purpuric macule or papule, which is mildly painful and pruritic [2,13]. The sting site may be difficult to see.

Over the next 24 hours after the sting, other cutaneous findings may develop [2,13]:

●Concentric, pruritic urticarial plaques centered around the sting site; local necrosis, swelling, erythema, and ecchymosis are especially noted in children

●Sterile lymphangitis and cellulitis with nonpitting edema (more commonly seen in adults and in stings on the extremities)

●Local or generalized erythematous eruption that may have regions of grouped red papules

●Local lacey purpuric plaques without signs of inflammation, induration, or ulcer

●Purpuric bullae up to 5 cm in diameter at or near the sting site

Early development of hemorrhagic bullae is associated with systemic signs of envenomation and further development of an indurated blue-black necrotic plaque with eventual deep skin ulceration at the site (picture 3) [13]. Patients with disseminated intravascular coagulation (DIC) can have generalized petechiae and easy bruising.

Systemic findings — One to two days after envenomation, patients may develop systemic signs of fever, pallor, fatigue, generalized edema (picture 4), and/or red urine [8,14]. These findings are most likely to develop in children younger than five years of age and indicate the presence of acute hemolysis. Petechiae, easy bruising, and bleeding point to DIC [13].

Victims of H. lepturus envenomation may uncommonly develop clinical findings of autonomic dysfunction (eg, salivation, diaphoresis, and/or cool extremities) but significant cardiotoxicity with heart failure and pulmonary edema occurs rarely and only in patients with other severe systemic effects [2,8].

ANCILLARY STUDIES — In patients with clinical findings suggestive of systemic H. lepturus envenomation, the following laboratory studies are suggested, whenever available, to assess for hemolysis, disseminated intravascular coagulation (DIC), hemolytic-uremic syndrome (HUS), and acute kidney injury:

●Complete blood count with peripheral smear

●Reticulocyte count

●Type and screen (including Coombs testing) for patients with signs of hemolytic anemia

●Total and direct serum bilirubin

●Aspartate aminotransferase and alanine aminotransferase

●Serum lactate dehydrogenase

●Serum haptoglobin

●Serum glucose

●Serum electrolytes

●Blood urea nitrogen (BUN) and serum creatinine

●Prothrombin time (PT) with international normalized ratio (INR)

●Activated partial thromboplastin time (aPTT)

●D-dimer and fibrinogen

●In patients with elevated BUN and creatinine, blood gas (venous or arterial)

●Urine dipstick and microscopic urinalysis

●Electrocardiogram (patients with electrolyte abnormalities)

Patients with systemic envenomation often have one or more of the following findings [2,3,8,14]:

●Evidence of intravascular hemolysis (rapidly decreasing hemoglobin, red blood cell fragmentation on peripheral blood smear, elevated reticulocyte count, elevated lactate dehydrogenase, and reduced haptoglobin)

●Hematuria, hemoglobinuria, proteinuria, pyuria, and/or urinary casts

●DIC (thrombocytopenia, prolonged PT/INR and aPTT with increased D-dimer and decreased fibrinogen levels)

●Acute kidney injury (uremia with increased creatinine which may be complicated by hyperkalemia and severe metabolic acidosis)

In children, hemolysis can be severe with a rapid drop in hemoglobin associated with DIC, microangiopathic anemia, acute pigment-induced kidney injury, and rarely, noninfectious HUS [2,8,14,15]. In adults, hemolysis is generally mild and resolves spontaneously in two to three weeks without treatment [2].

DIAGNOSIS — The diagnosis of H. lepturus scorpion envenomation is made clinically in patients who report being stung by a scorpion and present with a minimally painful or pruritic sting and characteristic skin findings. With observation, these patients may develop necrotic skin lesions, acute hemolytic anemia, disseminated intravascular coagulation (DIC), and/or acute kidney injury. (See 'Clinical manifestations' above and 'Ancillary studies' above.)

A presumptive diagnosis of H. lepturus envenomation is made in patients who present with cutaneous findings of a scorpion sting in association with hematuria or hemoglobinuria and laboratory findings of acute hemolysis with or without DIC, acute kidney injury, or hemolytic-uremic syndrome. (See 'Clinical manifestations' above and 'Ancillary studies' above.)

DIFFERENTIAL DIAGNOSIS — Conditions that can cause single ulcerated lesions similar to H. lepturus stings include infections, trauma, vascular diseases, pyoderma gangrenosum, and vasculitides.

