Dirk M. Elston, MD

Incidence and Characteristics

Stingrays are the most common cause of fish-related stings worldwide.¹ The Urolophidae and Dasyatidae stingray families are responsible for most marine stingray injuries, including approximately 1500 reported injuries in the United States annually.^1,2 Saltwater stingrays from these families commonly are encountered in shallow temperate and tropical coastal waters across the globe and possess dorsally and distally located spines capable of injuring humans that step on them (Figure 1).^1,3 Freshwater stingrays (Potamotrygonidae family)(Figure 2) are not present in North America but rather inhabit lakes and river systems in South America, Africa, Laos, and Vietnam.⁴ Although recent incidence is unknown, Marinkelle⁵ estimated that thousands of stingray injuries occurred annually in the freshwater of Columbia during the 1960s. Unfortunately, the annual worldwide incidence of stingray injuries is generally unknown and is difficult to estimate, in part because injuries often go unreported.

Stingrays are dorsoventrally flattened, diamond-shaped fish with light-colored ventral and dark-colored dorsal surfaces. They have strong pectoral wings that allow them to swim forward and backward and even launch off waves.³ Stingrays range in size from the palm of a human hand to 6.5 ft in width. They possess 1 or more spines (2.5 to >30 cm in length) that are disguised by much longer tails.^6,7 They often are encountered accidentally because they bury themselves in the sand or mud of shallow coastal waters or rivers with only their eyes and tails exposed to fool prey and avoid predators.

Injury Clinical Presentation

Stingray injuries typically involve the lower legs, ankles, or feet after stepping on a stingray.⁸ Fishermen can present with injuries of the upper extremities after handling fish with their hands.⁹ Other rarer injuries occur when individuals are swimming alongside stingrays or when stingrays catapult off waves into moving boats.^10,11 Stingrays impale victims by using their tails to direct a retroserrate barb composed of a strong cartilaginous material called vasodentin. The barb releases venom by breaking through the venom-containing integumentary sheath that encapsulates it. Stingray venom contains phosphodiesterase, serotonin, and 5′-nucleotidase. It causes severe pain, vasoconstriction, ischemia, and poor wound healing, along with systemic effects such as disorientation, syncope, seizures, salivation, nausea, vomiting, abdominal pain, diarrhea, muscle cramps or fasciculations, pruritus, allergic reaction, hypotension, cardiac arrhythmias, dyspnea, paralysis, and possibly death.^1,8,12,13

Management

Pain Relief
As with many marine envenomations, immersion in hot but not scalding water can inactivate venom and reduce symptoms.^8,9 In one retrospective review, 52 of 75 (69%) patients reporting to a California poison center with stingray injuries had improvement in pain within 1 hour of hot water immersion before any analgesics were instituted.⁸ In another review, 65 of 74 (88%) patients presenting to a California emergency department within 24 hours of sustaining a stingray injury had complete relief of pain within 30 minutes of hot water immersion. Patients who received analgesics in addition to hot water immersion did not require a second dose.⁹ In concordance with these studies, we suggest immersing areas affected by stingray injuries in hot water (temperature, 43.3°C to 46.1°C [110°F–115°F]; or as close to this range as tolerated) until pain subsides.^8,9,14 Ice packs are an alternative to hot water immersion that may be more readily available to patients. If pain does not resolve following hot water immersion or application of an ice pack, additional analgesics and xylocaine without epinephrine may be helpful.^9,15

Infection
One major complication of stingray injuries is infection.^8,9 Many bacterial species reside in stingray mucus, the marine environment, or on human skin that may be introduced during a single injury. Marine envenomations can involve organisms such as Vibrio, Aeromonas, and Mycobacterium species, which often are resistant to antibiotic prophylaxis covering common causes of soft-tissue infection such as Staphylococcus and Streptococcus species.^8,9,16,17 Additionally, physicians should cover for Clostridium species and ensure patients are up-to-date on vaccinations because severe cases of tetanus following stingray injuries have been reported.¹⁸ Lastly, fungal infections including fusariosis have been reported following stingray injuries and should be considered if a patient develops an infection.¹⁹

Several authors support the use of prophylactic broad-spectrum antibiotics in all but mild stingray injuries.^8,9,20,21 Although no standardized definition exists, mild injuries generally represent patients with superficial lacerations or less, while deeper lacerations and puncture wounds require prophylaxis. Several authors agree on the use of fluoroquinolone antibiotics (eg, ciprofloxacin 500 mg twice daily) for 5 to 7 days following severe stingray injuries.^1,9,13,22 Other proposed antibiotic regimens include trimethoprim-sulfamethoxazole (160/800 mg twice daily) or tetracycline (500 mg 4 times daily) for 7 days.¹³ Failure of ciprofloxacin therapy after 7 days has been reported, with resolution of infection after treatment with an intravenous cephalosporin for 7 days.²⁰ Failure of trimethoprim-sulfamethoxazole therapy also has been reported, with one case requiring levofloxacin for a much longer course.²¹ Clinical follow-up remains essential after prescribing prophylactic antibiotics, as resistance is common.

Foreign Bodies
Stingray injuries also are often complicated by foreign bodies or retained spines.^3,8 Although these complications are less severe than infection, all wounds should be explored for material under local anesthesia. Furthermore, there has been support for thorough debridement of necrotic tissue with referral to a hand specialist for deeper injuries to the hands as well as referral to a foot and ankle specialist for deeper injuries of the lower extremities.^23,24 More serious injuries with penetration of vital structures, such as through the chest or abdomen, require immediate exploration in an operating room.^1,24

Imaging
Routine imaging of stingray injuries remains controversial. In a case series of 119 patients presenting to a California emergency department with stingray injuries, Clark et al⁹ found that radiographs were not helpful. This finding likely is due in part to an inability to detect hypodense material such as integumentary or glandular tissue via radiography.³ However, radiographs have been used to identify retained stingray barbs in select cases in which retained barbs are suspected.^2,25 Lastly, ultrasonography potentially may offer a better first choice when a barb is not readily apparent; magnetic resonance imaging may be indicated for more involved areas and for further visualization of suspected hypodense material, though at a higher expense.^2,9

Biopsy
Biopsies of stingray injuries are rarely performed, and the findings are not well characterized. One case biopsied 2 months after injury showed a large zone of paucicellular necrosis with superficial ulceration and granulomatous inflammation. The stingray venom was most likely responsible for the pattern of necrosis noted in the biopsy.²¹

Avoidance and Prevention

Patients traveling to areas of the world inhabited by stingrays should receive counseling on how to avoid injury. Prior to entry, individuals can throw stones or use a long stick to clear their walking or swimming areas of venomous fish.²⁶ Polarized sunglasses may help spot stingrays in shallow water. Furthermore, wading through water with a shuffling gait can help individuals avoid stepping directly on a stingray and also warns stingrays that someone is in the area. Individuals who spend more time in coastal waters or river systems inhabited by stingrays may invest in protective stingray gear such as leg guards or specialized wading boots.²⁶ Lastly, fishermen should be advised to avoid handling stingrays with their hands and instead cut their fishing line to release the fish.

Incidence and Characteristics

Stingrays are the most common cause of fish-related stings worldwide.¹ The Urolophidae and Dasyatidae stingray families are responsible for most marine stingray injuries, including approximately 1500 reported injuries in the United States annually.^1,2 Saltwater stingrays from these families commonly are encountered in shallow temperate and tropical coastal waters across the globe and possess dorsally and distally located spines capable of injuring humans that step on them (Figure 1).^1,3 Freshwater stingrays (Potamotrygonidae family)(Figure 2) are not present in North America but rather inhabit lakes and river systems in South America, Africa, Laos, and Vietnam.⁴ Although recent incidence is unknown, Marinkelle⁵ estimated that thousands of stingray injuries occurred annually in the freshwater of Columbia during the 1960s. Unfortunately, the annual worldwide incidence of stingray injuries is generally unknown and is difficult to estimate, in part because injuries often go unreported.

Stingrays are dorsoventrally flattened, diamond-shaped fish with light-colored ventral and dark-colored dorsal surfaces. They have strong pectoral wings that allow them to swim forward and backward and even launch off waves.³ Stingrays range in size from the palm of a human hand to 6.5 ft in width. They possess 1 or more spines (2.5 to >30 cm in length) that are disguised by much longer tails.^6,7 They often are encountered accidentally because they bury themselves in the sand or mud of shallow coastal waters or rivers with only their eyes and tails exposed to fool prey and avoid predators.

Injury Clinical Presentation

Stingray injuries typically involve the lower legs, ankles, or feet after stepping on a stingray.⁸ Fishermen can present with injuries of the upper extremities after handling fish with their hands.⁹ Other rarer injuries occur when individuals are swimming alongside stingrays or when stingrays catapult off waves into moving boats.^10,11 Stingrays impale victims by using their tails to direct a retroserrate barb composed of a strong cartilaginous material called vasodentin. The barb releases venom by breaking through the venom-containing integumentary sheath that encapsulates it. Stingray venom contains phosphodiesterase, serotonin, and 5′-nucleotidase. It causes severe pain, vasoconstriction, ischemia, and poor wound healing, along with systemic effects such as disorientation, syncope, seizures, salivation, nausea, vomiting, abdominal pain, diarrhea, muscle cramps or fasciculations, pruritus, allergic reaction, hypotension, cardiac arrhythmias, dyspnea, paralysis, and possibly death.^1,8,12,13

Management

Pain Relief
As with many marine envenomations, immersion in hot but not scalding water can inactivate venom and reduce symptoms.^8,9 In one retrospective review, 52 of 75 (69%) patients reporting to a California poison center with stingray injuries had improvement in pain within 1 hour of hot water immersion before any analgesics were instituted.⁸ In another review, 65 of 74 (88%) patients presenting to a California emergency department within 24 hours of sustaining a stingray injury had complete relief of pain within 30 minutes of hot water immersion. Patients who received analgesics in addition to hot water immersion did not require a second dose.⁹ In concordance with these studies, we suggest immersing areas affected by stingray injuries in hot water (temperature, 43.3°C to 46.1°C [110°F–115°F]; or as close to this range as tolerated) until pain subsides.^8,9,14 Ice packs are an alternative to hot water immersion that may be more readily available to patients. If pain does not resolve following hot water immersion or application of an ice pack, additional analgesics and xylocaine without epinephrine may be helpful.^9,15

Infection
One major complication of stingray injuries is infection.^8,9 Many bacterial species reside in stingray mucus, the marine environment, or on human skin that may be introduced during a single injury. Marine envenomations can involve organisms such as Vibrio, Aeromonas, and Mycobacterium species, which often are resistant to antibiotic prophylaxis covering common causes of soft-tissue infection such as Staphylococcus and Streptococcus species.^8,9,16,17 Additionally, physicians should cover for Clostridium species and ensure patients are up-to-date on vaccinations because severe cases of tetanus following stingray injuries have been reported.¹⁸ Lastly, fungal infections including fusariosis have been reported following stingray injuries and should be considered if a patient develops an infection.¹⁹

Several authors support the use of prophylactic broad-spectrum antibiotics in all but mild stingray injuries.^8,9,20,21 Although no standardized definition exists, mild injuries generally represent patients with superficial lacerations or less, while deeper lacerations and puncture wounds require prophylaxis. Several authors agree on the use of fluoroquinolone antibiotics (eg, ciprofloxacin 500 mg twice daily) for 5 to 7 days following severe stingray injuries.^1,9,13,22 Other proposed antibiotic regimens include trimethoprim-sulfamethoxazole (160/800 mg twice daily) or tetracycline (500 mg 4 times daily) for 7 days.¹³ Failure of ciprofloxacin therapy after 7 days has been reported, with resolution of infection after treatment with an intravenous cephalosporin for 7 days.²⁰ Failure of trimethoprim-sulfamethoxazole therapy also has been reported, with one case requiring levofloxacin for a much longer course.²¹ Clinical follow-up remains essential after prescribing prophylactic antibiotics, as resistance is common.

Foreign Bodies
Stingray injuries also are often complicated by foreign bodies or retained spines.^3,8 Although these complications are less severe than infection, all wounds should be explored for material under local anesthesia. Furthermore, there has been support for thorough debridement of necrotic tissue with referral to a hand specialist for deeper injuries to the hands as well as referral to a foot and ankle specialist for deeper injuries of the lower extremities.^23,24 More serious injuries with penetration of vital structures, such as through the chest or abdomen, require immediate exploration in an operating room.^1,24

Imaging
Routine imaging of stingray injuries remains controversial. In a case series of 119 patients presenting to a California emergency department with stingray injuries, Clark et al⁹ found that radiographs were not helpful. This finding likely is due in part to an inability to detect hypodense material such as integumentary or glandular tissue via radiography.³ However, radiographs have been used to identify retained stingray barbs in select cases in which retained barbs are suspected.^2,25 Lastly, ultrasonography potentially may offer a better first choice when a barb is not readily apparent; magnetic resonance imaging may be indicated for more involved areas and for further visualization of suspected hypodense material, though at a higher expense.^2,9

Biopsy
Biopsies of stingray injuries are rarely performed, and the findings are not well characterized. One case biopsied 2 months after injury showed a large zone of paucicellular necrosis with superficial ulceration and granulomatous inflammation. The stingray venom was most likely responsible for the pattern of necrosis noted in the biopsy.²¹

Avoidance and Prevention

Patients traveling to areas of the world inhabited by stingrays should receive counseling on how to avoid injury. Prior to entry, individuals can throw stones or use a long stick to clear their walking or swimming areas of venomous fish.²⁶ Polarized sunglasses may help spot stingrays in shallow water. Furthermore, wading through water with a shuffling gait can help individuals avoid stepping directly on a stingray and also warns stingrays that someone is in the area. Individuals who spend more time in coastal waters or river systems inhabited by stingrays may invest in protective stingray gear such as leg guards or specialized wading boots.²⁶ Lastly, fishermen should be advised to avoid handling stingrays with their hands and instead cut their fishing line to release the fish.

Incidence and Characteristics

Stingrays are the most common cause of fish-related stings worldwide.¹ The Urolophidae and Dasyatidae stingray families are responsible for most marine stingray injuries, including approximately 1500 reported injuries in the United States annually.^1,2 Saltwater stingrays from these families commonly are encountered in shallow temperate and tropical coastal waters across the globe and possess dorsally and distally located spines capable of injuring humans that step on them (Figure 1).^1,3 Freshwater stingrays (Potamotrygonidae family)(Figure 2) are not present in North America but rather inhabit lakes and river systems in South America, Africa, Laos, and Vietnam.⁴ Although recent incidence is unknown, Marinkelle⁵ estimated that thousands of stingray injuries occurred annually in the freshwater of Columbia during the 1960s. Unfortunately, the annual worldwide incidence of stingray injuries is generally unknown and is difficult to estimate, in part because injuries often go unreported.

Stingrays are dorsoventrally flattened, diamond-shaped fish with light-colored ventral and dark-colored dorsal surfaces. They have strong pectoral wings that allow them to swim forward and backward and even launch off waves.³ Stingrays range in size from the palm of a human hand to 6.5 ft in width. They possess 1 or more spines (2.5 to >30 cm in length) that are disguised by much longer tails.^6,7 They often are encountered accidentally because they bury themselves in the sand or mud of shallow coastal waters or rivers with only their eyes and tails exposed to fool prey and avoid predators.

Injury Clinical Presentation

Stingray injuries typically involve the lower legs, ankles, or feet after stepping on a stingray.⁸ Fishermen can present with injuries of the upper extremities after handling fish with their hands.⁹ Other rarer injuries occur when individuals are swimming alongside stingrays or when stingrays catapult off waves into moving boats.^10,11 Stingrays impale victims by using their tails to direct a retroserrate barb composed of a strong cartilaginous material called vasodentin. The barb releases venom by breaking through the venom-containing integumentary sheath that encapsulates it. Stingray venom contains phosphodiesterase, serotonin, and 5′-nucleotidase. It causes severe pain, vasoconstriction, ischemia, and poor wound healing, along with systemic effects such as disorientation, syncope, seizures, salivation, nausea, vomiting, abdominal pain, diarrhea, muscle cramps or fasciculations, pruritus, allergic reaction, hypotension, cardiac arrhythmias, dyspnea, paralysis, and possibly death.^1,8,12,13

Management

Pain Relief
As with many marine envenomations, immersion in hot but not scalding water can inactivate venom and reduce symptoms.^8,9 In one retrospective review, 52 of 75 (69%) patients reporting to a California poison center with stingray injuries had improvement in pain within 1 hour of hot water immersion before any analgesics were instituted.⁸ In another review, 65 of 74 (88%) patients presenting to a California emergency department within 24 hours of sustaining a stingray injury had complete relief of pain within 30 minutes of hot water immersion. Patients who received analgesics in addition to hot water immersion did not require a second dose.⁹ In concordance with these studies, we suggest immersing areas affected by stingray injuries in hot water (temperature, 43.3°C to 46.1°C [110°F–115°F]; or as close to this range as tolerated) until pain subsides.^8,9,14 Ice packs are an alternative to hot water immersion that may be more readily available to patients. If pain does not resolve following hot water immersion or application of an ice pack, additional analgesics and xylocaine without epinephrine may be helpful.^9,15

Infection
One major complication of stingray injuries is infection.^8,9 Many bacterial species reside in stingray mucus, the marine environment, or on human skin that may be introduced during a single injury. Marine envenomations can involve organisms such as Vibrio, Aeromonas, and Mycobacterium species, which often are resistant to antibiotic prophylaxis covering common causes of soft-tissue infection such as Staphylococcus and Streptococcus species.^8,9,16,17 Additionally, physicians should cover for Clostridium species and ensure patients are up-to-date on vaccinations because severe cases of tetanus following stingray injuries have been reported.¹⁸ Lastly, fungal infections including fusariosis have been reported following stingray injuries and should be considered if a patient develops an infection.¹⁹

Several authors support the use of prophylactic broad-spectrum antibiotics in all but mild stingray injuries.^8,9,20,21 Although no standardized definition exists, mild injuries generally represent patients with superficial lacerations or less, while deeper lacerations and puncture wounds require prophylaxis. Several authors agree on the use of fluoroquinolone antibiotics (eg, ciprofloxacin 500 mg twice daily) for 5 to 7 days following severe stingray injuries.^1,9,13,22 Other proposed antibiotic regimens include trimethoprim-sulfamethoxazole (160/800 mg twice daily) or tetracycline (500 mg 4 times daily) for 7 days.¹³ Failure of ciprofloxacin therapy after 7 days has been reported, with resolution of infection after treatment with an intravenous cephalosporin for 7 days.²⁰ Failure of trimethoprim-sulfamethoxazole therapy also has been reported, with one case requiring levofloxacin for a much longer course.²¹ Clinical follow-up remains essential after prescribing prophylactic antibiotics, as resistance is common.

Foreign Bodies
Stingray injuries also are often complicated by foreign bodies or retained spines.^3,8 Although these complications are less severe than infection, all wounds should be explored for material under local anesthesia. Furthermore, there has been support for thorough debridement of necrotic tissue with referral to a hand specialist for deeper injuries to the hands as well as referral to a foot and ankle specialist for deeper injuries of the lower extremities.^23,24 More serious injuries with penetration of vital structures, such as through the chest or abdomen, require immediate exploration in an operating room.^1,24

Imaging
Routine imaging of stingray injuries remains controversial. In a case series of 119 patients presenting to a California emergency department with stingray injuries, Clark et al⁹ found that radiographs were not helpful. This finding likely is due in part to an inability to detect hypodense material such as integumentary or glandular tissue via radiography.³ However, radiographs have been used to identify retained stingray barbs in select cases in which retained barbs are suspected.^2,25 Lastly, ultrasonography potentially may offer a better first choice when a barb is not readily apparent; magnetic resonance imaging may be indicated for more involved areas and for further visualization of suspected hypodense material, though at a higher expense.^2,9

Biopsy
Biopsies of stingray injuries are rarely performed, and the findings are not well characterized. One case biopsied 2 months after injury showed a large zone of paucicellular necrosis with superficial ulceration and granulomatous inflammation. The stingray venom was most likely responsible for the pattern of necrosis noted in the biopsy.²¹

Avoidance and Prevention

Patients traveling to areas of the world inhabited by stingrays should receive counseling on how to avoid injury. Prior to entry, individuals can throw stones or use a long stick to clear their walking or swimming areas of venomous fish.²⁶ Polarized sunglasses may help spot stingrays in shallow water. Furthermore, wading through water with a shuffling gait can help individuals avoid stepping directly on a stingray and also warns stingrays that someone is in the area. Individuals who spend more time in coastal waters or river systems inhabited by stingrays may invest in protective stingray gear such as leg guards or specialized wading boots.²⁶ Lastly, fishermen should be advised to avoid handling stingrays with their hands and instead cut their fishing line to release the fish.

The Diagnosis: Ruptured Molluscum

Molluscum contagiosum (MC) is caused by a DNA virus (MC virus) belonging to the poxvirus family. Molluscum contagiosum is common and predominantly seen in children and young adults. In sexually active adults, the lesions commonly occur in the genital region, abdomen, and inner thighs. In immunocompromised individuals, including those with AIDS, the lesions are more extensive and may cause disfigurement.¹ Molluscum contagiosum involving epidermoid cysts has been reported.²

Histopathologically, MC can be classified as noninflammatory or inflammatory. In noninflamed lesions, multiple large, intracytoplasmic, eosinophilic inclusions (Henderson-Paterson bodies) appear within the lobulated endophytic and hyperplastic epidermis. Ultrastructurally, these bodies show membrane-bound collections of MC virus.¹ Replicating Henderson-Paterson bodies can result in rupture and inflammation. This case demonstrates a palisading granuloma containing keratin with few Henderson-Paterson bodies (quiz image) due to prior rupture of a molluscum or molluscoid cyst.

Rheumatoid nodules, the most characteristic histopathologic lesions of rheumatoid arthritis, are most commonly found in the subcutis at points of pressure and may occur in connective tissue of numerous organs. Rheumatoid nodules are firm, nontender, and mobile within the subcutaneous tissue but may be fixed to underlying structures including the periosteum, tendons, or bursae.^3,4 Occasionally, superficial nodules may perforate the epidermis.⁵ The inner central necrobiotic zone appears as intensely eosinophilic, amorphous fibrin and other cellular debris. This central area is surrounded by histiocytes in a palisaded configuration (Figure 1). Multinucleated foreign body giant cells also may be present. Occasionally, mast cells, eosinophils, and neutrophils are present.^6,7

Lupus miliaris disseminatus faciei presents with multiple discrete, smooth, yellow-brown to red, dome-shaped papules. The lesions typically are located on the central and lateral sides of the face and infrequently involve the neck. Other sites including the axillae, arms, hands, legs, and groin occasionally can be involved. Diascopy may reveal an apple jelly color.^8,9 The histopathologic hallmark of lupus miliaris disseminatus faciei is an epithelioid cell granuloma with central necrosis (Figure 2).