●Infections – Common infections that can become necrotic include staphylococcus and streptococcal infections, deep fungal infections, and atypical mycobacterial infections (table 1). In particular, community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) skin infections can begin with singular papules or pustules that may evolve to necrotic lesions. Infections occur both sporadically and as institutional epidemics in nursing homes, prisons, military barracks, and athletic facilities. Risk factors and epidemiology of CA-MRSA are discussed separately. Isolation of the infectious organism from pus helps to differentiate these infections from H. lepturus stings. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Epidemiology" and "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'Epidemiology and risk factors'.)

●Vascular disease – Foot and ankle ulcers can be seen in patients with chronic venous insufficiency, arterial insufficiency, or diabetes mellitus (table 2); a history of the underlying disease and the chronic course distinguish these lesions from H. lepturus stings. (See "Diagnostic evaluation of lower extremity chronic venous disease".)

●Pyoderma gangrenosum – Pyoderma gangrenosum is an idiopathic disorder in which dark, blue-red papules progress to necrotic ulcerating lesions. Patients may report a history of antecedent trauma at the site or have associated systemic illness such as inflammatory bowel disease, rheumatoid arthritis, solid organ or hematologic neoplasms, or hematologic disorders. Borders are typically irregular with undermined edges, and the lesion may have a purulent base (picture 5 and picture 6). Lesions may be bullous. Lack of typical signs of systemic scorpion envenomation (eg, hemolysis, disseminated intravascular coagulation, or acute kidney injury) in a patient with a commonly associated systemic illness helps to differentiate pyoderma gangrenosa from a scorpion sting; skin biopsy may be necessary to make this distinction. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis".)

●Vasculitis – Cutaneous vasculitis results from inflammation of the small or medium-sized blood vessels in the skin. Small blood vessels are capillaries, post-capillary venules, and non-muscular arterioles in the superficial and mid-dermis (<50 micrometers). Medium-sized vessels consist of 50 to 150 micrometer vessels with muscular walls in the deep dermis and subcutis. Cutaneous vasculitis occurs in a wide variety of clinical settings (table 3). Ulceration and tissue necrosis occur when vasculitis results in reduced vascular perfusion in the skin (picture 7A-B). Superficial ulcers can occur in patients with small vessel vasculitis; deep ulcers are usually the result of medium vessel disease. Less commonly, vasculitis and necrotizing vasculitis may present with singular lesions that show eschar or ulceration (picture 8) that may resemble pyoderma gangrenosum. (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'When to suspect cutaneous vasculitis'.)

Patients with vasculitis may have the presence of systemic findings consistent with connective tissue disease, recent symptoms of infection, or introduction of a medication within the past 7 to 10 days, which helps to differentiate them from victims of scorpion stings. However, skin biopsy is most definitive to establish the diagnosis of vasculitis. (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'Patient assessment' and "Evaluation of adults with cutaneous lesions of vasculitis", section on 'Skin biopsy to confirm vasculitis'.)

●Neutrophilic dermatosis of the dorsal hand – Neutrophilic dermatosis ("pustular vasculitis" of the dorsal hand is an ulcerating condition that is characterized by one or more ulcers on the hand and is felt by some to be a variant of Sweet disease. The lesions may be bullous or bullous hemorrhagic initially (picture 9). Skin biopsy shows neutrophilic infiltration. (See "Neutrophilic dermatoses", section on 'Neutrophilic dermatosis of the dorsal hands'.)

MANAGEMENT — All stings by H. lepturus have the potential for causing hemolytic anemia complicated by DIC and, especially in children, acute kidney injury. When managing victims of these stings, we encourage consultation with either a local physician with expertise managing H. lepturus stings or a regional poison control center; contact information for regional poison centers around the world is available separately. (See 'Additional resources' below.)

Local wound care and pruritus — Pain is generally mild and controlled by acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs, ie, ibuprofen). Pruritus may be treated with antihistamines (eg, diphenhydramine, cetirizine, or hydroxyzine).

The sting site should be cleansed and tetanus prophylaxis provided, as needed (table 4). Otherwise, wound care is supportive.

Excision of the site should be avoided because it does not prevent systemic toxicity and may create a larger and deeper wound. If extensive ulceration occurs, then surgical debridement and skin grafting may be necessary [2].

Antivenom — For patients with systemic toxicity after H. lepturus stings, we suggest that Razi polyvalent scorpion antivenom (Karaj, Iran) be administered intravenously as soon as possible after the sting, ideally within two hours [2,3,14,16]. Antivenom should be administered in an acute care setting with medications immediately available to treat potential anaphylaxis.

In clinical practice, Razi antivenom is frequently given intramuscularly. However, animal models suggest that this route is ineffective for neutralization of H. lepturus venom [17,18]. Although administration of antivenom is routine in local practice, evidence is lacking to show improved clinical outcomes in humans and adverse effects, such as allergic reactions, anaphylaxis, or serum sickness may be frequent [19]. More evidence is needed to establish the efficacy of this therapy. Development of a monovalent, scorpion-specific antivenom has also been suggested and candidate single-domain antibody fragments (nanobodies) antivenom has shown promise based upon in vitro and in vivo animal studies [19].