Epithelioid sarcoma (ES) is a soft tissue tumor with a known propensity for local recurrence, regional lymph node involvement, sporotrichoid spread, and distant metastases.¹⁰ The name was coined by Enzinger¹¹ in 1970 during a review of 62 cases of a “peculiar form of sarcoma that has repeatedly been confused with a chronic inflammatory process, a necrotizing granuloma, and a squamous cell carcinoma.” Epithelioid sarcoma tends to grow slowly in a nodular or multinodular manner along fascial structures and tendons, often with central necrosis and ulceration of the overlying skin. Histopathologically, classic ES shows nodular masses of uniform plump epithelioid cells with abundant eosinophilic cytoplasm and prominent central necrosis. A biphasic pattern is typical with spindle cells merging with epithelioid cells. Cellular atypia is relatively mild and mitoses are rare (Figure 3). Recurrent or metastatic lesions can show a greater degree of pleomorphism.¹² Given the low-grade atypia in early lesions, this sarcoma is easily misdiagnosed as granulomatous dermatitis. Immunohistochemically, the majority of ES cases are positive for cytokeratins and epithelial membrane antigen; SMARCB1/INI-1 expression is characteristically lost.¹³

Granulomatosis with polyangiitis (formerly Wegener granulomatosis) is an autoimmune vasculitis highly associated with antineutrophil cytoplasmic antibodies. Clinical manifestations include systemic necrotizing vasculitis; necrotizing glomerulonephritis; and granulomatous inflammation, which predominantly involves the upper respiratory tract, skin, and mucosa.^14,15 Skin involvement may be the initial manifestation of the disease and consists of palpable purpura, papules, ulcerations, vesicles, subcutaneous nodules, necrotizing ulcerations, papulonecrotic lesions, and petechiae. None of the findings are pathognomonic. The cutaneous histopathologic spectrum includes leukocytoclastic vasculitis, extravascular palisading granulomas, and granulomatous vasculitis.¹⁶ In the acute lesions of granulomatosis with polyangiitis, the predominant pattern of inflammation is not granulomatous but purulent with the appearance of an abscess. As it evolves, it develops a central zone of necrosis with extensive karyorrhectic debris and palisades of macrophages with scattered multinucleated giant cells (Figure 4).¹⁷

The Diagnosis: Ruptured Molluscum

Molluscum contagiosum (MC) is caused by a DNA virus (MC virus) belonging to the poxvirus family. Molluscum contagiosum is common and predominantly seen in children and young adults. In sexually active adults, the lesions commonly occur in the genital region, abdomen, and inner thighs. In immunocompromised individuals, including those with AIDS, the lesions are more extensive and may cause disfigurement.¹ Molluscum contagiosum involving epidermoid cysts has been reported.²

Histopathologically, MC can be classified as noninflammatory or inflammatory. In noninflamed lesions, multiple large, intracytoplasmic, eosinophilic inclusions (Henderson-Paterson bodies) appear within the lobulated endophytic and hyperplastic epidermis. Ultrastructurally, these bodies show membrane-bound collections of MC virus.¹ Replicating Henderson-Paterson bodies can result in rupture and inflammation. This case demonstrates a palisading granuloma containing keratin with few Henderson-Paterson bodies (quiz image) due to prior rupture of a molluscum or molluscoid cyst.

Rheumatoid nodules, the most characteristic histopathologic lesions of rheumatoid arthritis, are most commonly found in the subcutis at points of pressure and may occur in connective tissue of numerous organs. Rheumatoid nodules are firm, nontender, and mobile within the subcutaneous tissue but may be fixed to underlying structures including the periosteum, tendons, or bursae.^3,4 Occasionally, superficial nodules may perforate the epidermis.⁵ The inner central necrobiotic zone appears as intensely eosinophilic, amorphous fibrin and other cellular debris. This central area is surrounded by histiocytes in a palisaded configuration (Figure 1). Multinucleated foreign body giant cells also may be present. Occasionally, mast cells, eosinophils, and neutrophils are present.^6,7

Lupus miliaris disseminatus faciei presents with multiple discrete, smooth, yellow-brown to red, dome-shaped papules. The lesions typically are located on the central and lateral sides of the face and infrequently involve the neck. Other sites including the axillae, arms, hands, legs, and groin occasionally can be involved. Diascopy may reveal an apple jelly color.^8,9 The histopathologic hallmark of lupus miliaris disseminatus faciei is an epithelioid cell granuloma with central necrosis (Figure 2).

Epithelioid sarcoma (ES) is a soft tissue tumor with a known propensity for local recurrence, regional lymph node involvement, sporotrichoid spread, and distant metastases.¹⁰ The name was coined by Enzinger¹¹ in 1970 during a review of 62 cases of a “peculiar form of sarcoma that has repeatedly been confused with a chronic inflammatory process, a necrotizing granuloma, and a squamous cell carcinoma.” Epithelioid sarcoma tends to grow slowly in a nodular or multinodular manner along fascial structures and tendons, often with central necrosis and ulceration of the overlying skin. Histopathologically, classic ES shows nodular masses of uniform plump epithelioid cells with abundant eosinophilic cytoplasm and prominent central necrosis. A biphasic pattern is typical with spindle cells merging with epithelioid cells. Cellular atypia is relatively mild and mitoses are rare (Figure 3). Recurrent or metastatic lesions can show a greater degree of pleomorphism.¹² Given the low-grade atypia in early lesions, this sarcoma is easily misdiagnosed as granulomatous dermatitis. Immunohistochemically, the majority of ES cases are positive for cytokeratins and epithelial membrane antigen; SMARCB1/INI-1 expression is characteristically lost.¹³

Granulomatosis with polyangiitis (formerly Wegener granulomatosis) is an autoimmune vasculitis highly associated with antineutrophil cytoplasmic antibodies. Clinical manifestations include systemic necrotizing vasculitis; necrotizing glomerulonephritis; and granulomatous inflammation, which predominantly involves the upper respiratory tract, skin, and mucosa.^14,15 Skin involvement may be the initial manifestation of the disease and consists of palpable purpura, papules, ulcerations, vesicles, subcutaneous nodules, necrotizing ulcerations, papulonecrotic lesions, and petechiae. None of the findings are pathognomonic. The cutaneous histopathologic spectrum includes leukocytoclastic vasculitis, extravascular palisading granulomas, and granulomatous vasculitis.¹⁶ In the acute lesions of granulomatosis with polyangiitis, the predominant pattern of inflammation is not granulomatous but purulent with the appearance of an abscess. As it evolves, it develops a central zone of necrosis with extensive karyorrhectic debris and palisades of macrophages with scattered multinucleated giant cells (Figure 4).¹⁷

The Diagnosis: Ruptured Molluscum

Molluscum contagiosum (MC) is caused by a DNA virus (MC virus) belonging to the poxvirus family. Molluscum contagiosum is common and predominantly seen in children and young adults. In sexually active adults, the lesions commonly occur in the genital region, abdomen, and inner thighs. In immunocompromised individuals, including those with AIDS, the lesions are more extensive and may cause disfigurement.¹ Molluscum contagiosum involving epidermoid cysts has been reported.²

Histopathologically, MC can be classified as noninflammatory or inflammatory. In noninflamed lesions, multiple large, intracytoplasmic, eosinophilic inclusions (Henderson-Paterson bodies) appear within the lobulated endophytic and hyperplastic epidermis. Ultrastructurally, these bodies show membrane-bound collections of MC virus.¹ Replicating Henderson-Paterson bodies can result in rupture and inflammation. This case demonstrates a palisading granuloma containing keratin with few Henderson-Paterson bodies (quiz image) due to prior rupture of a molluscum or molluscoid cyst.

Rheumatoid nodules, the most characteristic histopathologic lesions of rheumatoid arthritis, are most commonly found in the subcutis at points of pressure and may occur in connective tissue of numerous organs. Rheumatoid nodules are firm, nontender, and mobile within the subcutaneous tissue but may be fixed to underlying structures including the periosteum, tendons, or bursae.^3,4 Occasionally, superficial nodules may perforate the epidermis.⁵ The inner central necrobiotic zone appears as intensely eosinophilic, amorphous fibrin and other cellular debris. This central area is surrounded by histiocytes in a palisaded configuration (Figure 1). Multinucleated foreign body giant cells also may be present. Occasionally, mast cells, eosinophils, and neutrophils are present.^6,7

Lupus miliaris disseminatus faciei presents with multiple discrete, smooth, yellow-brown to red, dome-shaped papules. The lesions typically are located on the central and lateral sides of the face and infrequently involve the neck. Other sites including the axillae, arms, hands, legs, and groin occasionally can be involved. Diascopy may reveal an apple jelly color.^8,9 The histopathologic hallmark of lupus miliaris disseminatus faciei is an epithelioid cell granuloma with central necrosis (Figure 2).

Epithelioid sarcoma (ES) is a soft tissue tumor with a known propensity for local recurrence, regional lymph node involvement, sporotrichoid spread, and distant metastases.¹⁰ The name was coined by Enzinger¹¹ in 1970 during a review of 62 cases of a “peculiar form of sarcoma that has repeatedly been confused with a chronic inflammatory process, a necrotizing granuloma, and a squamous cell carcinoma.” Epithelioid sarcoma tends to grow slowly in a nodular or multinodular manner along fascial structures and tendons, often with central necrosis and ulceration of the overlying skin. Histopathologically, classic ES shows nodular masses of uniform plump epithelioid cells with abundant eosinophilic cytoplasm and prominent central necrosis. A biphasic pattern is typical with spindle cells merging with epithelioid cells. Cellular atypia is relatively mild and mitoses are rare (Figure 3). Recurrent or metastatic lesions can show a greater degree of pleomorphism.¹² Given the low-grade atypia in early lesions, this sarcoma is easily misdiagnosed as granulomatous dermatitis. Immunohistochemically, the majority of ES cases are positive for cytokeratins and epithelial membrane antigen; SMARCB1/INI-1 expression is characteristically lost.¹³

Granulomatosis with polyangiitis (formerly Wegener granulomatosis) is an autoimmune vasculitis highly associated with antineutrophil cytoplasmic antibodies. Clinical manifestations include systemic necrotizing vasculitis; necrotizing glomerulonephritis; and granulomatous inflammation, which predominantly involves the upper respiratory tract, skin, and mucosa.^14,15 Skin involvement may be the initial manifestation of the disease and consists of palpable purpura, papules, ulcerations, vesicles, subcutaneous nodules, necrotizing ulcerations, papulonecrotic lesions, and petechiae. None of the findings are pathognomonic. The cutaneous histopathologic spectrum includes leukocytoclastic vasculitis, extravascular palisading granulomas, and granulomatous vasculitis.¹⁶ In the acute lesions of granulomatosis with polyangiitis, the predominant pattern of inflammation is not granulomatous but purulent with the appearance of an abscess. As it evolves, it develops a central zone of necrosis with extensive karyorrhectic debris and palisades of macrophages with scattered multinucleated giant cells (Figure 4).¹⁷

The lionfish (Pterois volitans) is a member of the Scorpaenidae family of venomous fish.^1-3 Lionfish are an invasive species originally from the Indian and Pacific oceans and the Red Sea that now are widely found throughout tropical and temperate oceans in both hemispheres. They are a popular aquarium fish and were inadvertently introduced in the Atlantic Ocean in South Florida during the late 1980s to early 1990s.^2,4 Since then, lionfish have spread into reef systems throughout the Atlantic Ocean, Caribbean Sea, and Gulf of Mexico in rapidly growing numbers, and they are now fo und all along the southeastern coast of the United States.⁵

Characteristics

Lionfish are brightly colored with red or maroon and white stripes, tentacles above the eyes and mouth, fan-shaped pectoral fins, and spines that deliver an especially painful venomous sting that often results in edema (Figure 1). They have 12 dorsal spines, 2 pelvic spines, and 3 anal spines.

Symptoms of Envenomation

As lionfish continue to spread to popular areas of the southeast Atlantic Ocean and Caribbean Sea, the chances of human contact with lionfish have increased. Lionfish stings are now the second most common marine envenomation injury after those caused by stingrays.⁴ Lionfish stings usually occur on the hands, fingers, or forearms during handling of the fish in ocean waters or in maintenance of aquariums. The mechanism of the venom apparatus is similar for all venomous fish. The spines have surrounding integumentary sheaths containing venom that rupture and inject venom when they penetrate the skin.⁶ The venom is a heat-labile neuromuscular toxin that causes edema (Figure 2), plasma extravasation, and thrombotic skin lesions.⁷

Wounds are classified into 3 categories: grade I consists of local erythema/ecchymosis, grade II involves vesicle or blister formation, and grade III denotes wounds that develop local necrosis.⁸ The sting causes immediate and severe throbbing pain, often described as excruciating or rated 10/10 on a basic pain scale, typically radiating up the affected limb. Puncture sites may bleed and often have associated redness and swelling. Pain may last up to 24 hours. Occasionally, foreign material may be left in the wound requiring removal. There also is a chance of secondary infection at the wound site, and severe envenomation can lead to local tissue necrosis.⁸ Systemic effects can occur in some cases, including nausea, vomiting, sweating, headache, dizziness, disorientation, palpitations, and even syncope.⁹ However, to our knowledge there are no documented cases of human death from a lionfish sting. Anaphylactic reactions are possible and require immediate treatment.⁶

A study conducted in the French West Indies evaluated 117 patients with lionfish envenomation and found that victims experienced severe pain and local edema (100%), paresthesia (90%), abdominal cramps (62%), extensive edema (53%), tachycardia (34%), skin rash (32%), gastrointestinal tract symptoms (28%), syncope (27%), transient weakness (24%), hypertension (21%), hypotension (18%), and hyperthermia (9%).⁹ Complications included local infection (18%) such as skin abscess (5%), skin necrosis (3%), and septic arthritis (2%). Twenty-two percent of patients were hospitalized and 8% required surgery. Local infectious complications were more frequent in those with multiple stings (19%). The study concluded that lionfish now represent a major health threat in the West Indies.⁹ As lionfish numbers have grown, health care providers are seeing increasing numbers of envenomation cases in areas of the coastal southeastern United States and Caribbean associated with considerable morbidity. Providers in nonendemic areas also may see envenomation injuries due to the lionfish popularity in home aquariums.⁹

Management

Individuals with lionfish stings should immerse the affected area in hot but not scalding water. Those with more serious injuries should seek medical attention. Home remedies that are generally contraindicated include application of topical papain or meat tenderizer.¹⁰ Data on ice packs are mixed, but because the toxin is heat labile, the most effective initial step in treatment is immersion of the affected area in water (temperature, 40°C to 45°C) for 30 to 90 minutes.⁶ The hot water inactivates the heat-labile toxin, leading to near-complete symptomatic relief in 80% of cases and moderate relief in an additional 14%. Immersion time more than 90 minutes considerably increases the risk for burns. Children should always be monitored to prevent burns. If a patient has received a nerve block for analgesia, the wound should not be immersed in hot water to avoid burns to the skin. The wound should be meticulously cleaned with saline irrigation, and radiography or ultrasonography should be performed as deemed necessary to look for any retained foreign bodies.⁸ Patients may require parenteral or oral analgesia as well as careful follow-up to ensure proper healing.⁹ Systemic symptoms require supportive care. Venomous fish wounds typically are small and superficial. Empiric antibiotic therapy is not advised for superficial wounds but may be required for clinically infected wounds.⁸ Tetanus prophylaxis should be given as appropriate to all affected patients. It has been noted that blister fluid contains high concentrations of lionfish venom, and when present, it increases the likelihood of converting the injury from a grade II to grade III wound with tissue necrosis; therefore, blisters should be drained or excised to decrease the chances of subsequent tissue necrosis.^11,12 If secondary infection such as cellulitis develops, antibiotics should be chosen to cover likely pathogens including common skin flora such as staphylococci and marine organisms such as Vibrio species. Wounds showing signs of infection should be cultured, with antibiotics adjusted according to sensitivities.⁵ Deeper wounds should be left open (unsutured) with a proper dressing to heal. Any wounds that involve vascular or joint structures require specialty management. Wounds involving joints may on occasion require surgical exploration and debridement.

Public Health Concerns

In an attempt to slow the growth of their population, human consumption of the fish has been encouraged. The lionfish toxin is inactivated by cooking, and the fish is considered a delicacy; however, a study in the Virgin Islands found that in areas with endemic ciguatera poisoning, 12% of lionfish carried amounts of the toxin above the level considered safe for consumption. This toxin is not inactivated by cooking or freezing and can lead to ciguatera fish poisoning for which there is no antidote and can be associated with prolonged neurotoxicity.¹³

Conclusion

As lionfish numbers continue to increase, physicians across multiple specialties and regions may see an increase in envenomation injuries. It is important that physicians are aware of how to recognize and treat lionfish stings, as prompt and comprehensive treatment provides benefit to the patient.

The lionfish (Pterois volitans) is a member of the Scorpaenidae family of venomous fish.^1-3 Lionfish are an invasive species originally from the Indian and Pacific oceans and the Red Sea that now are widely found throughout tropical and temperate oceans in both hemispheres. They are a popular aquarium fish and were inadvertently introduced in the Atlantic Ocean in South Florida during the late 1980s to early 1990s.^2,4 Since then, lionfish have spread into reef systems throughout the Atlantic Ocean, Caribbean Sea, and Gulf of Mexico in rapidly growing numbers, and they are now fo und all along the southeastern coast of the United States.⁵

Characteristics

Lionfish are brightly colored with red or maroon and white stripes, tentacles above the eyes and mouth, fan-shaped pectoral fins, and spines that deliver an especially painful venomous sting that often results in edema (Figure 1). They have 12 dorsal spines, 2 pelvic spines, and 3 anal spines.

Symptoms of Envenomation

As lionfish continue to spread to popular areas of the southeast Atlantic Ocean and Caribbean Sea, the chances of human contact with lionfish have increased. Lionfish stings are now the second most common marine envenomation injury after those caused by stingrays.⁴ Lionfish stings usually occur on the hands, fingers, or forearms during handling of the fish in ocean waters or in maintenance of aquariums. The mechanism of the venom apparatus is similar for all venomous fish. The spines have surrounding integumentary sheaths containing venom that rupture and inject venom when they penetrate the skin.⁶ The venom is a heat-labile neuromuscular toxin that causes edema (Figure 2), plasma extravasation, and thrombotic skin lesions.⁷

Wounds are classified into 3 categories: grade I consists of local erythema/ecchymosis, grade II involves vesicle or blister formation, and grade III denotes wounds that develop local necrosis.⁸ The sting causes immediate and severe throbbing pain, often described as excruciating or rated 10/10 on a basic pain scale, typically radiating up the affected limb. Puncture sites may bleed and often have associated redness and swelling. Pain may last up to 24 hours. Occasionally, foreign material may be left in the wound requiring removal. There also is a chance of secondary infection at the wound site, and severe envenomation can lead to local tissue necrosis.⁸ Systemic effects can occur in some cases, including nausea, vomiting, sweating, headache, dizziness, disorientation, palpitations, and even syncope.⁹ However, to our knowledge there are no documented cases of human death from a lionfish sting. Anaphylactic reactions are possible and require immediate treatment.⁶

A study conducted in the French West Indies evaluated 117 patients with lionfish envenomation and found that victims experienced severe pain and local edema (100%), paresthesia (90%), abdominal cramps (62%), extensive edema (53%), tachycardia (34%), skin rash (32%), gastrointestinal tract symptoms (28%), syncope (27%), transient weakness (24%), hypertension (21%), hypotension (18%), and hyperthermia (9%).⁹ Complications included local infection (18%) such as skin abscess (5%), skin necrosis (3%), and septic arthritis (2%). Twenty-two percent of patients were hospitalized and 8% required surgery. Local infectious complications were more frequent in those with multiple stings (19%). The study concluded that lionfish now represent a major health threat in the West Indies.⁹ As lionfish numbers have grown, health care providers are seeing increasing numbers of envenomation cases in areas of the coastal southeastern United States and Caribbean associated with considerable morbidity. Providers in nonendemic areas also may see envenomation injuries due to the lionfish popularity in home aquariums.⁹

Management

Individuals with lionfish stings should immerse the affected area in hot but not scalding water. Those with more serious injuries should seek medical attention. Home remedies that are generally contraindicated include application of topical papain or meat tenderizer.¹⁰ Data on ice packs are mixed, but because the toxin is heat labile, the most effective initial step in treatment is immersion of the affected area in water (temperature, 40°C to 45°C) for 30 to 90 minutes.⁶ The hot water inactivates the heat-labile toxin, leading to near-complete symptomatic relief in 80% of cases and moderate relief in an additional 14%. Immersion time more than 90 minutes considerably increases the risk for burns. Children should always be monitored to prevent burns. If a patient has received a nerve block for analgesia, the wound should not be immersed in hot water to avoid burns to the skin. The wound should be meticulously cleaned with saline irrigation, and radiography or ultrasonography should be performed as deemed necessary to look for any retained foreign bodies.⁸ Patients may require parenteral or oral analgesia as well as careful follow-up to ensure proper healing.⁹ Systemic symptoms require supportive care. Venomous fish wounds typically are small and superficial. Empiric antibiotic therapy is not advised for superficial wounds but may be required for clinically infected wounds.⁸ Tetanus prophylaxis should be given as appropriate to all affected patients. It has been noted that blister fluid contains high concentrations of lionfish venom, and when present, it increases the likelihood of converting the injury from a grade II to grade III wound with tissue necrosis; therefore, blisters should be drained or excised to decrease the chances of subsequent tissue necrosis.^11,12 If secondary infection such as cellulitis develops, antibiotics should be chosen to cover likely pathogens including common skin flora such as staphylococci and marine organisms such as Vibrio species. Wounds showing signs of infection should be cultured, with antibiotics adjusted according to sensitivities.⁵ Deeper wounds should be left open (unsutured) with a proper dressing to heal. Any wounds that involve vascular or joint structures require specialty management. Wounds involving joints may on occasion require surgical exploration and debridement.

Public Health Concerns

In an attempt to slow the growth of their population, human consumption of the fish has been encouraged. The lionfish toxin is inactivated by cooking, and the fish is considered a delicacy; however, a study in the Virgin Islands found that in areas with endemic ciguatera poisoning, 12% of lionfish carried amounts of the toxin above the level considered safe for consumption. This toxin is not inactivated by cooking or freezing and can lead to ciguatera fish poisoning for which there is no antidote and can be associated with prolonged neurotoxicity.¹³

Conclusion

As lionfish numbers continue to increase, physicians across multiple specialties and regions may see an increase in envenomation injuries. It is important that physicians are aware of how to recognize and treat lionfish stings, as prompt and comprehensive treatment provides benefit to the patient.

The lionfish (Pterois volitans) is a member of the Scorpaenidae family of venomous fish.^1-3 Lionfish are an invasive species originally from the Indian and Pacific oceans and the Red Sea that now are widely found throughout tropical and temperate oceans in both hemispheres. They are a popular aquarium fish and were inadvertently introduced in the Atlantic Ocean in South Florida during the late 1980s to early 1990s.^2,4 Since then, lionfish have spread into reef systems throughout the Atlantic Ocean, Caribbean Sea, and Gulf of Mexico in rapidly growing numbers, and they are now fo und all along the southeastern coast of the United States.⁵

Characteristics

Lionfish are brightly colored with red or maroon and white stripes, tentacles above the eyes and mouth, fan-shaped pectoral fins, and spines that deliver an especially painful venomous sting that often results in edema (Figure 1). They have 12 dorsal spines, 2 pelvic spines, and 3 anal spines.