Razi polyvalent scorpion antivenom is the only antivenom available to treat H. lepturus stings; it is an equine-derived, pepsin-digested antivenom that is directed against six venomous scorpions in Iran including H. lepturus [20]. However, in one analysis, only 18 percent of the antivenom contained F(ab')2, which raises concern regarding its purity [20]. Animal models show that Razi scorpion antivenom binds tightly to some components of H. lepturus venom but that subcutaneous or intramuscular routes are ineffective [17,18]. H. lepturus venom has a long half-life in the tissues and is cleared slowly [16]. Thus, intravenous administration of antivenom beyond two hours after the sting may still have some theoretical benefit.

Supportive care — Older patients with systemic manifestations of H. lepturus envenomation and all children, regardless of severity of envenomation, should receive care in an intensive care unit. Intravenous antivenom administration is considered by local experts as an important adjunct to supportive care because it potentially binds circulating venom and prevents further toxicity [2]. However, evidence is lacking to show improved outcomes in patients who receive antivenom versus supportive care alone.

Clinicians should evaluate for and anticipate the need to treat acute hemolysis, DIC, acute kidney injury, and rarely, hemolytic-uremic syndrome (HUS), or autonomic storm with cardiotoxicity. Children younger than five years of age are at greatest risk for developing life-threatening systemic toxicity.

Hemolysis — Patients with laboratory findings of hemolysis should receive frequent monitoring of hemoglobin or hematocrit (eg, every two to four hours, depending upon the rate of decline). Blood transfusions should be given to patients with symptomatic anemia (eg, hemodynamic instability or heart failure) [14]. Although not well established for victims of scorpion stings, a threshold of 7 g/dL for blood transfusion may also be appropriate in asymptomatic patients. (See "Red blood cell transfusion in infants and children: Indications", section on 'General principles' and "Indications and hemoglobin thresholds for RBC transfusion in adults".)

Disseminated intravascular coagulation (DIC) — DIC after H. lepturus envenomation is caused by intravascular hemolysis [8]. It is initially treated with transfusions of fresh frozen plasma (FFP) and, depending upon the degree of thrombocytopenia, platelets. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Prevention/treatment of bleeding' and "Disseminated intravascular coagulation in infants and children", section on 'Management'.)

Plasmapheresis has also been performed in severely affected patients with noninfectious HUS or severe DIC after H. lepturus stings [21,22]. In a small randomized unblinded trial, patients who received plasmapheresis and replacement with either fresh frozen plasma (FFP) or albumin had fewer deaths than controls (6 of 14 patients versus 13 of 15 patients) [21]. However, this trial is at a high risk of bias. Plasmapheresis is an invasive therapy that should not be routinely performed.

Acute kidney injury — Acute kidney injury is caused by direct toxic effects of the scorpion venom, hemolysis with hemoglobinuria, and, in patients with noninfectious HUS, microangiopathic renovascular changes.

Initial management for hemoglobinuria consists of aggressive fluid therapy to maintain urine output as for pigment-induced kidney injury and renal replacement therapy, as needed, for fluid overload, hyperkalemia, uremia, or metabolic acidosis. Bicarbonate therapy has not been evaluated in patients with hemolysis and many experts do not administer it unless rhabdomyolysis is also present. (See "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)", section on 'Treatment'.)

In patients with noninfectious HUS, initial management is supportive and includes red blood cell transfusions for anemia, platelet transfusions for thrombocytopenia with significant bleeding or DIC, and infusion of FFP to restore normal ADAMTS-13 levels. (See "Overview of hemolytic uremic syndrome in children".)

Autonomic storm with cardiotoxicity — Autonomic storm with cardiotoxicity after envenomation from H. lepturus is rare. It is treated supportively (table 5), in a manner similar to the treatment provided to patients with stings from scorpions that more commonly produce these findings. (See "Scorpion envenomation causing autonomic dysfunction (North Africa, Middle East, Asia, South America, and the Republic of Trinidad and Tobago)", section on 'Supportive care'.)

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

SUMMARY AND RECOMMENDATIONS

●Entymology – H. lepturus is a translucent to yellow, thin-tailed scorpion found in hot and humid regions of the Middle East, including south and southwest Iran, eastern Iraq, Yemen, West Pakistan, Oman, United Arab Emirates, and Saudi Arabia. (See 'Appearance and venom properties' above and 'Epidemiology' above.)