Symptoms of Envenomation

As lionfish continue to spread to popular areas of the southeast Atlantic Ocean and Caribbean Sea, the chances of human contact with lionfish have increased. Lionfish stings are now the second most common marine envenomation injury after those caused by stingrays.⁴ Lionfish stings usually occur on the hands, fingers, or forearms during handling of the fish in ocean waters or in maintenance of aquariums. The mechanism of the venom apparatus is similar for all venomous fish. The spines have surrounding integumentary sheaths containing venom that rupture and inject venom when they penetrate the skin.⁶ The venom is a heat-labile neuromuscular toxin that causes edema (Figure 2), plasma extravasation, and thrombotic skin lesions.⁷

Wounds are classified into 3 categories: grade I consists of local erythema/ecchymosis, grade II involves vesicle or blister formation, and grade III denotes wounds that develop local necrosis.⁸ The sting causes immediate and severe throbbing pain, often described as excruciating or rated 10/10 on a basic pain scale, typically radiating up the affected limb. Puncture sites may bleed and often have associated redness and swelling. Pain may last up to 24 hours. Occasionally, foreign material may be left in the wound requiring removal. There also is a chance of secondary infection at the wound site, and severe envenomation can lead to local tissue necrosis.⁸ Systemic effects can occur in some cases, including nausea, vomiting, sweating, headache, dizziness, disorientation, palpitations, and even syncope.⁹ However, to our knowledge there are no documented cases of human death from a lionfish sting. Anaphylactic reactions are possible and require immediate treatment.⁶

A study conducted in the French West Indies evaluated 117 patients with lionfish envenomation and found that victims experienced severe pain and local edema (100%), paresthesia (90%), abdominal cramps (62%), extensive edema (53%), tachycardia (34%), skin rash (32%), gastrointestinal tract symptoms (28%), syncope (27%), transient weakness (24%), hypertension (21%), hypotension (18%), and hyperthermia (9%).⁹ Complications included local infection (18%) such as skin abscess (5%), skin necrosis (3%), and septic arthritis (2%). Twenty-two percent of patients were hospitalized and 8% required surgery. Local infectious complications were more frequent in those with multiple stings (19%). The study concluded that lionfish now represent a major health threat in the West Indies.⁹ As lionfish numbers have grown, health care providers are seeing increasing numbers of envenomation cases in areas of the coastal southeastern United States and Caribbean associated with considerable morbidity. Providers in nonendemic areas also may see envenomation injuries due to the lionfish popularity in home aquariums.⁹

Management

Individuals with lionfish stings should immerse the affected area in hot but not scalding water. Those with more serious injuries should seek medical attention. Home remedies that are generally contraindicated include application of topical papain or meat tenderizer.¹⁰ Data on ice packs are mixed, but because the toxin is heat labile, the most effective initial step in treatment is immersion of the affected area in water (temperature, 40°C to 45°C) for 30 to 90 minutes.⁶ The hot water inactivates the heat-labile toxin, leading to near-complete symptomatic relief in 80% of cases and moderate relief in an additional 14%. Immersion time more than 90 minutes considerably increases the risk for burns. Children should always be monitored to prevent burns. If a patient has received a nerve block for analgesia, the wound should not be immersed in hot water to avoid burns to the skin. The wound should be meticulously cleaned with saline irrigation, and radiography or ultrasonography should be performed as deemed necessary to look for any retained foreign bodies.⁸ Patients may require parenteral or oral analgesia as well as careful follow-up to ensure proper healing.⁹ Systemic symptoms require supportive care. Venomous fish wounds typically are small and superficial. Empiric antibiotic therapy is not advised for superficial wounds but may be required for clinically infected wounds.⁸ Tetanus prophylaxis should be given as appropriate to all affected patients. It has been noted that blister fluid contains high concentrations of lionfish venom, and when present, it increases the likelihood of converting the injury from a grade II to grade III wound with tissue necrosis; therefore, blisters should be drained or excised to decrease the chances of subsequent tissue necrosis.^11,12 If secondary infection such as cellulitis develops, antibiotics should be chosen to cover likely pathogens including common skin flora such as staphylococci and marine organisms such as Vibrio species. Wounds showing signs of infection should be cultured, with antibiotics adjusted according to sensitivities.⁵ Deeper wounds should be left open (unsutured) with a proper dressing to heal. Any wounds that involve vascular or joint structures require specialty management. Wounds involving joints may on occasion require surgical exploration and debridement.

Public Health Concerns

In an attempt to slow the growth of their population, human consumption of the fish has been encouraged. The lionfish toxin is inactivated by cooking, and the fish is considered a delicacy; however, a study in the Virgin Islands found that in areas with endemic ciguatera poisoning, 12% of lionfish carried amounts of the toxin above the level considered safe for consumption. This toxin is not inactivated by cooking or freezing and can lead to ciguatera fish poisoning for which there is no antidote and can be associated with prolonged neurotoxicity.¹³

Conclusion

As lionfish numbers continue to increase, physicians across multiple specialties and regions may see an increase in envenomation injuries. It is important that physicians are aware of how to recognize and treat lionfish stings, as prompt and comprehensive treatment provides benefit to the patient.

Adult-onset Still disease (AOSD) is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, evanescent skin rash, and lymphadenopathy. ¹ The most commonly used criteria for diagnosing AOSD are the Yamaguchi criteria. ² The major criteria include high fever for more than 1 week, arthralgia for more than 2 weeks, leukocytosis, and an evanescent skin rash. The minor criteria consist of sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative rheumatoid factor and antinuclear antibodies. Classically, the skin rash is described as an evanescent, salmon-colored erythema involving the extremities. Nevertheless, unusual cutaneous eruptions have been reported in AOSD, including persistent pruritic papules and plaques. ³ Importantly, this atypical rash demonstrates specific histologic findings that are not found on routine histopathology of a typical evanescent rash. We describe 2 patients with this atypical cutaneous eruption along with the unique histopathologic findings of AOSD.

Case Reports

Patient 1
A 23-year-old Chinese woman presented with periodic fevers, persistent rash, and joint pain of 2 years’ duration. Her medical history included splenectomy for hepatosplenomegaly as well as evaluation by hematology for lymphadenopathy; a cervical lymph node biopsy showed lymphoid and follicular hyperplasia.

Twenty days later, the patient was referred to the dermatology department for evaluation of the persistent rash. The patient described a history of flushing of the face, severe joint pain in both arms and legs, aching muscles, and persistent sore throat. The patient did not report any history of drug ingestion. Physical examination revealed a fever (temperature, 39.2°C); swollen nontender lymph nodes in the neck, axillae, and groin; and salmon-colored and hyperpigmented patches and thin plaques over the neck, chest, abdomen, and arms (Figure 1). A splenectomy scar also was noted. Peripheral blood was collected for laboratory analyses, which revealed transaminitis and moderate hyperferritinemia (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. The patient was admitted to the hospital, and a skin biopsy was performed. Histology showed superficial dyskeratotic keratinocytes and sparse perivascular infiltration of neutrophils in the upper dermis (Figure 2).

The patient was diagnosed with AOSD based on fulfillment of the Yamaguchi criteria.² She was treated with methylprednisolone 60 mg daily and was discharged 14 days later. At 16-month follow-up, the patient demonstrated complete resolution of symptoms with a maintenance dose of prednisolone (7.5 mg daily).

Patient 2
A 23-year-old black woman presented to the emergency department 3 months postpartum with recurrent high fevers, worsening joint pain, and persistent itchy rash of 2 months’ duration. The patient had no history of travel, autoimmune disease, or sick contacts. She occasionally took aspirin for joint pain. Physical examination revealed a fever (temperature, 39.1°C) along with hyperpigmented patches and thin scaly hyperpigmented papules coalescing into a poorly demarcated V-shaped plaque on the upper back and posterior neck, extending to the chest in a shawl-like distribution (Figure 3). Submental lymphadenopathy was present. The spleen was not palpable.

Peripheral blood was collected for laboratory analysis and demonstrated transaminitis and a markedly high ferritin level (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. Skin biopsy was performed and demonstrated many necrotic keratinocytes, singly and in aggregates, distributed from the spinous layer to the stratum corneum. A neutrophilic infiltrate was present in the papillary dermis (Figure 4).

The patient met the Yamaguchi criteria and was subsequently diagnosed with AOSD. She was treated with intravenous methylprednisolone 20 mg every 8 hours and was discharged 1 week later on oral prednisone 60 mg daily to be tapered over a period of months. At 2-week follow-up, the patient continued to experience rash and joint pain; oral methotrexate 10 mg weekly was added to her regimen, as well as vitamin D, calcium, and folic acid supplementation. At the next 2-week follow-up the patient noted improvement in the rash as well as the joint pain, but both still persisted. Prednisone was decreased to 50 mg daily and methotrexate was increased to 15 mg weekly. The patient continued to show improvement over the subsequent 3 months, during which prednisone was tapered to 10 mg daily and methotrexate was increased to 20 mg weekly. The patient showed resolution of symptoms at 3-month follow-up on this regimen, with plans to continue the prednisone taper and maintain methotrexate dosing.

Comment

Adult-onset Still disease is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, salmon-pink evanescent erythema, and lymphadenopathy.² The condition also can cause liver dysfunction, splenomegaly, pericarditis, pleuritis, renal dysfunction, and a reactive hemophagocytic syndrome.¹ Furthermore, one review of the literature described an association with delayed-onset malignancy.⁴ Early diagnosis is important yet challenging, as AOSD is a diagnosis of exclusion. The Yamaguchi criteria are the most widely used method of diagnosis and demonstrate more than 90% sensitivity.In addition to the Yamaguchi criteria, marked hyperferritinemia is characteristic of AOSD and can act as an indicator of disease activity.⁵ Interestingly, both of our patients had elevated ferritin levels, with patient 2 showing marked elevation (Table). In both patients, all major criteria were fulfilled, except the typical skin rash.

The skin rash in AOSD, classically consisting of an evanescent, salmon-pink erythema predominantly involving the extremities, has been observed in up to 87% of AOSD patients.⁵ The histology of the typical evanescent rash is nonspecific, characterized by a relatively sparse, perivascular, mixed inflammatory infiltrate. Notably, other skin manifestations may be found in patients with AOSD.^1,2,5-16 Persistent pruritic papules and plaques are the most commonly reported nonclassical rash, presenting as erythematous, slightly scaly papules and plaques with a linear configuration typically on the trunk.² Both of our patients presented with this atypical eruption. Importantly, the histopathology of this unique rash displays distinctive features, which can aid in early diagnosis. Findings include dyskeratotic keratinocytes in the cornified layers as well as in the epidermis, and a sparse neutrophilic and/or lymphocytic infiltrate in the papillary dermis without vasculitis. These findings were evident in both histopathologic studies of our patients (Figures 2 and 4). Although not present in our patients, dermal mucin deposition has been demonstrated in some reports.^1,13,15

A 2015 review of the literature yielded 30 cases of AOSD with pruritic persistent papules and plaques.⁴ The study confirmed a linear, erythematous or brown rash on the back and neck in the majority of cases. Histologic findings were congruent with those reported in our 2 cases: necrotic keratinocytes in the upper epidermis with a neutrophilic infiltrate in the upper dermis without vasculitis. Most patients showed rapid resolution of the rash and symptoms with the use of prednisone, prednisolone, or intravenous pulsed methylprednisolone. Interestingly, a range of presentations were noted, including prurigo pigmentosalike urticarial papules; lichenoid papules; and dermatographismlike, dermatomyositislike, and lichen amyloidosis–like rashes.⁴ In our report, patient 2 presented with a rash in a dermat-omyositislike shawl distribution. It has been suggested that patients with dermatomyositislike rashes require more potent immunotherapy as compared to patients with other rash morphologies.⁴ The need for methotrexate in addition to a prednisone taper in the clinical course of patient 2 lends further support to this observation.

Conclusion

A clinically and pathologically distinct form of cutaneous disease—AOSD with persistent pruritic papules and plaques—was observed in our 2 patients. These histopathologic findings facilitated timely diagnosis in both patients. A range of clinical morphologies may exist in AOSD, an awareness of which is paramount. Adult-onset Still disease should be included in the differential diagnosis of a dermatomyositislike presentation in a shawl distribution. Prompt diagnosis is essential to ensure adequate therapy.

Adult-onset Still disease (AOSD) is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, evanescent skin rash, and lymphadenopathy. ¹ The most commonly used criteria for diagnosing AOSD are the Yamaguchi criteria. ² The major criteria include high fever for more than 1 week, arthralgia for more than 2 weeks, leukocytosis, and an evanescent skin rash. The minor criteria consist of sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative rheumatoid factor and antinuclear antibodies. Classically, the skin rash is described as an evanescent, salmon-colored erythema involving the extremities. Nevertheless, unusual cutaneous eruptions have been reported in AOSD, including persistent pruritic papules and plaques. ³ Importantly, this atypical rash demonstrates specific histologic findings that are not found on routine histopathology of a typical evanescent rash. We describe 2 patients with this atypical cutaneous eruption along with the unique histopathologic findings of AOSD.

Case Reports

Patient 1
A 23-year-old Chinese woman presented with periodic fevers, persistent rash, and joint pain of 2 years’ duration. Her medical history included splenectomy for hepatosplenomegaly as well as evaluation by hematology for lymphadenopathy; a cervical lymph node biopsy showed lymphoid and follicular hyperplasia.

Twenty days later, the patient was referred to the dermatology department for evaluation of the persistent rash. The patient described a history of flushing of the face, severe joint pain in both arms and legs, aching muscles, and persistent sore throat. The patient did not report any history of drug ingestion. Physical examination revealed a fever (temperature, 39.2°C); swollen nontender lymph nodes in the neck, axillae, and groin; and salmon-colored and hyperpigmented patches and thin plaques over the neck, chest, abdomen, and arms (Figure 1). A splenectomy scar also was noted. Peripheral blood was collected for laboratory analyses, which revealed transaminitis and moderate hyperferritinemia (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. The patient was admitted to the hospital, and a skin biopsy was performed. Histology showed superficial dyskeratotic keratinocytes and sparse perivascular infiltration of neutrophils in the upper dermis (Figure 2).

The patient was diagnosed with AOSD based on fulfillment of the Yamaguchi criteria.² She was treated with methylprednisolone 60 mg daily and was discharged 14 days later. At 16-month follow-up, the patient demonstrated complete resolution of symptoms with a maintenance dose of prednisolone (7.5 mg daily).

Patient 2
A 23-year-old black woman presented to the emergency department 3 months postpartum with recurrent high fevers, worsening joint pain, and persistent itchy rash of 2 months’ duration. The patient had no history of travel, autoimmune disease, or sick contacts. She occasionally took aspirin for joint pain. Physical examination revealed a fever (temperature, 39.1°C) along with hyperpigmented patches and thin scaly hyperpigmented papules coalescing into a poorly demarcated V-shaped plaque on the upper back and posterior neck, extending to the chest in a shawl-like distribution (Figure 3). Submental lymphadenopathy was present. The spleen was not palpable.

Peripheral blood was collected for laboratory analysis and demonstrated transaminitis and a markedly high ferritin level (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. Skin biopsy was performed and demonstrated many necrotic keratinocytes, singly and in aggregates, distributed from the spinous layer to the stratum corneum. A neutrophilic infiltrate was present in the papillary dermis (Figure 4).

The patient met the Yamaguchi criteria and was subsequently diagnosed with AOSD. She was treated with intravenous methylprednisolone 20 mg every 8 hours and was discharged 1 week later on oral prednisone 60 mg daily to be tapered over a period of months. At 2-week follow-up, the patient continued to experience rash and joint pain; oral methotrexate 10 mg weekly was added to her regimen, as well as vitamin D, calcium, and folic acid supplementation. At the next 2-week follow-up the patient noted improvement in the rash as well as the joint pain, but both still persisted. Prednisone was decreased to 50 mg daily and methotrexate was increased to 15 mg weekly. The patient continued to show improvement over the subsequent 3 months, during which prednisone was tapered to 10 mg daily and methotrexate was increased to 20 mg weekly. The patient showed resolution of symptoms at 3-month follow-up on this regimen, with plans to continue the prednisone taper and maintain methotrexate dosing.

Comment

Adult-onset Still disease is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, salmon-pink evanescent erythema, and lymphadenopathy.² The condition also can cause liver dysfunction, splenomegaly, pericarditis, pleuritis, renal dysfunction, and a reactive hemophagocytic syndrome.¹ Furthermore, one review of the literature described an association with delayed-onset malignancy.⁴ Early diagnosis is important yet challenging, as AOSD is a diagnosis of exclusion. The Yamaguchi criteria are the most widely used method of diagnosis and demonstrate more than 90% sensitivity.In addition to the Yamaguchi criteria, marked hyperferritinemia is characteristic of AOSD and can act as an indicator of disease activity.⁵ Interestingly, both of our patients had elevated ferritin levels, with patient 2 showing marked elevation (Table). In both patients, all major criteria were fulfilled, except the typical skin rash.

The skin rash in AOSD, classically consisting of an evanescent, salmon-pink erythema predominantly involving the extremities, has been observed in up to 87% of AOSD patients.⁵ The histology of the typical evanescent rash is nonspecific, characterized by a relatively sparse, perivascular, mixed inflammatory infiltrate. Notably, other skin manifestations may be found in patients with AOSD.^1,2,5-16 Persistent pruritic papules and plaques are the most commonly reported nonclassical rash, presenting as erythematous, slightly scaly papules and plaques with a linear configuration typically on the trunk.² Both of our patients presented with this atypical eruption. Importantly, the histopathology of this unique rash displays distinctive features, which can aid in early diagnosis. Findings include dyskeratotic keratinocytes in the cornified layers as well as in the epidermis, and a sparse neutrophilic and/or lymphocytic infiltrate in the papillary dermis without vasculitis. These findings were evident in both histopathologic studies of our patients (Figures 2 and 4). Although not present in our patients, dermal mucin deposition has been demonstrated in some reports.^1,13,15

A 2015 review of the literature yielded 30 cases of AOSD with pruritic persistent papules and plaques.⁴ The study confirmed a linear, erythematous or brown rash on the back and neck in the majority of cases. Histologic findings were congruent with those reported in our 2 cases: necrotic keratinocytes in the upper epidermis with a neutrophilic infiltrate in the upper dermis without vasculitis. Most patients showed rapid resolution of the rash and symptoms with the use of prednisone, prednisolone, or intravenous pulsed methylprednisolone. Interestingly, a range of presentations were noted, including prurigo pigmentosalike urticarial papules; lichenoid papules; and dermatographismlike, dermatomyositislike, and lichen amyloidosis–like rashes.⁴ In our report, patient 2 presented with a rash in a dermat-omyositislike shawl distribution. It has been suggested that patients with dermatomyositislike rashes require more potent immunotherapy as compared to patients with other rash morphologies.⁴ The need for methotrexate in addition to a prednisone taper in the clinical course of patient 2 lends further support to this observation.

Conclusion

A clinically and pathologically distinct form of cutaneous disease—AOSD with persistent pruritic papules and plaques—was observed in our 2 patients. These histopathologic findings facilitated timely diagnosis in both patients. A range of clinical morphologies may exist in AOSD, an awareness of which is paramount. Adult-onset Still disease should be included in the differential diagnosis of a dermatomyositislike presentation in a shawl distribution. Prompt diagnosis is essential to ensure adequate therapy.

Adult-onset Still disease (AOSD) is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, evanescent skin rash, and lymphadenopathy. ¹ The most commonly used criteria for diagnosing AOSD are the Yamaguchi criteria. ² The major criteria include high fever for more than 1 week, arthralgia for more than 2 weeks, leukocytosis, and an evanescent skin rash. The minor criteria consist of sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative rheumatoid factor and antinuclear antibodies. Classically, the skin rash is described as an evanescent, salmon-colored erythema involving the extremities. Nevertheless, unusual cutaneous eruptions have been reported in AOSD, including persistent pruritic papules and plaques. ³ Importantly, this atypical rash demonstrates specific histologic findings that are not found on routine histopathology of a typical evanescent rash. We describe 2 patients with this atypical cutaneous eruption along with the unique histopathologic findings of AOSD.

Case Reports

Patient 1
A 23-year-old Chinese woman presented with periodic fevers, persistent rash, and joint pain of 2 years’ duration. Her medical history included splenectomy for hepatosplenomegaly as well as evaluation by hematology for lymphadenopathy; a cervical lymph node biopsy showed lymphoid and follicular hyperplasia.

Twenty days later, the patient was referred to the dermatology department for evaluation of the persistent rash. The patient described a history of flushing of the face, severe joint pain in both arms and legs, aching muscles, and persistent sore throat. The patient did not report any history of drug ingestion. Physical examination revealed a fever (temperature, 39.2°C); swollen nontender lymph nodes in the neck, axillae, and groin; and salmon-colored and hyperpigmented patches and thin plaques over the neck, chest, abdomen, and arms (Figure 1). A splenectomy scar also was noted. Peripheral blood was collected for laboratory analyses, which revealed transaminitis and moderate hyperferritinemia (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. The patient was admitted to the hospital, and a skin biopsy was performed. Histology showed superficial dyskeratotic keratinocytes and sparse perivascular infiltration of neutrophils in the upper dermis (Figure 2).

The patient was diagnosed with AOSD based on fulfillment of the Yamaguchi criteria.² She was treated with methylprednisolone 60 mg daily and was discharged 14 days later. At 16-month follow-up, the patient demonstrated complete resolution of symptoms with a maintenance dose of prednisolone (7.5 mg daily).

Patient 2
A 23-year-old black woman presented to the emergency department 3 months postpartum with recurrent high fevers, worsening joint pain, and persistent itchy rash of 2 months’ duration. The patient had no history of travel, autoimmune disease, or sick contacts. She occasionally took aspirin for joint pain. Physical examination revealed a fever (temperature, 39.1°C) along with hyperpigmented patches and thin scaly hyperpigmented papules coalescing into a poorly demarcated V-shaped plaque on the upper back and posterior neck, extending to the chest in a shawl-like distribution (Figure 3). Submental lymphadenopathy was present. The spleen was not palpable.

Peripheral blood was collected for laboratory analysis and demonstrated transaminitis and a markedly high ferritin level (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. Skin biopsy was performed and demonstrated many necrotic keratinocytes, singly and in aggregates, distributed from the spinous layer to the stratum corneum. A neutrophilic infiltrate was present in the papillary dermis (Figure 4).