●Clinical manifestations – The sting of H. lepturus is relatively painless and frequently occurs at night while the patient is sleeping and is often not noticed until the morning. Patients come to medical attention because of cutaneous findings or, in those with hemolysis or kidney injury, signs of hemoglobinuria or hematuria. (See 'Presentation' above.)

Initial skin findings typically consist of a sting site with a central puncta and an erythematous or purpuric macule or papule, which is mildly painful and pruritic. Over the next 24 hours after the sting, other cutaneous findings may develop including concentric pruritic plaques, sterile lymphangitis and cellulitis, local or generalized erythematous eruption, purpuric plaques, or purpuric bullae up to 5 cm in diameter at or near the sting site. Early development of hemorrhagic bullae is associated with systemic signs of envenomation and further development of an indurated blue-black necrotic plaque with eventual deep skin ulceration at the site (picture 3). (See 'Skin findings' above.)

One to two days after envenomation, patients may develop systemic signs of fever, pallor, fatigue, generalized edema, and/or red urine. These findings are most likely to develop in children younger than five years of age and indicate the presence of acute hemolysis. Petechiae, easy bruising, and bleeding point to disseminated intravascular coagulation (DIC). (See 'Systemic findings' above.)

●Ancillary studies – In patients with clinical findings suggestive of systemic H. lepturus envenomation, the following laboratory studies are suggested, whenever available, to assess for hemolysis, DIC, hemolytic-uremic syndrome (HUS), and acute kidney injury (see 'Ancillary studies' above):

•Complete blood count with peripheral smear

•Reticulocyte count

•Type and screen (including Coombs testing) for patients with signs of hemolytic anemia

•Total and direct serum bilirubin

•Aspartate aminotransferase and alanine aminotransferase

•Serum lactate dehydrogenase

•Serum haptoglobin

•Serum glucose

•Serum electrolytes

•Blood urea nitrogen (BUN) and serum creatinine

•Prothrombin time (PT) with international normalized ratio (INR)

•Activated partial thromboplastin time (aPTT)

•D-dimer and fibrinogen

•In patients with elevated BUN and creatinine, blood gas (venous or arterial)

•Urine dipstick and microscopic urinalysis

•Electrocardiogram (patients with electrolyte abnormalities)

●Diagnosis – The diagnosis of H. lepturus scorpion envenomation is made clinically based upon a history of being stung by a translucent to yellow, thin-tailed scorpion and a minimally painful or pruritic sting site with characteristic skin findings. A presumptive diagnosis of H. lepturus envenomation is made in patients who present with cutaneous findings of a scorpion sting in association with hematuria or hemoglobinuria and laboratory findings of acute hemolysis with or without DIC, acute kidney injury, or HUS. (See 'Diagnosis' above.)

●Management – When managing victims of these stings, we encourage consultation with a local physician with expertise managing H. lepturus stings or a regional poison control center (see 'Management' above):

•Local wound care – Pain is generally mild and controlled by acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDS; ie, ibuprofen). Pruritus may be treated with antihistamines (eg, diphenhydramine, cetirizine, or hydroxyzine). The sting site should be cleansed and tetanus prophylaxis provided, as needed (table 4). Excision of the site should be avoided because it does not prevent systemic toxicity and may create a larger and deeper wound. (See 'Local wound care and pruritus' above.)

•Systemic toxicity – For patients with systemic toxicity after H. lepturus stings, we suggest that Razi polyvalent scorpion antivenom (Karaj, Iran) be administered intravenously (IV) as soon as possible after the sting, ideally within two hours (Grade 2C). (See 'Antivenom' above.)

●Supportive care – Clinicians should evaluate for and anticipate the need to treat acute hemolysis, DIC, acute kidney injury, and rarely, HUS or autonomic storm with cardiotoxicity. Children <10 years old and older adults are at highest risk. Potential interventions include (see 'Supportive care' above):

•Symptomatic anemia – Blood transfusions (see 'Hemolysis' above)

•DIC – Transfusions of fresh frozen plasma (FFP) and, depending upon the degree of thrombocytopenia, platelets; if available, plasmapheresis with FFP replacement may reduce mortality in severely affected patients (see 'Disseminated intravascular coagulation (DIC)' above)

•Acute kidney injury – Aggressive fluid therapy to maintain urine output as for pigment-induced kidney injury and renal replacement therapy, as needed, for fluid overload, hyperkalemia, uremia, or metabolic acidosis (see 'Acute kidney injury' above)

•Noninfectious HUS – Red blood cell transfusions for anemia, platelet transfusions for thrombocytopenia with significant bleeding or DIC, and infusion of FFP to restore normal ADAMTS-13 levels (see 'Acute kidney injury' above)