The patient met the Yamaguchi criteria and was subsequently diagnosed with AOSD. She was treated with intravenous methylprednisolone 20 mg every 8 hours and was discharged 1 week later on oral prednisone 60 mg daily to be tapered over a period of months. At 2-week follow-up, the patient continued to experience rash and joint pain; oral methotrexate 10 mg weekly was added to her regimen, as well as vitamin D, calcium, and folic acid supplementation. At the next 2-week follow-up the patient noted improvement in the rash as well as the joint pain, but both still persisted. Prednisone was decreased to 50 mg daily and methotrexate was increased to 15 mg weekly. The patient continued to show improvement over the subsequent 3 months, during which prednisone was tapered to 10 mg daily and methotrexate was increased to 20 mg weekly. The patient showed resolution of symptoms at 3-month follow-up on this regimen, with plans to continue the prednisone taper and maintain methotrexate dosing.

Comment

Adult-onset Still disease is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, salmon-pink evanescent erythema, and lymphadenopathy.² The condition also can cause liver dysfunction, splenomegaly, pericarditis, pleuritis, renal dysfunction, and a reactive hemophagocytic syndrome.¹ Furthermore, one review of the literature described an association with delayed-onset malignancy.⁴ Early diagnosis is important yet challenging, as AOSD is a diagnosis of exclusion. The Yamaguchi criteria are the most widely used method of diagnosis and demonstrate more than 90% sensitivity.In addition to the Yamaguchi criteria, marked hyperferritinemia is characteristic of AOSD and can act as an indicator of disease activity.⁵ Interestingly, both of our patients had elevated ferritin levels, with patient 2 showing marked elevation (Table). In both patients, all major criteria were fulfilled, except the typical skin rash.

The skin rash in AOSD, classically consisting of an evanescent, salmon-pink erythema predominantly involving the extremities, has been observed in up to 87% of AOSD patients.⁵ The histology of the typical evanescent rash is nonspecific, characterized by a relatively sparse, perivascular, mixed inflammatory infiltrate. Notably, other skin manifestations may be found in patients with AOSD.^1,2,5-16 Persistent pruritic papules and plaques are the most commonly reported nonclassical rash, presenting as erythematous, slightly scaly papules and plaques with a linear configuration typically on the trunk.² Both of our patients presented with this atypical eruption. Importantly, the histopathology of this unique rash displays distinctive features, which can aid in early diagnosis. Findings include dyskeratotic keratinocytes in the cornified layers as well as in the epidermis, and a sparse neutrophilic and/or lymphocytic infiltrate in the papillary dermis without vasculitis. These findings were evident in both histopathologic studies of our patients (Figures 2 and 4). Although not present in our patients, dermal mucin deposition has been demonstrated in some reports.^1,13,15

A 2015 review of the literature yielded 30 cases of AOSD with pruritic persistent papules and plaques.⁴ The study confirmed a linear, erythematous or brown rash on the back and neck in the majority of cases. Histologic findings were congruent with those reported in our 2 cases: necrotic keratinocytes in the upper epidermis with a neutrophilic infiltrate in the upper dermis without vasculitis. Most patients showed rapid resolution of the rash and symptoms with the use of prednisone, prednisolone, or intravenous pulsed methylprednisolone. Interestingly, a range of presentations were noted, including prurigo pigmentosalike urticarial papules; lichenoid papules; and dermatographismlike, dermatomyositislike, and lichen amyloidosis–like rashes.⁴ In our report, patient 2 presented with a rash in a dermat-omyositislike shawl distribution. It has been suggested that patients with dermatomyositislike rashes require more potent immunotherapy as compared to patients with other rash morphologies.⁴ The need for methotrexate in addition to a prednisone taper in the clinical course of patient 2 lends further support to this observation.

Conclusion

A clinically and pathologically distinct form of cutaneous disease—AOSD with persistent pruritic papules and plaques—was observed in our 2 patients. These histopathologic findings facilitated timely diagnosis in both patients. A range of clinical morphologies may exist in AOSD, an awareness of which is paramount. Adult-onset Still disease should be included in the differential diagnosis of a dermatomyositislike presentation in a shawl distribution. Prompt diagnosis is essential to ensure adequate therapy.

The Ixodes tick is prevalent in temperate climates worldwide. During a blood meal, pathogens may be transmitted from the tick to its host. Borrelia burgdorferi, a spirochete responsible for Lyme disease, is the most prevalent pathogen transmitted by Ixodes ticks.¹ Borrelia mayonii recently was identified as an additional cause of Lyme disease in the United States.²

The Ixodes tick also is associated with several less common pathogens, including Babesia microti and the tick-borne encephalitis virus, which have been recognized as Ixodes-associated pathogens for many years.^3,4 Other pathogens have been identified, including Anaplasma phagocytophilum, recognized in the 1990s as the cause of human granulocytic anaplasmosis, as well as the Powassan virus and Borrelia miyamotoi.^5-7 Additionally, tick paralysis has been associated with toxins in the saliva of various species of several genera of ticks, including some Ixodes species.⁸ Due to an overlap in geographic distribution (Figure) and disease presentations (eTable), it is important that physicians be familiar with these regional pathogens transmitted by Ixodes ticks.

Human Granulocytic Anaplasmosis

Formerly known as human granulocytic ehrlichiosis, human granulocytic anaplasmosis is caused by A phagocytophilum and is transmitted by Ixodes scapularis, Ixodes pacificus, and Ixodes persulcatus. The incidence of human granulocytic anaplasmosis in the United States increased 12-fold from 2001 to 2011.⁹

Presenting symptoms generally are nonspecific, including fever, night sweats, headache, myalgias, and arthralgias, often resulting in misdiagnosis as a viral infection. Laboratory abnormalities include mild transaminitis, leukopenia, and thrombocytopenia.^9,10 Although most infections resolve spontaneously, 3% of patients develop serious complications. The mortality rate is 0.6%.¹¹

A diagnosis of human granulocytic anaplasmosis should be suspected in patients with a viral-like illness and exposure to ticks in an endemic area. The diagnosis can be confirmed by polymerase chain reaction (PCR), acute- and convalescent-phase serologic testing, or direct fluorescent antibody screening. Characteristic morulae may be present in granulocytes.¹² Treatment typically includes doxycycline, which also covers B burgdorferi coinfection. When a diagnosis of human granulocytic anaplasmosis is suspected, treatment should never be delayed to await laboratory confirmation. If no clinical improvement is seen within 48 hours, alternate diagnoses or coinfection with B microti should be considered.¹⁰

Babesiosis

The protozoan B microti causes babesiosis in the United States, with Babesia divergens being more common in Europe.¹³ Reported cases of babesiosis in New York increased as much as 20-fold from 2001 to 2008.¹⁴ Transmission primarily is from the Ixodes tick but rarely can occur from blood transfusion.¹⁵ Tick attachment for at least 36 hours is required for transmission.¹³

The clinical presentation of babesiosis ranges from asymptomatic to fatal. Symptoms generally are nonspecific, resembling a viral infection and including headache, nausea, diarrhea, arthralgia, and myalgia. Laboratory evaluation may reveal hemolytic anemia, thrombocytopenia, transaminitis, and elevated blood urea nitrogen and creatinine levels.¹⁶ Rash is not typical. Resolution of symptoms generally occurs within 2 weeks of presentation, although anemia may persist for months.¹³ Severe disease is more common among elderly and immunocompromised patients. Complications include respiratory failure, renal failure, congestive heart failure, and disseminated intravascular coagulation. The mortality rate in the United States is approximately 10%.^10,16

A diagnosis of babesiosis is made based on the presence of flulike symptoms, laboratory results, and history of recent travel to an endemic area. A thin blood smear allows identification of the organism in erythrocytes as ring forms or tetrads (a “Maltese cross” appearance).¹⁷ Polymerase chain reaction is more sensitive than a blood smear, especially in early disease.¹⁸ Indirect fluorescent antibody testing is species-specific but cannot verify active infection.¹⁰

Treatment of babesiosis is indicated for symptomatic patients with active infection. Positive serology alone is not an indication for treatment. Asymptomatic patients with positive serology should have diagnostic testing repeated in 3 months with subsequent treatment if parasitemia persists. Mild disease is treated with atovaquone plus azithromycin or clindamycin plus quinine. Severe babesiosis is treated with quinine and intravenous clindamycin and may require exchange transfusion.¹⁰ Coinfection with B burgdorferi should be considered in patients with flulike symptoms and erythema migrans or treatment failure. Coinfection is diagnosed by Lyme serology plus PCR for B microti. This is an important consideration because treatment of babesiosis does not eradicate B burgdorferi infection.¹⁹

Powassan Virus

Powassan virus is a flavivirus that causes encephalitis. It is transmitted by Ixodes cookei (Powassan virus, lineage I) in the Great Lakes region and by I scapularis (Powassan virus, lineage II, or deer tick virus) in the northeastern United States. Transmission can occur within 15 minutes of tick attachment.^6,20,21

Patients typically present with fever, headache, altered mental status, seizures, and focal neurologic deficits. Gastrointestinal symptoms and rash also have been reported.²¹ The diagnosis is made based on clinical presentation and laboratory testing with PCR or enzyme-linked immunosorbent assay (ELISA). Cross-reactivity on ELISA exists, necessitating confirmation with a neutralizing antibody or PCR. Treatment is supportive. Corticosteroids and intravenous immunoglobulin have been proposed as treatment modalities, but evidence of their efficacy is limited.²²

Tick-borne Encephalitis

Tick-borne encephalitis is caused by the flavivirus tick-borne encephalitis virus in Europe and Asia. The tick-borne encephalitis virus is transmitted by Ixodes ricinus in Europe and by Ixodes persulcatus in eastern Russia, China, and Japan. It also has been associated with consumption of unpasteurized milk.^23,24

Tick-borne encephalitis presents in a biphasic pattern. The initial viremic phase can persist for as long as 8 days with headache, nausea, myalgia, and fever. One-third of patients then enter an asymptomatic phase, followed by virus penetration into the central nervous system. The neurologic phase produces continued headache and fever with photophobia, focal neurologic deficits, seizures, respiratory depression, or coma. Neurologic sequelae persist in 10% to 20% of patients.^25,26

In the viremic stage, diagnosis is made with PCR or culture. During the latent phase or neurologic phase, serologic testing for tick-borne encephalitis virus antibodies is indicated. Neutralizing antibody evaluation may be necessary due to cross-reactivity among flaviviruses.²⁷ Treatment is supportive. An inactivated vaccine is available for high-risk populations.²⁸

Borrelia miyamotoi Disease

Borrelia miyamotoi is a symbiont of the Ixodes tick formerly believed to have no pathogenic significance; however, B miyamotoi was isolated in febrile patients in Russia in 2011⁷ and was identified as a pathogen in both North America²⁹ and Europe in 2013.³⁰ Disease presentation includes nonspecific symptoms of fever, fatigue, headache, arthralgia, myalgia, and nausea. Rash is uncommon. Laboratory abnormalities include leukopenia, thrombocytopenia, and transaminitis.^31,32 Meningoencephalitis may occur in immunocompromised patients.^29,30

The diagnosis of B miyamotoi disease is confirmed by PCR or serology. An ELISA that is positive for B burgdorferi IgM but negative with confirmatory immunoblot suggests B miyamotoi disease. Seroconversion using a glpQ protein ELISA also can be assessed.³¹ If ELISA is positive, Lyme disease can be excluded because B burgdorferi does not possess g1pQ. Treatment is with doxycycline.³²

Tick Paralysis

Tick paralysis is an intoxication with holocyclotoxin from the saliva of gravid hard ticks. In the United States, intoxication is associated with ticks of various species of Amblyomma, Dermacentor, and Ixodes in the Northwest, Southeast, and Northeast. In Australia, intoxication is associated with Ixodes.³³ Patients present with weakness and fatigue, progressing to ascending flaccid paralysis with sensory sparing. The treatment is tick removal.^8,33

Conclusion

Arthropods carry many regional pathogens. Physicians outside of those regions should seek a travel history and be alert for imported disease.

The Ixodes tick is prevalent in temperate climates worldwide. During a blood meal, pathogens may be transmitted from the tick to its host. Borrelia burgdorferi, a spirochete responsible for Lyme disease, is the most prevalent pathogen transmitted by Ixodes ticks.¹ Borrelia mayonii recently was identified as an additional cause of Lyme disease in the United States.²

The Ixodes tick also is associated with several less common pathogens, including Babesia microti and the tick-borne encephalitis virus, which have been recognized as Ixodes-associated pathogens for many years.^3,4 Other pathogens have been identified, including Anaplasma phagocytophilum, recognized in the 1990s as the cause of human granulocytic anaplasmosis, as well as the Powassan virus and Borrelia miyamotoi.^5-7 Additionally, tick paralysis has been associated with toxins in the saliva of various species of several genera of ticks, including some Ixodes species.⁸ Due to an overlap in geographic distribution (Figure) and disease presentations (eTable), it is important that physicians be familiar with these regional pathogens transmitted by Ixodes ticks.

Human Granulocytic Anaplasmosis

Formerly known as human granulocytic ehrlichiosis, human granulocytic anaplasmosis is caused by A phagocytophilum and is transmitted by Ixodes scapularis, Ixodes pacificus, and Ixodes persulcatus. The incidence of human granulocytic anaplasmosis in the United States increased 12-fold from 2001 to 2011.⁹

Presenting symptoms generally are nonspecific, including fever, night sweats, headache, myalgias, and arthralgias, often resulting in misdiagnosis as a viral infection. Laboratory abnormalities include mild transaminitis, leukopenia, and thrombocytopenia.^9,10 Although most infections resolve spontaneously, 3% of patients develop serious complications. The mortality rate is 0.6%.¹¹

A diagnosis of human granulocytic anaplasmosis should be suspected in patients with a viral-like illness and exposure to ticks in an endemic area. The diagnosis can be confirmed by polymerase chain reaction (PCR), acute- and convalescent-phase serologic testing, or direct fluorescent antibody screening. Characteristic morulae may be present in granulocytes.¹² Treatment typically includes doxycycline, which also covers B burgdorferi coinfection. When a diagnosis of human granulocytic anaplasmosis is suspected, treatment should never be delayed to await laboratory confirmation. If no clinical improvement is seen within 48 hours, alternate diagnoses or coinfection with B microti should be considered.¹⁰

Babesiosis

The protozoan B microti causes babesiosis in the United States, with Babesia divergens being more common in Europe.¹³ Reported cases of babesiosis in New York increased as much as 20-fold from 2001 to 2008.¹⁴ Transmission primarily is from the Ixodes tick but rarely can occur from blood transfusion.¹⁵ Tick attachment for at least 36 hours is required for transmission.¹³

The clinical presentation of babesiosis ranges from asymptomatic to fatal. Symptoms generally are nonspecific, resembling a viral infection and including headache, nausea, diarrhea, arthralgia, and myalgia. Laboratory evaluation may reveal hemolytic anemia, thrombocytopenia, transaminitis, and elevated blood urea nitrogen and creatinine levels.¹⁶ Rash is not typical. Resolution of symptoms generally occurs within 2 weeks of presentation, although anemia may persist for months.¹³ Severe disease is more common among elderly and immunocompromised patients. Complications include respiratory failure, renal failure, congestive heart failure, and disseminated intravascular coagulation. The mortality rate in the United States is approximately 10%.^10,16

A diagnosis of babesiosis is made based on the presence of flulike symptoms, laboratory results, and history of recent travel to an endemic area. A thin blood smear allows identification of the organism in erythrocytes as ring forms or tetrads (a “Maltese cross” appearance).¹⁷ Polymerase chain reaction is more sensitive than a blood smear, especially in early disease.¹⁸ Indirect fluorescent antibody testing is species-specific but cannot verify active infection.¹⁰

Treatment of babesiosis is indicated for symptomatic patients with active infection. Positive serology alone is not an indication for treatment. Asymptomatic patients with positive serology should have diagnostic testing repeated in 3 months with subsequent treatment if parasitemia persists. Mild disease is treated with atovaquone plus azithromycin or clindamycin plus quinine. Severe babesiosis is treated with quinine and intravenous clindamycin and may require exchange transfusion.¹⁰ Coinfection with B burgdorferi should be considered in patients with flulike symptoms and erythema migrans or treatment failure. Coinfection is diagnosed by Lyme serology plus PCR for B microti. This is an important consideration because treatment of babesiosis does not eradicate B burgdorferi infection.¹⁹

Powassan Virus

Powassan virus is a flavivirus that causes encephalitis. It is transmitted by Ixodes cookei (Powassan virus, lineage I) in the Great Lakes region and by I scapularis (Powassan virus, lineage II, or deer tick virus) in the northeastern United States. Transmission can occur within 15 minutes of tick attachment.^6,20,21

Patients typically present with fever, headache, altered mental status, seizures, and focal neurologic deficits. Gastrointestinal symptoms and rash also have been reported.²¹ The diagnosis is made based on clinical presentation and laboratory testing with PCR or enzyme-linked immunosorbent assay (ELISA). Cross-reactivity on ELISA exists, necessitating confirmation with a neutralizing antibody or PCR. Treatment is supportive. Corticosteroids and intravenous immunoglobulin have been proposed as treatment modalities, but evidence of their efficacy is limited.²²

Tick-borne Encephalitis

Tick-borne encephalitis is caused by the flavivirus tick-borne encephalitis virus in Europe and Asia. The tick-borne encephalitis virus is transmitted by Ixodes ricinus in Europe and by Ixodes persulcatus in eastern Russia, China, and Japan. It also has been associated with consumption of unpasteurized milk.^23,24

Tick-borne encephalitis presents in a biphasic pattern. The initial viremic phase can persist for as long as 8 days with headache, nausea, myalgia, and fever. One-third of patients then enter an asymptomatic phase, followed by virus penetration into the central nervous system. The neurologic phase produces continued headache and fever with photophobia, focal neurologic deficits, seizures, respiratory depression, or coma. Neurologic sequelae persist in 10% to 20% of patients.^25,26

In the viremic stage, diagnosis is made with PCR or culture. During the latent phase or neurologic phase, serologic testing for tick-borne encephalitis virus antibodies is indicated. Neutralizing antibody evaluation may be necessary due to cross-reactivity among flaviviruses.²⁷ Treatment is supportive. An inactivated vaccine is available for high-risk populations.²⁸

Borrelia miyamotoi Disease

Borrelia miyamotoi is a symbiont of the Ixodes tick formerly believed to have no pathogenic significance; however, B miyamotoi was isolated in febrile patients in Russia in 2011⁷ and was identified as a pathogen in both North America²⁹ and Europe in 2013.³⁰ Disease presentation includes nonspecific symptoms of fever, fatigue, headache, arthralgia, myalgia, and nausea. Rash is uncommon. Laboratory abnormalities include leukopenia, thrombocytopenia, and transaminitis.^31,32 Meningoencephalitis may occur in immunocompromised patients.^29,30

The diagnosis of B miyamotoi disease is confirmed by PCR or serology. An ELISA that is positive for B burgdorferi IgM but negative with confirmatory immunoblot suggests B miyamotoi disease. Seroconversion using a glpQ protein ELISA also can be assessed.³¹ If ELISA is positive, Lyme disease can be excluded because B burgdorferi does not possess g1pQ. Treatment is with doxycycline.³²

Tick Paralysis

Tick paralysis is an intoxication with holocyclotoxin from the saliva of gravid hard ticks. In the United States, intoxication is associated with ticks of various species of Amblyomma, Dermacentor, and Ixodes in the Northwest, Southeast, and Northeast. In Australia, intoxication is associated with Ixodes.³³ Patients present with weakness and fatigue, progressing to ascending flaccid paralysis with sensory sparing. The treatment is tick removal.^8,33

Conclusion

Arthropods carry many regional pathogens. Physicians outside of those regions should seek a travel history and be alert for imported disease.

The Ixodes tick is prevalent in temperate climates worldwide. During a blood meal, pathogens may be transmitted from the tick to its host. Borrelia burgdorferi, a spirochete responsible for Lyme disease, is the most prevalent pathogen transmitted by Ixodes ticks.¹ Borrelia mayonii recently was identified as an additional cause of Lyme disease in the United States.²

The Ixodes tick also is associated with several less common pathogens, including Babesia microti and the tick-borne encephalitis virus, which have been recognized as Ixodes-associated pathogens for many years.^3,4 Other pathogens have been identified, including Anaplasma phagocytophilum, recognized in the 1990s as the cause of human granulocytic anaplasmosis, as well as the Powassan virus and Borrelia miyamotoi.^5-7 Additionally, tick paralysis has been associated with toxins in the saliva of various species of several genera of ticks, including some Ixodes species.⁸ Due to an overlap in geographic distribution (Figure) and disease presentations (eTable), it is important that physicians be familiar with these regional pathogens transmitted by Ixodes ticks.

Human Granulocytic Anaplasmosis

Formerly known as human granulocytic ehrlichiosis, human granulocytic anaplasmosis is caused by A phagocytophilum and is transmitted by Ixodes scapularis, Ixodes pacificus, and Ixodes persulcatus. The incidence of human granulocytic anaplasmosis in the United States increased 12-fold from 2001 to 2011.⁹

Presenting symptoms generally are nonspecific, including fever, night sweats, headache, myalgias, and arthralgias, often resulting in misdiagnosis as a viral infection. Laboratory abnormalities include mild transaminitis, leukopenia, and thrombocytopenia.^9,10 Although most infections resolve spontaneously, 3% of patients develop serious complications. The mortality rate is 0.6%.¹¹

A diagnosis of human granulocytic anaplasmosis should be suspected in patients with a viral-like illness and exposure to ticks in an endemic area. The diagnosis can be confirmed by polymerase chain reaction (PCR), acute- and convalescent-phase serologic testing, or direct fluorescent antibody screening. Characteristic morulae may be present in granulocytes.¹² Treatment typically includes doxycycline, which also covers B burgdorferi coinfection. When a diagnosis of human granulocytic anaplasmosis is suspected, treatment should never be delayed to await laboratory confirmation. If no clinical improvement is seen within 48 hours, alternate diagnoses or coinfection with B microti should be considered.¹⁰

Babesiosis

The protozoan B microti causes babesiosis in the United States, with Babesia divergens being more common in Europe.¹³ Reported cases of babesiosis in New York increased as much as 20-fold from 2001 to 2008.¹⁴ Transmission primarily is from the Ixodes tick but rarely can occur from blood transfusion.¹⁵ Tick attachment for at least 36 hours is required for transmission.¹³

The clinical presentation of babesiosis ranges from asymptomatic to fatal. Symptoms generally are nonspecific, resembling a viral infection and including headache, nausea, diarrhea, arthralgia, and myalgia. Laboratory evaluation may reveal hemolytic anemia, thrombocytopenia, transaminitis, and elevated blood urea nitrogen and creatinine levels.¹⁶ Rash is not typical. Resolution of symptoms generally occurs within 2 weeks of presentation, although anemia may persist for months.¹³ Severe disease is more common among elderly and immunocompromised patients. Complications include respiratory failure, renal failure, congestive heart failure, and disseminated intravascular coagulation. The mortality rate in the United States is approximately 10%.^10,16

A diagnosis of babesiosis is made based on the presence of flulike symptoms, laboratory results, and history of recent travel to an endemic area. A thin blood smear allows identification of the organism in erythrocytes as ring forms or tetrads (a “Maltese cross” appearance).¹⁷ Polymerase chain reaction is more sensitive than a blood smear, especially in early disease.¹⁸ Indirect fluorescent antibody testing is species-specific but cannot verify active infection.¹⁰

Treatment of babesiosis is indicated for symptomatic patients with active infection. Positive serology alone is not an indication for treatment. Asymptomatic patients with positive serology should have diagnostic testing repeated in 3 months with subsequent treatment if parasitemia persists. Mild disease is treated with atovaquone plus azithromycin or clindamycin plus quinine. Severe babesiosis is treated with quinine and intravenous clindamycin and may require exchange transfusion.¹⁰ Coinfection with B burgdorferi should be considered in patients with flulike symptoms and erythema migrans or treatment failure. Coinfection is diagnosed by Lyme serology plus PCR for B microti. This is an important consideration because treatment of babesiosis does not eradicate B burgdorferi infection.¹⁹

Powassan Virus

Powassan virus is a flavivirus that causes encephalitis. It is transmitted by Ixodes cookei (Powassan virus, lineage I) in the Great Lakes region and by I scapularis (Powassan virus, lineage II, or deer tick virus) in the northeastern United States. Transmission can occur within 15 minutes of tick attachment.^6,20,21

Patients typically present with fever, headache, altered mental status, seizures, and focal neurologic deficits. Gastrointestinal symptoms and rash also have been reported.²¹ The diagnosis is made based on clinical presentation and laboratory testing with PCR or enzyme-linked immunosorbent assay (ELISA). Cross-reactivity on ELISA exists, necessitating confirmation with a neutralizing antibody or PCR. Treatment is supportive. Corticosteroids and intravenous immunoglobulin have been proposed as treatment modalities, but evidence of their efficacy is limited.²²

Tick-borne Encephalitis

Tick-borne encephalitis is caused by the flavivirus tick-borne encephalitis virus in Europe and Asia. The tick-borne encephalitis virus is transmitted by Ixodes ricinus in Europe and by Ixodes persulcatus in eastern Russia, China, and Japan. It also has been associated with consumption of unpasteurized milk.^23,24

Tick-borne encephalitis presents in a biphasic pattern. The initial viremic phase can persist for as long as 8 days with headache, nausea, myalgia, and fever. One-third of patients then enter an asymptomatic phase, followed by virus penetration into the central nervous system. The neurologic phase produces continued headache and fever with photophobia, focal neurologic deficits, seizures, respiratory depression, or coma. Neurologic sequelae persist in 10% to 20% of patients.^25,26

In the viremic stage, diagnosis is made with PCR or culture. During the latent phase or neurologic phase, serologic testing for tick-borne encephalitis virus antibodies is indicated. Neutralizing antibody evaluation may be necessary due to cross-reactivity among flaviviruses.²⁷ Treatment is supportive. An inactivated vaccine is available for high-risk populations.²⁸

Borrelia miyamotoi Disease

Borrelia miyamotoi is a symbiont of the Ixodes tick formerly believed to have no pathogenic significance; however, B miyamotoi was isolated in febrile patients in Russia in 2011⁷ and was identified as a pathogen in both North America²⁹ and Europe in 2013.³⁰ Disease presentation includes nonspecific symptoms of fever, fatigue, headache, arthralgia, myalgia, and nausea. Rash is uncommon. Laboratory abnormalities include leukopenia, thrombocytopenia, and transaminitis.^31,32 Meningoencephalitis may occur in immunocompromised patients.^29,30

The diagnosis of B miyamotoi disease is confirmed by PCR or serology. An ELISA that is positive for B burgdorferi IgM but negative with confirmatory immunoblot suggests B miyamotoi disease. Seroconversion using a glpQ protein ELISA also can be assessed.³¹ If ELISA is positive, Lyme disease can be excluded because B burgdorferi does not possess g1pQ. Treatment is with doxycycline.³²

Tick Paralysis

Tick paralysis is an intoxication with holocyclotoxin from the saliva of gravid hard ticks. In the United States, intoxication is associated with ticks of various species of Amblyomma, Dermacentor, and Ixodes in the Northwest, Southeast, and Northeast. In Australia, intoxication is associated with Ixodes.³³ Patients present with weakness and fatigue, progressing to ascending flaccid paralysis with sensory sparing. The treatment is tick removal.^8,33

Conclusion

Arthropods carry many regional pathogens. Physicians outside of those regions should seek a travel history and be alert for imported disease.

The Diagnosis: Metastatic Crohn Disease

Crohn disease (CD), a chronic inflammatory granulomatous disease of the gastrointestinal tract, has a wide spectrum of presentations.¹ The condition may affect the vulva, perineum, or perianal skin by direct extension from the gastrointestinal tract or may appear as a separate and distinct cutaneous focus of disease referred to as metastatic Crohn disease (MCD).²

Cutaneous lesions of MCD include ulcers, fissures, sinus tracts, abscesses, and vegetative plaques, which typically extend in continuity with sites of intra-abdominal disease to the perineum, buttocks, or abdominal wall, as well as ostomy sites or incisional scars. Erythema nodosum and pyoderma gangrenosum are the most common nonspecific cutaneous manifestations. Other cutaneous lesions described in CD include polyarteritis nodosa, psoriasis, erythema multiforme, erythema elevatum diutinum, epidermolysis bullosa acquisita, acne fulminans, pyoderma faciale, neutrophilic lobular panniculitis, granulomatous vasculitis, and porokeratosis.³

Perianal skin is the most common site of cutaneous involvement in individuals with CD. It is a marker of more severe disease and is associated with multiple surgical interventions and frequent relapses and has been reported in 22% of patients with CD.⁴ Most already had an existing diagnosis of gastrointestinal CD, which was active in one-third of individuals; however, 20% presented with disease at nongastrointestinal sites 2 months to 4 years prior to developing the gastrointestinal CD manifestations.⁵ Our patient presented with lesions on the perianal skin of 2 years' duration and a 6-month history of diarrhea. A colonoscopy demonstrated shallow ulcers involving the ileocecal portion of the gut, colon, and rectum. A biopsy from intestinal mucosal tissue showed acute and chronic inflammation with necrosis mixed with granulomatous inflammation, suggestive of CD.

Microscopically, the dominant histologic features of MCD are similar to those of bowel lesions, including an inflammatory infiltrate commonly consisting of sterile noncaseating sarcoidal granulomas, foreign body and Langhans giant cells, epithelioid histiocytes, and plasma cells surrounded by numerous mononuclear cells within the dermis with occasional extension into the subcutis (quiz image). Less common features include collagen degeneration, an infiltrate rich in eosinophils, dermal edema, and mixed lichenoid and granulomatous dermatitis.⁶

Metastatic CD often is misdiagnosed. A detailed history and physical examination may help narrow the differential; however, biopsy is necessary to establish a diagnosis of MCD. The histologic differential diagnosis of sarcoidal granulomatous inflammation of genital skin includes sarcoidosis, rheumatoid arthritis, leprosy or other mycobacterial and parasitic infection, granulomatosis with polyangiitis (GPA), and granulomatous infiltrate associated with certain exogenous material (eg, silica, zirconium, beryllium, tattoo pigment).

Sarcoidosis is a multiorgan disease that most frequently affects the lungs, skin, and lymph nodes. Its etiopathogenesis has not been clearly elucidated.⁷ Cutaneous lesions are present in 20% to 35% of patients.⁸ Given the wide variability of clinical manifestations, cutaneous sarcoidosis is another one of the great imitators. Cutaneous lesions are classified as specific and nonspecific depending on the presence of noncaseating granulomas on histologic studies and include maculopapules, plaques, nodules, lupus pernio, scar infiltration, alopecia, ulcerative lesions, and hypopigmentation. The most common nonspecific lesion of cutaneous sarcoidosis is erythema nodosum. Other manifestations include calcifications, prurigo, erythema multiforme, nail clubbing, and Sweet syndrome.⁹

Histologic findings in sarcoidosis generally are independent of the respective organ and clinical disease presentation. The epidermis usually remains unchanged, whereas the dermis shows a superficial and deep nodular granulomatous infiltrate. Granulomas consist of epithelioid cells with only few giant cells and no surrounding lymphocytes or a very sparse lymphocytic infiltrate ("naked" granuloma)(Figure 1). Foreign bodies, including silica, are known to be able to induce sarcoid granulomas, especially in patients with sarcoidosis. A sarcoidal reaction in long-standing scar tissue points to a diagnosis of sarcoidosis.¹⁰

Cutaneous tuberculosis primarily is caused by Mycobacterium tuberculosis and less frequently Mycobacterium bovis.^11,12 The manifestations of cutaneous tuberculosis depends on various factors such as the type of infection, mode of dissemination, host immunity, and whether it is a first-time infection or a recurrence. In Europe, the head and neck regions are most frequently affected.¹³ Lesions present as red-brown papules coalescing into a plaque. The tissue, especially in central parts of the lesion, is fragile (probe phenomenon). Diascopy shows the typical apple jelly-like color.

Histologically, cutaneous tuberculosis is characterized by typical tuberculoid granulomas with epithelioid cells and Langhans giant cells at the center surrounded by lymphocytes (Figure 2). Caseous necrosis as well as fibrosis may occur,^14,15 and the granulomas tend to coalesce.

Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a complex, multisystemic disease with varying manifestations. The condition has been defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tracts and necrotizing vasculitis affecting predominantly small- to medium-sized vessels.¹⁶ The etiology of GPA is thought to be linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Antineutrophil cytoplasmic antibodies play an important role in the pathogenesis of this disease. Cutaneous vasculitis secondary to GPA can present as papules, nodules, palpable purpura, ulcers resembling pyoderma gangrenosum, or necrotizing lesions leading to gangrene.¹⁷

The predominant histopathologic pattern in cutaneous lesions of GPA is leukocytoclastic vasculitis, which is present in up to 50% of biopsies.¹⁸ Characteristic findings that aid in establishing the diagnosis include histologic evidence of focal necrosis, fibrinoid degeneration, palisading granuloma surrounding neutrophils (Figure 3), and granulomatous vasculitis involving muscular vessel walls.¹⁹ Nonpalisading foci of necrosis or fibrinoid degeneration may precede the development of the typical palisading granuloma.²⁰

The typical histopathologic pattern of cutaneous amebiasis is ulceration with vascular necrosis (Figure 4).²¹ The organisms have prominent round nuclei and nucleoli and the cytoplasm may have a scalloped border.

The Diagnosis: Metastatic Crohn Disease

Crohn disease (CD), a chronic inflammatory granulomatous disease of the gastrointestinal tract, has a wide spectrum of presentations.¹ The condition may affect the vulva, perineum, or perianal skin by direct extension from the gastrointestinal tract or may appear as a separate and distinct cutaneous focus of disease referred to as metastatic Crohn disease (MCD).²

Cutaneous lesions of MCD include ulcers, fissures, sinus tracts, abscesses, and vegetative plaques, which typically extend in continuity with sites of intra-abdominal disease to the perineum, buttocks, or abdominal wall, as well as ostomy sites or incisional scars. Erythema nodosum and pyoderma gangrenosum are the most common nonspecific cutaneous manifestations. Other cutaneous lesions described in CD include polyarteritis nodosa, psoriasis, erythema multiforme, erythema elevatum diutinum, epidermolysis bullosa acquisita, acne fulminans, pyoderma faciale, neutrophilic lobular panniculitis, granulomatous vasculitis, and porokeratosis.³

Perianal skin is the most common site of cutaneous involvement in individuals with CD. It is a marker of more severe disease and is associated with multiple surgical interventions and frequent relapses and has been reported in 22% of patients with CD.⁴ Most already had an existing diagnosis of gastrointestinal CD, which was active in one-third of individuals; however, 20% presented with disease at nongastrointestinal sites 2 months to 4 years prior to developing the gastrointestinal CD manifestations.⁵ Our patient presented with lesions on the perianal skin of 2 years' duration and a 6-month history of diarrhea. A colonoscopy demonstrated shallow ulcers involving the ileocecal portion of the gut, colon, and rectum. A biopsy from intestinal mucosal tissue showed acute and chronic inflammation with necrosis mixed with granulomatous inflammation, suggestive of CD.

Microscopically, the dominant histologic features of MCD are similar to those of bowel lesions, including an inflammatory infiltrate commonly consisting of sterile noncaseating sarcoidal granulomas, foreign body and Langhans giant cells, epithelioid histiocytes, and plasma cells surrounded by numerous mononuclear cells within the dermis with occasional extension into the subcutis (quiz image). Less common features include collagen degeneration, an infiltrate rich in eosinophils, dermal edema, and mixed lichenoid and granulomatous dermatitis.⁶

Metastatic CD often is misdiagnosed. A detailed history and physical examination may help narrow the differential; however, biopsy is necessary to establish a diagnosis of MCD. The histologic differential diagnosis of sarcoidal granulomatous inflammation of genital skin includes sarcoidosis, rheumatoid arthritis, leprosy or other mycobacterial and parasitic infection, granulomatosis with polyangiitis (GPA), and granulomatous infiltrate associated with certain exogenous material (eg, silica, zirconium, beryllium, tattoo pigment).

Sarcoidosis is a multiorgan disease that most frequently affects the lungs, skin, and lymph nodes. Its etiopathogenesis has not been clearly elucidated.⁷ Cutaneous lesions are present in 20% to 35% of patients.⁸ Given the wide variability of clinical manifestations, cutaneous sarcoidosis is another one of the great imitators. Cutaneous lesions are classified as specific and nonspecific depending on the presence of noncaseating granulomas on histologic studies and include maculopapules, plaques, nodules, lupus pernio, scar infiltration, alopecia, ulcerative lesions, and hypopigmentation. The most common nonspecific lesion of cutaneous sarcoidosis is erythema nodosum. Other manifestations include calcifications, prurigo, erythema multiforme, nail clubbing, and Sweet syndrome.⁹

Histologic findings in sarcoidosis generally are independent of the respective organ and clinical disease presentation. The epidermis usually remains unchanged, whereas the dermis shows a superficial and deep nodular granulomatous infiltrate. Granulomas consist of epithelioid cells with only few giant cells and no surrounding lymphocytes or a very sparse lymphocytic infiltrate ("naked" granuloma)(Figure 1). Foreign bodies, including silica, are known to be able to induce sarcoid granulomas, especially in patients with sarcoidosis. A sarcoidal reaction in long-standing scar tissue points to a diagnosis of sarcoidosis.¹⁰

Cutaneous tuberculosis primarily is caused by Mycobacterium tuberculosis and less frequently Mycobacterium bovis.^11,12 The manifestations of cutaneous tuberculosis depends on various factors such as the type of infection, mode of dissemination, host immunity, and whether it is a first-time infection or a recurrence. In Europe, the head and neck regions are most frequently affected.¹³ Lesions present as red-brown papules coalescing into a plaque. The tissue, especially in central parts of the lesion, is fragile (probe phenomenon). Diascopy shows the typical apple jelly-like color.

Histologically, cutaneous tuberculosis is characterized by typical tuberculoid granulomas with epithelioid cells and Langhans giant cells at the center surrounded by lymphocytes (Figure 2). Caseous necrosis as well as fibrosis may occur,^14,15 and the granulomas tend to coalesce.

Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a complex, multisystemic disease with varying manifestations. The condition has been defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tracts and necrotizing vasculitis affecting predominantly small- to medium-sized vessels.¹⁶ The etiology of GPA is thought to be linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Antineutrophil cytoplasmic antibodies play an important role in the pathogenesis of this disease. Cutaneous vasculitis secondary to GPA can present as papules, nodules, palpable purpura, ulcers resembling pyoderma gangrenosum, or necrotizing lesions leading to gangrene.¹⁷

The predominant histopathologic pattern in cutaneous lesions of GPA is leukocytoclastic vasculitis, which is present in up to 50% of biopsies.¹⁸ Characteristic findings that aid in establishing the diagnosis include histologic evidence of focal necrosis, fibrinoid degeneration, palisading granuloma surrounding neutrophils (Figure 3), and granulomatous vasculitis involving muscular vessel walls.¹⁹ Nonpalisading foci of necrosis or fibrinoid degeneration may precede the development of the typical palisading granuloma.²⁰

The typical histopathologic pattern of cutaneous amebiasis is ulceration with vascular necrosis (Figure 4).²¹ The organisms have prominent round nuclei and nucleoli and the cytoplasm may have a scalloped border.

The Diagnosis: Metastatic Crohn Disease

Crohn disease (CD), a chronic inflammatory granulomatous disease of the gastrointestinal tract, has a wide spectrum of presentations.¹ The condition may affect the vulva, perineum, or perianal skin by direct extension from the gastrointestinal tract or may appear as a separate and distinct cutaneous focus of disease referred to as metastatic Crohn disease (MCD).²

Cutaneous lesions of MCD include ulcers, fissures, sinus tracts, abscesses, and vegetative plaques, which typically extend in continuity with sites of intra-abdominal disease to the perineum, buttocks, or abdominal wall, as well as ostomy sites or incisional scars. Erythema nodosum and pyoderma gangrenosum are the most common nonspecific cutaneous manifestations. Other cutaneous lesions described in CD include polyarteritis nodosa, psoriasis, erythema multiforme, erythema elevatum diutinum, epidermolysis bullosa acquisita, acne fulminans, pyoderma faciale, neutrophilic lobular panniculitis, granulomatous vasculitis, and porokeratosis.³

Perianal skin is the most common site of cutaneous involvement in individuals with CD. It is a marker of more severe disease and is associated with multiple surgical interventions and frequent relapses and has been reported in 22% of patients with CD.⁴ Most already had an existing diagnosis of gastrointestinal CD, which was active in one-third of individuals; however, 20% presented with disease at nongastrointestinal sites 2 months to 4 years prior to developing the gastrointestinal CD manifestations.⁵ Our patient presented with lesions on the perianal skin of 2 years' duration and a 6-month history of diarrhea. A colonoscopy demonstrated shallow ulcers involving the ileocecal portion of the gut, colon, and rectum. A biopsy from intestinal mucosal tissue showed acute and chronic inflammation with necrosis mixed with granulomatous inflammation, suggestive of CD.

Microscopically, the dominant histologic features of MCD are similar to those of bowel lesions, including an inflammatory infiltrate commonly consisting of sterile noncaseating sarcoidal granulomas, foreign body and Langhans giant cells, epithelioid histiocytes, and plasma cells surrounded by numerous mononuclear cells within the dermis with occasional extension into the subcutis (quiz image). Less common features include collagen degeneration, an infiltrate rich in eosinophils, dermal edema, and mixed lichenoid and granulomatous dermatitis.⁶

Metastatic CD often is misdiagnosed. A detailed history and physical examination may help narrow the differential; however, biopsy is necessary to establish a diagnosis of MCD. The histologic differential diagnosis of sarcoidal granulomatous inflammation of genital skin includes sarcoidosis, rheumatoid arthritis, leprosy or other mycobacterial and parasitic infection, granulomatosis with polyangiitis (GPA), and granulomatous infiltrate associated with certain exogenous material (eg, silica, zirconium, beryllium, tattoo pigment).

Sarcoidosis is a multiorgan disease that most frequently affects the lungs, skin, and lymph nodes. Its etiopathogenesis has not been clearly elucidated.⁷ Cutaneous lesions are present in 20% to 35% of patients.⁸ Given the wide variability of clinical manifestations, cutaneous sarcoidosis is another one of the great imitators. Cutaneous lesions are classified as specific and nonspecific depending on the presence of noncaseating granulomas on histologic studies and include maculopapules, plaques, nodules, lupus pernio, scar infiltration, alopecia, ulcerative lesions, and hypopigmentation. The most common nonspecific lesion of cutaneous sarcoidosis is erythema nodosum. Other manifestations include calcifications, prurigo, erythema multiforme, nail clubbing, and Sweet syndrome.⁹

Histologic findings in sarcoidosis generally are independent of the respective organ and clinical disease presentation. The epidermis usually remains unchanged, whereas the dermis shows a superficial and deep nodular granulomatous infiltrate. Granulomas consist of epithelioid cells with only few giant cells and no surrounding lymphocytes or a very sparse lymphocytic infiltrate ("naked" granuloma)(Figure 1). Foreign bodies, including silica, are known to be able to induce sarcoid granulomas, especially in patients with sarcoidosis. A sarcoidal reaction in long-standing scar tissue points to a diagnosis of sarcoidosis.¹⁰

Cutaneous tuberculosis primarily is caused by Mycobacterium tuberculosis and less frequently Mycobacterium bovis.^11,12 The manifestations of cutaneous tuberculosis depends on various factors such as the type of infection, mode of dissemination, host immunity, and whether it is a first-time infection or a recurrence. In Europe, the head and neck regions are most frequently affected.¹³ Lesions present as red-brown papules coalescing into a plaque. The tissue, especially in central parts of the lesion, is fragile (probe phenomenon). Diascopy shows the typical apple jelly-like color.

Histologically, cutaneous tuberculosis is characterized by typical tuberculoid granulomas with epithelioid cells and Langhans giant cells at the center surrounded by lymphocytes (Figure 2). Caseous necrosis as well as fibrosis may occur,^14,15 and the granulomas tend to coalesce.

Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a complex, multisystemic disease with varying manifestations. The condition has been defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tracts and necrotizing vasculitis affecting predominantly small- to medium-sized vessels.¹⁶ The etiology of GPA is thought to be linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Antineutrophil cytoplasmic antibodies play an important role in the pathogenesis of this disease. Cutaneous vasculitis secondary to GPA can present as papules, nodules, palpable purpura, ulcers resembling pyoderma gangrenosum, or necrotizing lesions leading to gangrene.¹⁷

The predominant histopathologic pattern in cutaneous lesions of GPA is leukocytoclastic vasculitis, which is present in up to 50% of biopsies.¹⁸ Characteristic findings that aid in establishing the diagnosis include histologic evidence of focal necrosis, fibrinoid degeneration, palisading granuloma surrounding neutrophils (Figure 3), and granulomatous vasculitis involving muscular vessel walls.¹⁹ Nonpalisading foci of necrosis or fibrinoid degeneration may precede the development of the typical palisading granuloma.²⁰

The typical histopathologic pattern of cutaneous amebiasis is ulceration with vascular necrosis (Figure 4).²¹ The organisms have prominent round nuclei and nucleoli and the cytoplasm may have a scalloped border.

Ticks are ectoparasitic hemophages that feed on mammals, reptiles, and birds. The Ixodidae family comprises the hard ticks. A hard dorsal plate, scutum, and capitulum that extends outward from the body are features that distinguish the hard tick. ¹Ixodes is the largest genus of hard ticks, with more than 250 species localized in temperate climates.² It has an inornate scutum and lacks festoons (Figure 1).¹ The Ixodes ricinus species complex accounts for most species relevant to the spread of human disease (Figure 2), with Ixodes scapularis in the northeastern, north midwestern, and southern United States; Ixodes pacificus in western United States; I ricinus in Europe and North Africa; and Ixodes persulcatus in Russia and Asia. Ixodes holocyclus is endemic to Australia.^3,4

Life Cycle

Ixodes species progress through 4 life stages—egg, larvae, nymph, and adult—during their 3-host life cycle. Lifespan is 2 to 6 years, varying with environmental factors. A blood meal is required between each stage. Female ticks have a small scutum, allowing the abdomen to engorge during meals (Figure 3).

Larvae hatch in the early summer and remain dormant until the spring, emerging as a nymph. Following a blood meal, the nymph molts and reemerges as an adult in autumn. During autumn and winter, the female lays as many as 2000 eggs that emerge in early summer.⁵ Nymphs are small and easily undetected for the duration required for pathogen transmission, making nymphs the stage most likely to transmit disease.⁶

The majority of tick-borne diseases present from May to July, corresponding to nymph activity. Fewer cases present in the autumn and early spring because the adult female feeds during cooler months.⁷

Larvae have 6 legs and are about the size of a sesame seed when engorged. Nymphs are slightly larger with 8 legs. Adults are largest and have 8 legs. Following a blood meal, the tick becomes engorged, increasing in size and lightening in color (Figure 3).¹

Ticks are found in low-lying shrubs and tall grass as well as on the forest floor. They search for a host by detecting CO₂, warmth, the smell of sweat, and the color white, prompting attachment.⁸ Habitats hospitable to Ixodes have expanded in the wake of climate, environmental, and socioeconomic changes, potentially contributing to the increasing incidence and expansion of zoonoses associated with this vector.^9,10

Local Reactions

A tick bite may induce local hypersensitivity, leading to a red papule or plaque at the bite site, followed by swelling, warmth, and erythema. A cellular immune reaction induces induration and pruritus. Hard ticks are less likely than soft ticks to cause a serious local reaction.^11,12

A variety of clinical and histologic features are observed following an arthropod bite. Histologically, acute tick bites show a neutrophilic infiltrate with fibrin deposition. Chronic reactions demonstrate a wedge-shaped, mixed infiltrate with prominent endothelial swelling. Eosinophilic cellulitis, or Wells syndrome, reveals tissue eosinophilia and flame figures.¹³ Tick mouthparts may be identified in the tissue. B-cell hyperplasia is seen in Borrelia lymphocytoma and is more common in Europe, presenting as erythematous to plum–colored nodules on the ear and areola.¹⁴

Lyme Disease

Disease manifestations vary by location. Lyme disease is associated with Borrelia burgdorferi and the recently identified Borrelia mayonii in the United States¹⁵; in Europe and Asia, acrodermatitis chronica atrophicans is associated with Borrelia afzelii and neuroborreliosis, with Borrelia garinii. Lyme disease is the most common tick-borne illness in the United States.¹⁶ The I ricinus species complex is the most common vector harboring Borrelia species.¹⁷ At least 36 hours of tick adherence is required for disease transmission.¹⁸ The incubation period is 3 to 20 days (median, 12 days).¹⁹

Clinical Findings
Erythema migrans is the most characteristic sign, seen in 80% of cases of Lyme disease. The typical rash is a centrifugally spreading, erythematous, annular patch with central clearing at the site of the tick bite.²⁰ Atypical rashes include vesicular, indurated, ulcerated, and follicular variants.²¹ Histopathology commonly shows a superficial and deep perivascular lymphocytic infiltrate with plasma cells, histiocytes, and eosinophils.²² Typically, the rash resolves in 3 to 5 weeks.¹⁸

Early disseminated Lyme disease can present with any of the following findings: multiple erythema migrans; neurologic involvement, including cranial nerve palsy and meningitis; and Lyme carditis, which may result in atrioventricular block.^23,24 Late findings include arthritis, encephalopathy, and polyneuropathy. A late cutaneous manifestation, acrodermatitis chronica atrophicans, is rare in the United States but occurs in as many as 10% of Lyme disease cases in Europe. An initial inflammatory response manifests as blue-red erythema and edema of the extensor surfaces of the extremities, commonly on the dorsal hands, feet, elbows, and knees. Firm fibrotic nodules may develop later over the olecranon and patella.^23,24

The term chronic Lyme disease has been used to describe the persistence of symptoms after treatment; however, large clinical trials have not detected a difference in symptom frequency between patients with a history of Lyme disease and matched controls.^25,26 Many patients with chronic Lyme disease may instead have posttreatment Lyme disease syndrome, described as nonspecific symptoms including fatigue, arthralgia, and decreased mental acuity following treatment of confirmed Lyme disease. Symptoms generally improve within 1 year.²⁷

Laboratory Testing
The gold standard for laboratory diagnosis of Lyme disease is 2-tiered serologic testing. First, an enzyme immunoassay or immunofluorescence assay is used to screen for antibodies. A Western blot follows if the result of the screen is positive or equivocal. Western blot testing for IgM and IgG is used when illness duration is less than 4 weeks; after 4 weeks, a Western blot for IgG alone is sufficient.^27,28 The 2-tiered test has 99% specificity. Sensitivity increases with duration of disease (29%–40% with erythema migrans; 42%–87% in early disseminated disease; 97%–100% in late disease).^29,30 A false-positive result can occur in the presence of infectious mononucleosis, an autoimmune disorder, and syphilis. If serologic testing is negative and suspicion remains high, testing should be repeated in 2 to 4 weeks.³¹ When a patient in a Lyme-endemic area presents with typical erythema migrans, serologic testing is unnecessary prior to treatment.³²

Management
Treatment of Lyme disease centers on antibiotic therapy (Table). First-line treatment of early disseminated disease is doxycycline for 14 days (range, 10–21 days).²⁷ In pregnant women, children younger than 8 years, and tetracycline-allergic patients, amoxicillin or cefuroxime axetil for 14 days (range, 14–21 days) may be used.³³ For erythema migrans without complications, doxycycline for 10 days is effective. Complications that require hospitalization are treated with intravenous ceftriaxone.²⁷ Re-treatment in patients with posttreatment Lyme disease syndrome is not recommended.³⁴ Prophylaxis with a single dose of doxycycline 200 mg may be indicated when all of the following conditions are met: (1) the patient is in an area where more than 20% of Ixodes ticks are infected with B burgdorferi, (2) the attached tick is I scapularis, (3) the tick has been attached for more than 36 hours, and (4) treatment is begun within 72 hours of tick removal.²⁷

Ticks are ectoparasitic hemophages that feed on mammals, reptiles, and birds. The Ixodidae family comprises the hard ticks. A hard dorsal plate, scutum, and capitulum that extends outward from the body are features that distinguish the hard tick. ¹Ixodes is the largest genus of hard ticks, with more than 250 species localized in temperate climates.² It has an inornate scutum and lacks festoons (Figure 1).¹ The Ixodes ricinus species complex accounts for most species relevant to the spread of human disease (Figure 2), with Ixodes scapularis in the northeastern, north midwestern, and southern United States; Ixodes pacificus in western United States; I ricinus in Europe and North Africa; and Ixodes persulcatus in Russia and Asia. Ixodes holocyclus is endemic to Australia.^3,4

Life Cycle

Ixodes species progress through 4 life stages—egg, larvae, nymph, and adult—during their 3-host life cycle. Lifespan is 2 to 6 years, varying with environmental factors. A blood meal is required between each stage. Female ticks have a small scutum, allowing the abdomen to engorge during meals (Figure 3).

Larvae hatch in the early summer and remain dormant until the spring, emerging as a nymph. Following a blood meal, the nymph molts and reemerges as an adult in autumn. During autumn and winter, the female lays as many as 2000 eggs that emerge in early summer.⁵ Nymphs are small and easily undetected for the duration required for pathogen transmission, making nymphs the stage most likely to transmit disease.⁶

The majority of tick-borne diseases present from May to July, corresponding to nymph activity. Fewer cases present in the autumn and early spring because the adult female feeds during cooler months.⁷

Larvae have 6 legs and are about the size of a sesame seed when engorged. Nymphs are slightly larger with 8 legs. Adults are largest and have 8 legs. Following a blood meal, the tick becomes engorged, increasing in size and lightening in color (Figure 3).¹

Ticks are found in low-lying shrubs and tall grass as well as on the forest floor. They search for a host by detecting CO₂, warmth, the smell of sweat, and the color white, prompting attachment.⁸ Habitats hospitable to Ixodes have expanded in the wake of climate, environmental, and socioeconomic changes, potentially contributing to the increasing incidence and expansion of zoonoses associated with this vector.^9,10

Local Reactions

A tick bite may induce local hypersensitivity, leading to a red papule or plaque at the bite site, followed by swelling, warmth, and erythema. A cellular immune reaction induces induration and pruritus. Hard ticks are less likely than soft ticks to cause a serious local reaction.^11,12

A variety of clinical and histologic features are observed following an arthropod bite. Histologically, acute tick bites show a neutrophilic infiltrate with fibrin deposition. Chronic reactions demonstrate a wedge-shaped, mixed infiltrate with prominent endothelial swelling. Eosinophilic cellulitis, or Wells syndrome, reveals tissue eosinophilia and flame figures.¹³ Tick mouthparts may be identified in the tissue. B-cell hyperplasia is seen in Borrelia lymphocytoma and is more common in Europe, presenting as erythematous to plum–colored nodules on the ear and areola.¹⁴

Lyme Disease

Disease manifestations vary by location. Lyme disease is associated with Borrelia burgdorferi and the recently identified Borrelia mayonii in the United States¹⁵; in Europe and Asia, acrodermatitis chronica atrophicans is associated with Borrelia afzelii and neuroborreliosis, with Borrelia garinii. Lyme disease is the most common tick-borne illness in the United States.¹⁶ The I ricinus species complex is the most common vector harboring Borrelia species.¹⁷ At least 36 hours of tick adherence is required for disease transmission.¹⁸ The incubation period is 3 to 20 days (median, 12 days).¹⁹

Clinical Findings
Erythema migrans is the most characteristic sign, seen in 80% of cases of Lyme disease. The typical rash is a centrifugally spreading, erythematous, annular patch with central clearing at the site of the tick bite.²⁰ Atypical rashes include vesicular, indurated, ulcerated, and follicular variants.²¹ Histopathology commonly shows a superficial and deep perivascular lymphocytic infiltrate with plasma cells, histiocytes, and eosinophils.²² Typically, the rash resolves in 3 to 5 weeks.¹⁸

Early disseminated Lyme disease can present with any of the following findings: multiple erythema migrans; neurologic involvement, including cranial nerve palsy and meningitis; and Lyme carditis, which may result in atrioventricular block.^23,24 Late findings include arthritis, encephalopathy, and polyneuropathy. A late cutaneous manifestation, acrodermatitis chronica atrophicans, is rare in the United States but occurs in as many as 10% of Lyme disease cases in Europe. An initial inflammatory response manifests as blue-red erythema and edema of the extensor surfaces of the extremities, commonly on the dorsal hands, feet, elbows, and knees. Firm fibrotic nodules may develop later over the olecranon and patella.^23,24

The term chronic Lyme disease has been used to describe the persistence of symptoms after treatment; however, large clinical trials have not detected a difference in symptom frequency between patients with a history of Lyme disease and matched controls.^25,26 Many patients with chronic Lyme disease may instead have posttreatment Lyme disease syndrome, described as nonspecific symptoms including fatigue, arthralgia, and decreased mental acuity following treatment of confirmed Lyme disease. Symptoms generally improve within 1 year.²⁷

Laboratory Testing
The gold standard for laboratory diagnosis of Lyme disease is 2-tiered serologic testing. First, an enzyme immunoassay or immunofluorescence assay is used to screen for antibodies. A Western blot follows if the result of the screen is positive or equivocal. Western blot testing for IgM and IgG is used when illness duration is less than 4 weeks; after 4 weeks, a Western blot for IgG alone is sufficient.^27,28 The 2-tiered test has 99% specificity. Sensitivity increases with duration of disease (29%–40% with erythema migrans; 42%–87% in early disseminated disease; 97%–100% in late disease).^29,30 A false-positive result can occur in the presence of infectious mononucleosis, an autoimmune disorder, and syphilis. If serologic testing is negative and suspicion remains high, testing should be repeated in 2 to 4 weeks.³¹ When a patient in a Lyme-endemic area presents with typical erythema migrans, serologic testing is unnecessary prior to treatment.³²

Management
Treatment of Lyme disease centers on antibiotic therapy (Table). First-line treatment of early disseminated disease is doxycycline for 14 days (range, 10–21 days).²⁷ In pregnant women, children younger than 8 years, and tetracycline-allergic patients, amoxicillin or cefuroxime axetil for 14 days (range, 14–21 days) may be used.³³ For erythema migrans without complications, doxycycline for 10 days is effective. Complications that require hospitalization are treated with intravenous ceftriaxone.²⁷ Re-treatment in patients with posttreatment Lyme disease syndrome is not recommended.³⁴ Prophylaxis with a single dose of doxycycline 200 mg may be indicated when all of the following conditions are met: (1) the patient is in an area where more than 20% of Ixodes ticks are infected with B burgdorferi, (2) the attached tick is I scapularis, (3) the tick has been attached for more than 36 hours, and (4) treatment is begun within 72 hours of tick removal.²⁷

Ticks are ectoparasitic hemophages that feed on mammals, reptiles, and birds. The Ixodidae family comprises the hard ticks. A hard dorsal plate, scutum, and capitulum that extends outward from the body are features that distinguish the hard tick. ¹Ixodes is the largest genus of hard ticks, with more than 250 species localized in temperate climates.² It has an inornate scutum and lacks festoons (Figure 1).¹ The Ixodes ricinus species complex accounts for most species relevant to the spread of human disease (Figure 2), with Ixodes scapularis in the northeastern, north midwestern, and southern United States; Ixodes pacificus in western United States; I ricinus in Europe and North Africa; and Ixodes persulcatus in Russia and Asia. Ixodes holocyclus is endemic to Australia.^3,4

Life Cycle

Ixodes species progress through 4 life stages—egg, larvae, nymph, and adult—during their 3-host life cycle. Lifespan is 2 to 6 years, varying with environmental factors. A blood meal is required between each stage. Female ticks have a small scutum, allowing the abdomen to engorge during meals (Figure 3).

Larvae hatch in the early summer and remain dormant until the spring, emerging as a nymph. Following a blood meal, the nymph molts and reemerges as an adult in autumn. During autumn and winter, the female lays as many as 2000 eggs that emerge in early summer.⁵ Nymphs are small and easily undetected for the duration required for pathogen transmission, making nymphs the stage most likely to transmit disease.⁶

The majority of tick-borne diseases present from May to July, corresponding to nymph activity. Fewer cases present in the autumn and early spring because the adult female feeds during cooler months.⁷

Larvae have 6 legs and are about the size of a sesame seed when engorged. Nymphs are slightly larger with 8 legs. Adults are largest and have 8 legs. Following a blood meal, the tick becomes engorged, increasing in size and lightening in color (Figure 3).¹

Ticks are found in low-lying shrubs and tall grass as well as on the forest floor. They search for a host by detecting CO₂, warmth, the smell of sweat, and the color white, prompting attachment.⁸ Habitats hospitable to Ixodes have expanded in the wake of climate, environmental, and socioeconomic changes, potentially contributing to the increasing incidence and expansion of zoonoses associated with this vector.^9,10

Local Reactions

A tick bite may induce local hypersensitivity, leading to a red papule or plaque at the bite site, followed by swelling, warmth, and erythema. A cellular immune reaction induces induration and pruritus. Hard ticks are less likely than soft ticks to cause a serious local reaction.^11,12

A variety of clinical and histologic features are observed following an arthropod bite. Histologically, acute tick bites show a neutrophilic infiltrate with fibrin deposition. Chronic reactions demonstrate a wedge-shaped, mixed infiltrate with prominent endothelial swelling. Eosinophilic cellulitis, or Wells syndrome, reveals tissue eosinophilia and flame figures.¹³ Tick mouthparts may be identified in the tissue. B-cell hyperplasia is seen in Borrelia lymphocytoma and is more common in Europe, presenting as erythematous to plum–colored nodules on the ear and areola.¹⁴

Lyme Disease

Disease manifestations vary by location. Lyme disease is associated with Borrelia burgdorferi and the recently identified Borrelia mayonii in the United States¹⁵; in Europe and Asia, acrodermatitis chronica atrophicans is associated with Borrelia afzelii and neuroborreliosis, with Borrelia garinii. Lyme disease is the most common tick-borne illness in the United States.¹⁶ The I ricinus species complex is the most common vector harboring Borrelia species.¹⁷ At least 36 hours of tick adherence is required for disease transmission.¹⁸ The incubation period is 3 to 20 days (median, 12 days).¹⁹

Clinical Findings
Erythema migrans is the most characteristic sign, seen in 80% of cases of Lyme disease. The typical rash is a centrifugally spreading, erythematous, annular patch with central clearing at the site of the tick bite.²⁰ Atypical rashes include vesicular, indurated, ulcerated, and follicular variants.²¹ Histopathology commonly shows a superficial and deep perivascular lymphocytic infiltrate with plasma cells, histiocytes, and eosinophils.²² Typically, the rash resolves in 3 to 5 weeks.¹⁸

Early disseminated Lyme disease can present with any of the following findings: multiple erythema migrans; neurologic involvement, including cranial nerve palsy and meningitis; and Lyme carditis, which may result in atrioventricular block.^23,24 Late findings include arthritis, encephalopathy, and polyneuropathy. A late cutaneous manifestation, acrodermatitis chronica atrophicans, is rare in the United States but occurs in as many as 10% of Lyme disease cases in Europe. An initial inflammatory response manifests as blue-red erythema and edema of the extensor surfaces of the extremities, commonly on the dorsal hands, feet, elbows, and knees. Firm fibrotic nodules may develop later over the olecranon and patella.^23,24

The term chronic Lyme disease has been used to describe the persistence of symptoms after treatment; however, large clinical trials have not detected a difference in symptom frequency between patients with a history of Lyme disease and matched controls.^25,26 Many patients with chronic Lyme disease may instead have posttreatment Lyme disease syndrome, described as nonspecific symptoms including fatigue, arthralgia, and decreased mental acuity following treatment of confirmed Lyme disease. Symptoms generally improve within 1 year.²⁷

Laboratory Testing
The gold standard for laboratory diagnosis of Lyme disease is 2-tiered serologic testing. First, an enzyme immunoassay or immunofluorescence assay is used to screen for antibodies. A Western blot follows if the result of the screen is positive or equivocal. Western blot testing for IgM and IgG is used when illness duration is less than 4 weeks; after 4 weeks, a Western blot for IgG alone is sufficient.^27,28 The 2-tiered test has 99% specificity. Sensitivity increases with duration of disease (29%–40% with erythema migrans; 42%–87% in early disseminated disease; 97%–100% in late disease).^29,30 A false-positive result can occur in the presence of infectious mononucleosis, an autoimmune disorder, and syphilis. If serologic testing is negative and suspicion remains high, testing should be repeated in 2 to 4 weeks.³¹ When a patient in a Lyme-endemic area presents with typical erythema migrans, serologic testing is unnecessary prior to treatment.³²

Management
Treatment of Lyme disease centers on antibiotic therapy (Table). First-line treatment of early disseminated disease is doxycycline for 14 days (range, 10–21 days).²⁷ In pregnant women, children younger than 8 years, and tetracycline-allergic patients, amoxicillin or cefuroxime axetil for 14 days (range, 14–21 days) may be used.³³ For erythema migrans without complications, doxycycline for 10 days is effective. Complications that require hospitalization are treated with intravenous ceftriaxone.²⁷ Re-treatment in patients with posttreatment Lyme disease syndrome is not recommended.³⁴ Prophylaxis with a single dose of doxycycline 200 mg may be indicated when all of the following conditions are met: (1) the patient is in an area where more than 20% of Ixodes ticks are infected with B burgdorferi, (2) the attached tick is I scapularis, (3) the tick has been attached for more than 36 hours, and (4) treatment is begun within 72 hours of tick removal.²⁷

Identification

Phlebotomine sand flies are the only member of the Psychodidae family that are capable of taking blood.¹ The mouthparts of the sand fly are toothed distally, and the maxilla and mandible are utilized in a sawtooth fashion to take a bloodmeal.² The flies are very small (ie, only 1.5–3.5 mm in length), which makes their identification difficult.¹ Sand flies can be distinguished by the appearance of their wings, which often are covered in hair and extend across the back in a V shape.³ The adult sand fly is hairy with a 6- to 8-segmented abdomen, and the color can range from gray to yellow to brown.² Phlebotomine sand flies can be further identified by their long antennae, dark eyes, and small heads (Figure).²

As is the case with all Diptera, the sand fly goes through 4 complete life stages from egg to larva to pupa to adult.³ Female sand flies will lay their eggs following a blood meal and have been found to take multiple blood meals in a single cycle.² On average, the eggs will hatch in 6 to 17 days but are temperature dependent.³ The subsequent larvae and pupa stages last 20 to 30 days and 6 to 13 days, respectively.¹ The larvae are white in color with short antennae and dark heads.⁴ Sand flies prefer to lay their eggs in areas where adequate resting places are available and where their larvae will thrive.^4,5 The larvae require warm moist environments to succeed and thus are commonly found in animal burrows.³ Once fully developed, the adult sand fly can live up to 6 weeks.²

Sand Fly Vector

Although it is more common in rural forested areas, the sand fly also can be found in urban areas, including heavily populated cities in Brazil.⁶ Sand flies are most active during hot humid seasons but depending on the local climate may remain active year-round.^1,7 For example, in tropical regions of Asia, the number of sand flies increases substantially during the monsoon season compared to the dry season.² Phlebotomine sand flies are most active at dusk and during the night⁵ but may become agitated during the daytime if their environment is disturbed.¹

Host selection usually is broad and includes a wide variety of vertebrates.² In the United States, host species are thought to include small rodents, foxes, armadillos, and opossums.⁸ One study found that visceral leishmaniasis in foxhounds is able to develop fully in sand flies, thus posing an emerging risk to the American population.⁹

Distribution

The Phlebotominae family contains approximately 700 different species of sand flies but only 21 are known vectors of disease.¹⁰ The great majority belong to 1 of 3 genuses: Phlebotomus, Sergentomyia, and Lutzomyia.¹¹ The vectors are commonly divided into Old World species, dominated by the Phlebotomus genus, and New World species, which exclusively refers to the Lutzomyia genus.³ The Old World and New World distinction helps to classify the various vectors and subsequently the diseases they transmit. Old World refers to those vectors found in Southwest and Central Asia, the Indian subcontinent, the Middle East, and East Africa, as well as Southern Europe.⁶ New World refers to vectors found predominantly in Brazil and other parts of Latin America but also Mexico and the United States.⁶ Sand flies are found to be endemic in 90 countries and on each continent, except Australia.⁵ Although the vector can be found in a variety of environments, sand flies prefer moist environments that typify tropical and subtropical climates, thus it is not surprising that the highest diversity of Phlebotominae in the world can be found in the Amazon basin.¹²

Disease Transmission

Leishmania refers to a genus of intracellular protozoa found in both the Old World and the New World that causes a variety of clinical syndromes.⁵ Approximately 20 Leishmania species are known to cause human disease that includes localized cutaneous, diffuse cutaneous, mucosal cutaneous, and visceral infections.¹³ Cases of all forms of leishmaniasis worldwide have increased rapidly over the last few decades from multiple factors including war in endemic regions, increased numbers of immunodeficient individuals, and increased travel to endemic areas.¹⁴ In the United States, leishmaniasis is caused by both imported and autochthonous forms of transmission and often mirrors recent travel and immigration patterns.^14,15

Sand flies also serve as vectors for sandfly fever, also known as Pappataci fever. Although sandfly fever commonly causes a mild febrile illness, it has been shown to be a considerable cause of aseptic meningitis.¹⁶ A number of novel Phleboviruses have been isolated as causes of sandfly fever, including Massilia virus, Granada virus, and Punique virus.^16-18 A form of sandfly fever caused by the Toscana virus has a predilection for the nervous system and can cause encephalitis.¹⁹ Sandfly fever can be found in both the Old World and New World and thus poses a global risk.² Additionally, Phlebotominae also have been found to transmit the Changuinola virus, a type of bunyavirus that is known to cause febrile illness in Panama.²⁰ Vesicular stomatitis, also carried by sand flies, is a known cause of febrile disease in North and South America, including the United States.² In 2013, the Niakha virus, a novel type of Rhabdoviridae, was isolated from Phlebotominae in Senegal.²¹ The sand fly is noted to transmit another type of Rhabdoviridae in India and Africa, known as the Chandipura virus.²² Although originally thought to cause mild febrile disease, it was the primary cause of multiple outbreaks of fatal encephalitis in India in 2003^23,24 and again in 2012.²²

Sand flies also are known to serve as vectors for the bacterium Bartonella bacilliformis, which is responsible for bartonellosis.²⁵ The disease is divided into 2 forms, which can occur separately or in succession, and is endemic to the Andes region of Peru, Ecuador, and Colombia. The first form is Oroya fever, an acute febrile hemolytic anemia that is fatal in 40% to 88% of cases without intervention.²⁵ This bacterium also causes verruga peruana, an endemic form of bacillary angiomatosis that can persist for years.² Two reports suggested that bartonellosis also can be caused by Bartonella rochalimae and Candidatus Bartonella ancashi.^26,27

Vector Control

Prevention is key to reducing the risk of the various diseases caused by the Phlebotominae vector. Vector control often falls into a few categories, including residual sprays, barriers, and topical repellants.³ It appears that residual sprays applied to houses and animal shelters are the most utilized and effective form of control, with the pyrethroid insecticides having the highest sand fly–specific toxicity.^3,28 Insecticides also have been applied to animal burrows where sand flies are known to reproduce; one study in Kenya showed a 90% reduction in the sand fly population following treatment of termite and animal burrows with a pyrethroid spray.²⁹ Studies by Perich et al^30,31 in 1995 and 2003 showed that using barrier sprays can be an effective protective measure. The investigators applied a 100-m barrier using a pyrethroid spray on vegetation and reported a notable decrease in sand flies for over an 80-day period.^30,31

For personal protection, barrier methods are important adjunct methods of preventing individual exposures. Due to the small size of sand flies, ordinary bed nets are not effective and those treated with insecticides should be used,¹⁵ which may ultimately prove to be the most sustainable way to prevent sand fly–borne disease.³² Protective attire also should be worn, as sand flies are not able to penetrate clothing.² N,N-diethyl-meta-toluamide (DEET)–based repellants should be applied to exposed skin.¹⁵ Finally, it is important to avoid exposure from dusk to dawn when sand flies are most active.¹⁵

Rise in Autochthonous Cutaneous Leishmaniasis in the United States

With the increased amount of worldwide tourism, especially to endemic areas, providers will continue to see rising numbers of leishmaniasis in the United States. It is difficult to determine the incidence of the disease in the United States, but one study has shown that leishmaniasis accounts for 143 of every 1000 dermatologic diseases acquired by South American tourists.^33,34 In addition, the number of autochthonous cases reported in the United States continues to grow. Although only 29 cases were reported between 1903 and 1996, 13 cases were reported between 2000 and 2008.³⁵ Another report in 2013 described an additional 3 cases in the states of Texas and Oklahoma.³⁵ The cases have continued to move in a northeasterly pattern, suggesting a possible shift in the location of sand fly populations. Each of these cases in which a specific species of Leishmania was identified showed transmission of Leishmania mexicana.³⁵ Most cases of cutaneous disease have occurred in Texas and Oklahoma. The first known case outside of this region was reported in 2014 in North Dakota.⁸ Leishmania donovani, brought into the United States with European foxhounds, also is spreading.⁸ One species of sand fly, Leishmania shannoni, has now been discovered in 16 states,^36-42 where it serves as a potential vector for L mexicana.^43,44

Identification

Phlebotomine sand flies are the only member of the Psychodidae family that are capable of taking blood.¹ The mouthparts of the sand fly are toothed distally, and the maxilla and mandible are utilized in a sawtooth fashion to take a bloodmeal.² The flies are very small (ie, only 1.5–3.5 mm in length), which makes their identification difficult.¹ Sand flies can be distinguished by the appearance of their wings, which often are covered in hair and extend across the back in a V shape.³ The adult sand fly is hairy with a 6- to 8-segmented abdomen, and the color can range from gray to yellow to brown.² Phlebotomine sand flies can be further identified by their long antennae, dark eyes, and small heads (Figure).²

As is the case with all Diptera, the sand fly goes through 4 complete life stages from egg to larva to pupa to adult.³ Female sand flies will lay their eggs following a blood meal and have been found to take multiple blood meals in a single cycle.² On average, the eggs will hatch in 6 to 17 days but are temperature dependent.³ The subsequent larvae and pupa stages last 20 to 30 days and 6 to 13 days, respectively.¹ The larvae are white in color with short antennae and dark heads.⁴ Sand flies prefer to lay their eggs in areas where adequate resting places are available and where their larvae will thrive.^4,5 The larvae require warm moist environments to succeed and thus are commonly found in animal burrows.³ Once fully developed, the adult sand fly can live up to 6 weeks.²

Sand Fly Vector

Although it is more common in rural forested areas, the sand fly also can be found in urban areas, including heavily populated cities in Brazil.⁶ Sand flies are most active during hot humid seasons but depending on the local climate may remain active year-round.^1,7 For example, in tropical regions of Asia, the number of sand flies increases substantially during the monsoon season compared to the dry season.² Phlebotomine sand flies are most active at dusk and during the night⁵ but may become agitated during the daytime if their environment is disturbed.¹

Host selection usually is broad and includes a wide variety of vertebrates.² In the United States, host species are thought to include small rodents, foxes, armadillos, and opossums.⁸ One study found that visceral leishmaniasis in foxhounds is able to develop fully in sand flies, thus posing an emerging risk to the American population.⁹

Distribution

The Phlebotominae family contains approximately 700 different species of sand flies but only 21 are known vectors of disease.¹⁰ The great majority belong to 1 of 3 genuses: Phlebotomus, Sergentomyia, and Lutzomyia.¹¹ The vectors are commonly divided into Old World species, dominated by the Phlebotomus genus, and New World species, which exclusively refers to the Lutzomyia genus.³ The Old World and New World distinction helps to classify the various vectors and subsequently the diseases they transmit. Old World refers to those vectors found in Southwest and Central Asia, the Indian subcontinent, the Middle East, and East Africa, as well as Southern Europe.⁶ New World refers to vectors found predominantly in Brazil and other parts of Latin America but also Mexico and the United States.⁶ Sand flies are found to be endemic in 90 countries and on each continent, except Australia.⁵ Although the vector can be found in a variety of environments, sand flies prefer moist environments that typify tropical and subtropical climates, thus it is not surprising that the highest diversity of Phlebotominae in the world can be found in the Amazon basin.¹²

Disease Transmission

Leishmania refers to a genus of intracellular protozoa found in both the Old World and the New World that causes a variety of clinical syndromes.⁵ Approximately 20 Leishmania species are known to cause human disease that includes localized cutaneous, diffuse cutaneous, mucosal cutaneous, and visceral infections.¹³ Cases of all forms of leishmaniasis worldwide have increased rapidly over the last few decades from multiple factors including war in endemic regions, increased numbers of immunodeficient individuals, and increased travel to endemic areas.¹⁴ In the United States, leishmaniasis is caused by both imported and autochthonous forms of transmission and often mirrors recent travel and immigration patterns.^14,15

Sand flies also serve as vectors for sandfly fever, also known as Pappataci fever. Although sandfly fever commonly causes a mild febrile illness, it has been shown to be a considerable cause of aseptic meningitis.¹⁶ A number of novel Phleboviruses have been isolated as causes of sandfly fever, including Massilia virus, Granada virus, and Punique virus.^16-18 A form of sandfly fever caused by the Toscana virus has a predilection for the nervous system and can cause encephalitis.¹⁹ Sandfly fever can be found in both the Old World and New World and thus poses a global risk.² Additionally, Phlebotominae also have been found to transmit the Changuinola virus, a type of bunyavirus that is known to cause febrile illness in Panama.²⁰ Vesicular stomatitis, also carried by sand flies, is a known cause of febrile disease in North and South America, including the United States.² In 2013, the Niakha virus, a novel type of Rhabdoviridae, was isolated from Phlebotominae in Senegal.²¹ The sand fly is noted to transmit another type of Rhabdoviridae in India and Africa, known as the Chandipura virus.²² Although originally thought to cause mild febrile disease, it was the primary cause of multiple outbreaks of fatal encephalitis in India in 2003^23,24 and again in 2012.²²

Sand flies also are known to serve as vectors for the bacterium Bartonella bacilliformis, which is responsible for bartonellosis.²⁵ The disease is divided into 2 forms, which can occur separately or in succession, and is endemic to the Andes region of Peru, Ecuador, and Colombia. The first form is Oroya fever, an acute febrile hemolytic anemia that is fatal in 40% to 88% of cases without intervention.²⁵ This bacterium also causes verruga peruana, an endemic form of bacillary angiomatosis that can persist for years.² Two reports suggested that bartonellosis also can be caused by Bartonella rochalimae and Candidatus Bartonella ancashi.^26,27

Vector Control

Prevention is key to reducing the risk of the various diseases caused by the Phlebotominae vector. Vector control often falls into a few categories, including residual sprays, barriers, and topical repellants.³ It appears that residual sprays applied to houses and animal shelters are the most utilized and effective form of control, with the pyrethroid insecticides having the highest sand fly–specific toxicity.^3,28 Insecticides also have been applied to animal burrows where sand flies are known to reproduce; one study in Kenya showed a 90% reduction in the sand fly population following treatment of termite and animal burrows with a pyrethroid spray.²⁹ Studies by Perich et al^30,31 in 1995 and 2003 showed that using barrier sprays can be an effective protective measure. The investigators applied a 100-m barrier using a pyrethroid spray on vegetation and reported a notable decrease in sand flies for over an 80-day period.^30,31

For personal protection, barrier methods are important adjunct methods of preventing individual exposures. Due to the small size of sand flies, ordinary bed nets are not effective and those treated with insecticides should be used,¹⁵ which may ultimately prove to be the most sustainable way to prevent sand fly–borne disease.³² Protective attire also should be worn, as sand flies are not able to penetrate clothing.² N,N-diethyl-meta-toluamide (DEET)–based repellants should be applied to exposed skin.¹⁵ Finally, it is important to avoid exposure from dusk to dawn when sand flies are most active.¹⁵

Rise in Autochthonous Cutaneous Leishmaniasis in the United States

With the increased amount of worldwide tourism, especially to endemic areas, providers will continue to see rising numbers of leishmaniasis in the United States. It is difficult to determine the incidence of the disease in the United States, but one study has shown that leishmaniasis accounts for 143 of every 1000 dermatologic diseases acquired by South American tourists.^33,34 In addition, the number of autochthonous cases reported in the United States continues to grow. Although only 29 cases were reported between 1903 and 1996, 13 cases were reported between 2000 and 2008.³⁵ Another report in 2013 described an additional 3 cases in the states of Texas and Oklahoma.³⁵ The cases have continued to move in a northeasterly pattern, suggesting a possible shift in the location of sand fly populations. Each of these cases in which a specific species of Leishmania was identified showed transmission of Leishmania mexicana.³⁵ Most cases of cutaneous disease have occurred in Texas and Oklahoma. The first known case outside of this region was reported in 2014 in North Dakota.⁸ Leishmania donovani, brought into the United States with European foxhounds, also is spreading.⁸ One species of sand fly, Leishmania shannoni, has now been discovered in 16 states,^36-42 where it serves as a potential vector for L mexicana.^43,44

Identification

Phlebotomine sand flies are the only member of the Psychodidae family that are capable of taking blood.¹ The mouthparts of the sand fly are toothed distally, and the maxilla and mandible are utilized in a sawtooth fashion to take a bloodmeal.² The flies are very small (ie, only 1.5–3.5 mm in length), which makes their identification difficult.¹ Sand flies can be distinguished by the appearance of their wings, which often are covered in hair and extend across the back in a V shape.³ The adult sand fly is hairy with a 6- to 8-segmented abdomen, and the color can range from gray to yellow to brown.² Phlebotomine sand flies can be further identified by their long antennae, dark eyes, and small heads (Figure).²

As is the case with all Diptera, the sand fly goes through 4 complete life stages from egg to larva to pupa to adult.³ Female sand flies will lay their eggs following a blood meal and have been found to take multiple blood meals in a single cycle.² On average, the eggs will hatch in 6 to 17 days but are temperature dependent.³ The subsequent larvae and pupa stages last 20 to 30 days and 6 to 13 days, respectively.¹ The larvae are white in color with short antennae and dark heads.⁴ Sand flies prefer to lay their eggs in areas where adequate resting places are available and where their larvae will thrive.^4,5 The larvae require warm moist environments to succeed and thus are commonly found in animal burrows.³ Once fully developed, the adult sand fly can live up to 6 weeks.²

Sand Fly Vector

Although it is more common in rural forested areas, the sand fly also can be found in urban areas, including heavily populated cities in Brazil.⁶ Sand flies are most active during hot humid seasons but depending on the local climate may remain active year-round.^1,7 For example, in tropical regions of Asia, the number of sand flies increases substantially during the monsoon season compared to the dry season.² Phlebotomine sand flies are most active at dusk and during the night⁵ but may become agitated during the daytime if their environment is disturbed.¹

Host selection usually is broad and includes a wide variety of vertebrates.² In the United States, host species are thought to include small rodents, foxes, armadillos, and opossums.⁸ One study found that visceral leishmaniasis in foxhounds is able to develop fully in sand flies, thus posing an emerging risk to the American population.⁹

Distribution

The Phlebotominae family contains approximately 700 different species of sand flies but only 21 are known vectors of disease.¹⁰ The great majority belong to 1 of 3 genuses: Phlebotomus, Sergentomyia, and Lutzomyia.¹¹ The vectors are commonly divided into Old World species, dominated by the Phlebotomus genus, and New World species, which exclusively refers to the Lutzomyia genus.³ The Old World and New World distinction helps to classify the various vectors and subsequently the diseases they transmit. Old World refers to those vectors found in Southwest and Central Asia, the Indian subcontinent, the Middle East, and East Africa, as well as Southern Europe.⁶ New World refers to vectors found predominantly in Brazil and other parts of Latin America but also Mexico and the United States.⁶ Sand flies are found to be endemic in 90 countries and on each continent, except Australia.⁵ Although the vector can be found in a variety of environments, sand flies prefer moist environments that typify tropical and subtropical climates, thus it is not surprising that the highest diversity of Phlebotominae in the world can be found in the Amazon basin.¹²

Disease Transmission

Leishmania refers to a genus of intracellular protozoa found in both the Old World and the New World that causes a variety of clinical syndromes.⁵ Approximately 20 Leishmania species are known to cause human disease that includes localized cutaneous, diffuse cutaneous, mucosal cutaneous, and visceral infections.¹³ Cases of all forms of leishmaniasis worldwide have increased rapidly over the last few decades from multiple factors including war in endemic regions, increased numbers of immunodeficient individuals, and increased travel to endemic areas.¹⁴ In the United States, leishmaniasis is caused by both imported and autochthonous forms of transmission and often mirrors recent travel and immigration patterns.^14,15

Sand flies also serve as vectors for sandfly fever, also known as Pappataci fever. Although sandfly fever commonly causes a mild febrile illness, it has been shown to be a considerable cause of aseptic meningitis.¹⁶ A number of novel Phleboviruses have been isolated as causes of sandfly fever, including Massilia virus, Granada virus, and Punique virus.^16-18 A form of sandfly fever caused by the Toscana virus has a predilection for the nervous system and can cause encephalitis.¹⁹ Sandfly fever can be found in both the Old World and New World and thus poses a global risk.² Additionally, Phlebotominae also have been found to transmit the Changuinola virus, a type of bunyavirus that is known to cause febrile illness in Panama.²⁰ Vesicular stomatitis, also carried by sand flies, is a known cause of febrile disease in North and South America, including the United States.² In 2013, the Niakha virus, a novel type of Rhabdoviridae, was isolated from Phlebotominae in Senegal.²¹ The sand fly is noted to transmit another type of Rhabdoviridae in India and Africa, known as the Chandipura virus.²² Although originally thought to cause mild febrile disease, it was the primary cause of multiple outbreaks of fatal encephalitis in India in 2003^23,24 and again in 2012.²²

Sand flies also are known to serve as vectors for the bacterium Bartonella bacilliformis, which is responsible for bartonellosis.²⁵ The disease is divided into 2 forms, which can occur separately or in succession, and is endemic to the Andes region of Peru, Ecuador, and Colombia. The first form is Oroya fever, an acute febrile hemolytic anemia that is fatal in 40% to 88% of cases without intervention.²⁵ This bacterium also causes verruga peruana, an endemic form of bacillary angiomatosis that can persist for years.² Two reports suggested that bartonellosis also can be caused by Bartonella rochalimae and Candidatus Bartonella ancashi.^26,27

Vector Control

Prevention is key to reducing the risk of the various diseases caused by the Phlebotominae vector. Vector control often falls into a few categories, including residual sprays, barriers, and topical repellants.³ It appears that residual sprays applied to houses and animal shelters are the most utilized and effective form of control, with the pyrethroid insecticides having the highest sand fly–specific toxicity.^3,28 Insecticides also have been applied to animal burrows where sand flies are known to reproduce; one study in Kenya showed a 90% reduction in the sand fly population following treatment of termite and animal burrows with a pyrethroid spray.²⁹ Studies by Perich et al^30,31 in 1995 and 2003 showed that using barrier sprays can be an effective protective measure. The investigators applied a 100-m barrier using a pyrethroid spray on vegetation and reported a notable decrease in sand flies for over an 80-day period.^30,31

For personal protection, barrier methods are important adjunct methods of preventing individual exposures. Due to the small size of sand flies, ordinary bed nets are not effective and those treated with insecticides should be used,¹⁵ which may ultimately prove to be the most sustainable way to prevent sand fly–borne disease.³² Protective attire also should be worn, as sand flies are not able to penetrate clothing.² N,N-diethyl-meta-toluamide (DEET)–based repellants should be applied to exposed skin.¹⁵ Finally, it is important to avoid exposure from dusk to dawn when sand flies are most active.¹⁵

Rise in Autochthonous Cutaneous Leishmaniasis in the United States

With the increased amount of worldwide tourism, especially to endemic areas, providers will continue to see rising numbers of leishmaniasis in the United States. It is difficult to determine the incidence of the disease in the United States, but one study has shown that leishmaniasis accounts for 143 of every 1000 dermatologic diseases acquired by South American tourists.^33,34 In addition, the number of autochthonous cases reported in the United States continues to grow. Although only 29 cases were reported between 1903 and 1996, 13 cases were reported between 2000 and 2008.³⁵ Another report in 2013 described an additional 3 cases in the states of Texas and Oklahoma.³⁵ The cases have continued to move in a northeasterly pattern, suggesting a possible shift in the location of sand fly populations. Each of these cases in which a specific species of Leishmania was identified showed transmission of Leishmania mexicana.³⁵ Most cases of cutaneous disease have occurred in Texas and Oklahoma. The first known case outside of this region was reported in 2014 in North Dakota.⁸ Leishmania donovani, brought into the United States with European foxhounds, also is spreading.⁸ One species of sand fly, Leishmania shannoni, has now been discovered in 16 states,^36-42 where it serves as a potential vector for L mexicana.^43,44

The Diagnosis: Atypical Vascular Lesion

Atypical vascular lesion (AVL)(quiz image), named by Fineberg and Rosen,¹ is a vascular lesion that arises on mammary skin with a history of radiation exposure. Clinically, AVL can present as a papule or erythematous patch that manifests 3 to 7 years after radiation therapy.^2,3 There are 2 histologic subtypes of AVL: lymphatic and vascular.^2,4 Lymphatic-type AVL is comprised of a symmetric distribution of thin, dilated, and anastomosing vessels usually found in the superficial and mid dermis. The vessels are lined by flat or hobnail protuberant endothelial cells that lack nuclear irregularity or pleomorphism; however, hyperchromatism of endothelial cell nuclei is a common finding. Vascular-type AVL is morphologically similar to a capillary hemangioma, and histologic features include irregular growth of capillary-sized vessels that extend to the dermis and subcutis.^2,4 Atypical vascular lesions are benign lesions but may be a precursor to angiosarcoma. Along with vascular markers, D2-40 typically is positive. Surgical excision with clear margins is recommended when the lesion is small.^4,5 Observation is more appropriate for extensive lesions.

Angiosarcoma can arise spontaneously or in association with radiation or chronic lymphedema. Given the shared risk factors and presentation with AVL, it is essential to differentiate angiosarcoma from AVL. Primary cutaneous angiosarcoma usually presents on the head of elderly patients as an ecchymotic patch or plaque with ulceration.⁴ Secondary angiosarcoma may arise following radiation or chronic lymphedema (Stewart-Treves syndrome); however, some authors now prefer to consider lymphangiosarcoma arising in chronic lymphedematous limbs a distinct entity.⁶ Surgical excision with wide margins is the mainstay of therapy, but angiosarcoma has high recurrence rates, and the 5-year survival rate has been reported to be as low as 35%.⁷ Histologic overlap with AVL includes dissecting anastomosing vessels lined by hyperchromatic nuclei; however, angiosarcoma is distinguished by endothelial cell layering, nuclear pleomorphism, and prominent nucleoli (Figure 1).^4,8 Increased positivity for Ki-67 immunostain, which indicates cell proliferation, may be used to distinguish angiosarcoma from an AVL (Figure 1 [inset]).⁹ Further, in contrast to AVL, radiation-induced angiosarcoma is characterized by amplification of C-MYC, a regulator gene, and FLT4 (FMS-related tyrosine kinase 4), a gene encoding vascular endothelial growth factor receptor 3. Gene amplification may be detected through immunohistochemistry or fluorescence in situ hybridization.¹⁰ Ki-67 labeling showed less than 10% staining in endothelial cells in our case (quiz image [inset]), and fluorescence in situ hybridization was negative for C-MYC amplification, supporting the diagnosis of AVL.

Lymphangioma circumscriptum, the most common superficial lymphangioma, is a hamartomatous malformation that usually occurs at the axillary folds, neck, and trunk. It clinically presents as small agminated vesicles with a characteristic frog spawn appearance.¹¹ Dermoscopic features include yellow lacunae that may alternate with a dark red color secondary to extravasation of erythrocytes.¹² These clinical features often lead to a differential diagnosis of verrucae, angiokeratoma, and angiosarcoma. Lymphangioma circumscriptum histologically is characterized by an overgrowth of dilated lymphatic vessels that fill the papillary dermis. The vessels are composed of flat endothelial cells typically filled with acellular proteinaceous debris and occasional erythrocytes (Figure 2). As the lesion traverses deeper into the dermis, the caliber of the lymphatic channel becomes narrower. The presence of deep lymphatic cisterns with surrounding smooth muscle is helpful to differentiate lymphangioma circumscriptum from other lymphatic malformations such as acquired lymphangiectasia. Treatment options include surgical excision, sclerosing agents, and destructive modalities such as cryotherapy.

Hobnail hemangioma, originally termed targetoid hemosiderotic hemangioma by Santa Cruz and Aronberg,¹³ presents as a violaceous papule or nodule surrounded by a characteristic brown halo on the leg. Trauma has been proposed as the inciting factor for the clinical appearance of hobnail hemangioma.¹⁴ Microscopically, the lesion shows vessels in a wedge shape. The superficial component has telangiectatic vessels with focal areas of papillary projections lined by endothelial cells. Although the endothelial nuclei typically project into the lumen, the nuclei are small, bland, and without mitotic activity.¹⁵ Deeper components show slit-shaped vasculature with dermal collagen dissection. Hemosiderin, extravasated red blood cells, and inflammation are found adjacent to the vessels (Figure 3). Given the benign nature, hobnail hemangiomas may be monitored.

Kaposi sarcoma (KS) is a low-grade vascular neoplasm associated with human herpesvirus 8 that arises in multiple clinical settings, especially in immunosuppression secondary to human immunodeficiency virus. There are 3 distinct clinical stages: patch, plaque, and tumor. The patch stage appears as red macules that blend into larger plaques; the tumor stage is defined as larger nodules developing from plaques. Histologic features differ by stage. Similar to angiosarcoma, KS is comprised of anastomosing vessels that dissect collagen bundles; endothelial cell atypia is minimal. A useful feature of KS is its propensity to involve adnexa and display the promontory sign, which involves the tumor growing into normal vasculature (Figure 4).¹⁶ Positive immunohistochemistry for human herpesvirus 8 aids in confirmation of the diagnosis. Treatment options for KS are numerous but include destructive modalities, chemotherapeutic agents such as doxorubicin, or highly active antiretroviral therapy for AIDS-related KS.¹⁷

The Diagnosis: Atypical Vascular Lesion

Atypical vascular lesion (AVL)(quiz image), named by Fineberg and Rosen,¹ is a vascular lesion that arises on mammary skin with a history of radiation exposure. Clinically, AVL can present as a papule or erythematous patch that manifests 3 to 7 years after radiation therapy.^2,3 There are 2 histologic subtypes of AVL: lymphatic and vascular.^2,4 Lymphatic-type AVL is comprised of a symmetric distribution of thin, dilated, and anastomosing vessels usually found in the superficial and mid dermis. The vessels are lined by flat or hobnail protuberant endothelial cells that lack nuclear irregularity or pleomorphism; however, hyperchromatism of endothelial cell nuclei is a common finding. Vascular-type AVL is morphologically similar to a capillary hemangioma, and histologic features include irregular growth of capillary-sized vessels that extend to the dermis and subcutis.^2,4 Atypical vascular lesions are benign lesions but may be a precursor to angiosarcoma. Along with vascular markers, D2-40 typically is positive. Surgical excision with clear margins is recommended when the lesion is small.^4,5 Observation is more appropriate for extensive lesions.

Angiosarcoma can arise spontaneously or in association with radiation or chronic lymphedema. Given the shared risk factors and presentation with AVL, it is essential to differentiate angiosarcoma from AVL. Primary cutaneous angiosarcoma usually presents on the head of elderly patients as an ecchymotic patch or plaque with ulceration.⁴ Secondary angiosarcoma may arise following radiation or chronic lymphedema (Stewart-Treves syndrome); however, some authors now prefer to consider lymphangiosarcoma arising in chronic lymphedematous limbs a distinct entity.⁶ Surgical excision with wide margins is the mainstay of therapy, but angiosarcoma has high recurrence rates, and the 5-year survival rate has been reported to be as low as 35%.⁷ Histologic overlap with AVL includes dissecting anastomosing vessels lined by hyperchromatic nuclei; however, angiosarcoma is distinguished by endothelial cell layering, nuclear pleomorphism, and prominent nucleoli (Figure 1).^4,8 Increased positivity for Ki-67 immunostain, which indicates cell proliferation, may be used to distinguish angiosarcoma from an AVL (Figure 1 [inset]).⁹ Further, in contrast to AVL, radiation-induced angiosarcoma is characterized by amplification of C-MYC, a regulator gene, and FLT4 (FMS-related tyrosine kinase 4), a gene encoding vascular endothelial growth factor receptor 3. Gene amplification may be detected through immunohistochemistry or fluorescence in situ hybridization.¹⁰ Ki-67 labeling showed less than 10% staining in endothelial cells in our case (quiz image [inset]), and fluorescence in situ hybridization was negative for C-MYC amplification, supporting the diagnosis of AVL.

Lymphangioma circumscriptum, the most common superficial lymphangioma, is a hamartomatous malformation that usually occurs at the axillary folds, neck, and trunk. It clinically presents as small agminated vesicles with a characteristic frog spawn appearance.¹¹ Dermoscopic features include yellow lacunae that may alternate with a dark red color secondary to extravasation of erythrocytes.¹² These clinical features often lead to a differential diagnosis of verrucae, angiokeratoma, and angiosarcoma. Lymphangioma circumscriptum histologically is characterized by an overgrowth of dilated lymphatic vessels that fill the papillary dermis. The vessels are composed of flat endothelial cells typically filled with acellular proteinaceous debris and occasional erythrocytes (Figure 2). As the lesion traverses deeper into the dermis, the caliber of the lymphatic channel becomes narrower. The presence of deep lymphatic cisterns with surrounding smooth muscle is helpful to differentiate lymphangioma circumscriptum from other lymphatic malformations such as acquired lymphangiectasia. Treatment options include surgical excision, sclerosing agents, and destructive modalities such as cryotherapy.

Hobnail hemangioma, originally termed targetoid hemosiderotic hemangioma by Santa Cruz and Aronberg,¹³ presents as a violaceous papule or nodule surrounded by a characteristic brown halo on the leg. Trauma has been proposed as the inciting factor for the clinical appearance of hobnail hemangioma.¹⁴ Microscopically, the lesion shows vessels in a wedge shape. The superficial component has telangiectatic vessels with focal areas of papillary projections lined by endothelial cells. Although the endothelial nuclei typically project into the lumen, the nuclei are small, bland, and without mitotic activity.¹⁵ Deeper components show slit-shaped vasculature with dermal collagen dissection. Hemosiderin, extravasated red blood cells, and inflammation are found adjacent to the vessels (Figure 3). Given the benign nature, hobnail hemangiomas may be monitored.

Kaposi sarcoma (KS) is a low-grade vascular neoplasm associated with human herpesvirus 8 that arises in multiple clinical settings, especially in immunosuppression secondary to human immunodeficiency virus. There are 3 distinct clinical stages: patch, plaque, and tumor. The patch stage appears as red macules that blend into larger plaques; the tumor stage is defined as larger nodules developing from plaques. Histologic features differ by stage. Similar to angiosarcoma, KS is comprised of anastomosing vessels that dissect collagen bundles; endothelial cell atypia is minimal. A useful feature of KS is its propensity to involve adnexa and display the promontory sign, which involves the tumor growing into normal vasculature (Figure 4).¹⁶ Positive immunohistochemistry for human herpesvirus 8 aids in confirmation of the diagnosis. Treatment options for KS are numerous but include destructive modalities, chemotherapeutic agents such as doxorubicin, or highly active antiretroviral therapy for AIDS-related KS.¹⁷

The Diagnosis: Atypical Vascular Lesion

Atypical vascular lesion (AVL)(quiz image), named by Fineberg and Rosen,¹ is a vascular lesion that arises on mammary skin with a history of radiation exposure. Clinically, AVL can present as a papule or erythematous patch that manifests 3 to 7 years after radiation therapy.^2,3 There are 2 histologic subtypes of AVL: lymphatic and vascular.^2,4 Lymphatic-type AVL is comprised of a symmetric distribution of thin, dilated, and anastomosing vessels usually found in the superficial and mid dermis. The vessels are lined by flat or hobnail protuberant endothelial cells that lack nuclear irregularity or pleomorphism; however, hyperchromatism of endothelial cell nuclei is a common finding. Vascular-type AVL is morphologically similar to a capillary hemangioma, and histologic features include irregular growth of capillary-sized vessels that extend to the dermis and subcutis.^2,4 Atypical vascular lesions are benign lesions but may be a precursor to angiosarcoma. Along with vascular markers, D2-40 typically is positive. Surgical excision with clear margins is recommended when the lesion is small.^4,5 Observation is more appropriate for extensive lesions.

Angiosarcoma can arise spontaneously or in association with radiation or chronic lymphedema. Given the shared risk factors and presentation with AVL, it is essential to differentiate angiosarcoma from AVL. Primary cutaneous angiosarcoma usually presents on the head of elderly patients as an ecchymotic patch or plaque with ulceration.⁴ Secondary angiosarcoma may arise following radiation or chronic lymphedema (Stewart-Treves syndrome); however, some authors now prefer to consider lymphangiosarcoma arising in chronic lymphedematous limbs a distinct entity.⁶ Surgical excision with wide margins is the mainstay of therapy, but angiosarcoma has high recurrence rates, and the 5-year survival rate has been reported to be as low as 35%.⁷ Histologic overlap with AVL includes dissecting anastomosing vessels lined by hyperchromatic nuclei; however, angiosarcoma is distinguished by endothelial cell layering, nuclear pleomorphism, and prominent nucleoli (Figure 1).^4,8 Increased positivity for Ki-67 immunostain, which indicates cell proliferation, may be used to distinguish angiosarcoma from an AVL (Figure 1 [inset]).⁹ Further, in contrast to AVL, radiation-induced angiosarcoma is characterized by amplification of C-MYC, a regulator gene, and FLT4 (FMS-related tyrosine kinase 4), a gene encoding vascular endothelial growth factor receptor 3. Gene amplification may be detected through immunohistochemistry or fluorescence in situ hybridization.¹⁰ Ki-67 labeling showed less than 10% staining in endothelial cells in our case (quiz image [inset]), and fluorescence in situ hybridization was negative for C-MYC amplification, supporting the diagnosis of AVL.

Lymphangioma circumscriptum, the most common superficial lymphangioma, is a hamartomatous malformation that usually occurs at the axillary folds, neck, and trunk. It clinically presents as small agminated vesicles with a characteristic frog spawn appearance.¹¹ Dermoscopic features include yellow lacunae that may alternate with a dark red color secondary to extravasation of erythrocytes.¹² These clinical features often lead to a differential diagnosis of verrucae, angiokeratoma, and angiosarcoma. Lymphangioma circumscriptum histologically is characterized by an overgrowth of dilated lymphatic vessels that fill the papillary dermis. The vessels are composed of flat endothelial cells typically filled with acellular proteinaceous debris and occasional erythrocytes (Figure 2). As the lesion traverses deeper into the dermis, the caliber of the lymphatic channel becomes narrower. The presence of deep lymphatic cisterns with surrounding smooth muscle is helpful to differentiate lymphangioma circumscriptum from other lymphatic malformations such as acquired lymphangiectasia. Treatment options include surgical excision, sclerosing agents, and destructive modalities such as cryotherapy.

Hobnail hemangioma, originally termed targetoid hemosiderotic hemangioma by Santa Cruz and Aronberg,¹³ presents as a violaceous papule or nodule surrounded by a characteristic brown halo on the leg. Trauma has been proposed as the inciting factor for the clinical appearance of hobnail hemangioma.¹⁴ Microscopically, the lesion shows vessels in a wedge shape. The superficial component has telangiectatic vessels with focal areas of papillary projections lined by endothelial cells. Although the endothelial nuclei typically project into the lumen, the nuclei are small, bland, and without mitotic activity.¹⁵ Deeper components show slit-shaped vasculature with dermal collagen dissection. Hemosiderin, extravasated red blood cells, and inflammation are found adjacent to the vessels (Figure 3). Given the benign nature, hobnail hemangiomas may be monitored.

Kaposi sarcoma (KS) is a low-grade vascular neoplasm associated with human herpesvirus 8 that arises in multiple clinical settings, especially in immunosuppression secondary to human immunodeficiency virus. There are 3 distinct clinical stages: patch, plaque, and tumor. The patch stage appears as red macules that blend into larger plaques; the tumor stage is defined as larger nodules developing from plaques. Histologic features differ by stage. Similar to angiosarcoma, KS is comprised of anastomosing vessels that dissect collagen bundles; endothelial cell atypia is minimal. A useful feature of KS is its propensity to involve adnexa and display the promontory sign, which involves the tumor growing into normal vasculature (Figure 4).¹⁶ Positive immunohistochemistry for human herpesvirus 8 aids in confirmation of the diagnosis. Treatment options for KS are numerous but include destructive modalities, chemotherapeutic agents such as doxorubicin, or highly active antiretroviral therapy for AIDS-related KS.¹⁷

Background and Distribution

The Dermacentor ticks belong to the family Ixodidae (hard ticks). The 2 best-known ticks of the genus are Dermacentor andersoni (Rocky Mountain wood tick)(Figure, A) and Dermacentor variabilis (American dog tick)(Figure, B). The Dermacentor ticks are large ticks with small anterior mouthparts that attach to a rectangular basis capituli (Figure, A). Both ticks exhibit widely spaced eyes and posterior festoons as well as bifid coxa 1 (the attachment site for the first pair of legs) and enlarged coxa 4. As adults, these ticks display an ornate hard dorsal plate, or scutum, with numerous pits. Female ticks have a much smaller scutum, allowing for abdominal engorgement during feeding.¹ Although D andersoni tends to have a brown to yellow hue, the specimens of D variabilis display a somewhat silver color pattern.

Dermacentor ticks can be found throughout most of North America, with the northern distribution limits of both species previously occurring in the province of Saskatchewan, Canada. Although the range of D andersoni has remained relatively stable within this distribution, the distribution of D variabilis recently has expanded westward and northward of these limits.² The ranges of the 2 species overlap in certain areas, though D andersoni primarily is found in the Rocky Mountain and northwestern states as well as southwestern Canada, whereas D variabilis can be found throughout most parts of the United States, except in the Rocky Mountain states.³ Within these regions the ticks can be found in heavily wooded areas, but they most commonly inhabit fields with tall grass, crops, bushes, and shrubbery, often clustering where these types of vegetation form clearly defined edges.⁴ The diseases transmitted by the Dermacentor ticks include Rocky Mountain spotted fever (RMSF), Colorado tick fever, tularemia, tick paralysis, and even human monocytic erlichiosis, though Amblyomma americanum is the major vector for human monocytic erlichiosis.

Rocky Mountain Spotted Fever

Both species of ticks are known to serve as vectors for RMSF, but D variabilis is the major vector in the United States, especially in the eastern and southeastern parts of the United States. Overall, the majority of cases occur in North Carolina, South Carolina, Tennessee, and Oklahoma,⁵ with North Carolina having the highest incidence. In endemic areas, RMSF should be suspected in any patient with fever and headache, and empiric treatment with antibiotics should be started while awaiting the results of diagnostic tests. Serologic testing with indirect fluorescent antibodies is widely available and is considered the best method for detection; although the sensitivity is poor during the first 10 to 12 days of infection, it increases to 94% during days 14 to 21.⁶ Therapeutic decisions should be influenced by clinical suspicion and epidemiologic data. Treatment should be started promptly and should never be delayed until confirmatory tests are available. Doxycycline is considered the gold standard therapy in both adults and children, with a typical treatment duration of 10 days. The only other recommended agent for pregnant women in the first or second trimesters or patients with severe hypersensitivity reactions to tetracyclines is chloramphenicol.⁷

Colorado Tick Fever

Colorado tick fever, also known as mountain fever, is an arboviral infection transmitted by D andersoni. Its distribution coincides with the tick’s natural geographic range in the western United States and Rocky Mountains. Colorado tick fever causes an acute febrile illness consisting of chills, headaches, myalgia, retro-orbital pain, and malaise, which tend to occur within 3 to 5 days of the tick bite. Some cases may be accompanied by a nonspecific rash that may be morbilliform or petechial in appearance. Notably, approximately half of all patients will experience transient resolution of symptoms for 24 to 48 hours followed by a recurrence of fever, a phenomenon that has been referred to as saddleback fever. Routine laboratory findings may include leukopenia, thrombocytopenia, and a peripheral smear with atypical lymphocytes. Reverse transcription polymerase chain reaction is both sensitive and specific for detecting viral loads in the blood during the first week of infection, though testing does not alter management, which is largely supportive.⁸

Tularemia

Tularemia is a relatively rare disease but has been documented in every US state except Hawaii.⁹ The disease is caused by Francisella tularensis, a small, aerobic, gram-negative coccobacillus transmitted via inhalation, bitingflies, or tick bites; the most common ticks to transmit the disease include D andersoni, D variabilis, and A americanum.¹⁰ Clinical manifestations depend on the form of exposure, with tick bites most often resulting in an ulcerated skin lesion at the site of the vector bite accompanied by regional lymphadenopathy and systemic symptoms such as fever, chills, myalgia, and headache.¹¹ Mucosal manifestations such as pharyngitis, conjunctivitis, and other ocular lesions also are commonly seen. Diagnosis most frequently is made using serology because F tularensis is both challenging and dangerous to culture; in fact, because of the high risk of contagion, F tularensis should only be cultured in biosafety level 3 laboratories. Polymerase chain reaction assays can be used on tissue samples with decent sensitivity (78%) and specificity (96%); however, these assays cannot distinguish between Francisella subspecies and are not readily available to most clinicians.¹² First-line therapy for the treatment of tularemia is streptomycin given as twice-daily intramuscular injections over the course of 7 to 10 days. Alternative agents include gentamicin, ciprofloxacin, imipenem, doxycycline, and chloramphenicol.¹⁰ Because tularemia is relatively rare, a high index of suspicion is necessary to reduce the morbidity and mortality associated with the disease.

Tick Paralysis

More than 40 different species of ticks have been implicated worldwide as causes of tick paralysis, though D andersoni has been the most common in North America. Female patients account for most cases, possibly because long hair conceals ticks on the scalp or neck, the preferred attachment locations for Dermacentor ticks.¹³ The classic presentation of tick paralysis is an acute, flaccid, ascending paralysis that occurs from a neurotoxin in the tick saliva that impairs afferent nerve signal propagation.^14,15 The paralysis progresses over hours to days and typically occurs 5 to 6 days after attachment of the tick. Notably, there is no associated fever with tick paralysis, and without intervention, patients may die of respiratory failure. Overall, the condition carries a fatality rate of nearly 10%¹⁶ but reverses rapidly if the tick is identified and removed.

Protection against tick bites and tick-borne illnesses includes avoidance of infested areas, treatment of populated habitats with insecticide sprays, use of topical repellants prior to outdoor activities, and diligent full-body tick checks upon return from tick-heavy areas. Permethrin can be used to treat clothing and remains protective through multiple washings. Ticks typically survive washing of untreated clothing but are killed by prolonged drying in a dryer. Pets may be treated with oral, intramuscular, or topical agents prescribed by a veterinarian to prevent tick attachments.

Conclusion

Accurate identification of Dermacentor ticks allows for appropriate surveillance for associated diseases and can improve patient outcomes. Patients who engage in outdoor activities in endemic areas should take steps to avoid exposure, use appropriate acaricides and repellents, and perform tick checks after returning indoors.

Background and Distribution

The Dermacentor ticks belong to the family Ixodidae (hard ticks). The 2 best-known ticks of the genus are Dermacentor andersoni (Rocky Mountain wood tick)(Figure, A) and Dermacentor variabilis (American dog tick)(Figure, B). The Dermacentor ticks are large ticks with small anterior mouthparts that attach to a rectangular basis capituli (Figure, A). Both ticks exhibit widely spaced eyes and posterior festoons as well as bifid coxa 1 (the attachment site for the first pair of legs) and enlarged coxa 4. As adults, these ticks display an ornate hard dorsal plate, or scutum, with numerous pits. Female ticks have a much smaller scutum, allowing for abdominal engorgement during feeding.¹ Although D andersoni tends to have a brown to yellow hue, the specimens of D variabilis display a somewhat silver color pattern.

Dermacentor ticks can be found throughout most of North America, with the northern distribution limits of both species previously occurring in the province of Saskatchewan, Canada. Although the range of D andersoni has remained relatively stable within this distribution, the distribution of D variabilis recently has expanded westward and northward of these limits.² The ranges of the 2 species overlap in certain areas, though D andersoni primarily is found in the Rocky Mountain and northwestern states as well as southwestern Canada, whereas D variabilis can be found throughout most parts of the United States, except in the Rocky Mountain states.³ Within these regions the ticks can be found in heavily wooded areas, but they most commonly inhabit fields with tall grass, crops, bushes, and shrubbery, often clustering where these types of vegetation form clearly defined edges.⁴ The diseases transmitted by the Dermacentor ticks include Rocky Mountain spotted fever (RMSF), Colorado tick fever, tularemia, tick paralysis, and even human monocytic erlichiosis, though Amblyomma americanum is the major vector for human monocytic erlichiosis.

Rocky Mountain Spotted Fever

Both species of ticks are known to serve as vectors for RMSF, but D variabilis is the major vector in the United States, especially in the eastern and southeastern parts of the United States. Overall, the majority of cases occur in North Carolina, South Carolina, Tennessee, and Oklahoma,⁵ with North Carolina having the highest incidence. In endemic areas, RMSF should be suspected in any patient with fever and headache, and empiric treatment with antibiotics should be started while awaiting the results of diagnostic tests. Serologic testing with indirect fluorescent antibodies is widely available and is considered the best method for detection; although the sensitivity is poor during the first 10 to 12 days of infection, it increases to 94% during days 14 to 21.⁶ Therapeutic decisions should be influenced by clinical suspicion and epidemiologic data. Treatment should be started promptly and should never be delayed until confirmatory tests are available. Doxycycline is considered the gold standard therapy in both adults and children, with a typical treatment duration of 10 days. The only other recommended agent for pregnant women in the first or second trimesters or patients with severe hypersensitivity reactions to tetracyclines is chloramphenicol.⁷

Colorado Tick Fever

Colorado tick fever, also known as mountain fever, is an arboviral infection transmitted by D andersoni. Its distribution coincides with the tick’s natural geographic range in the western United States and Rocky Mountains. Colorado tick fever causes an acute febrile illness consisting of chills, headaches, myalgia, retro-orbital pain, and malaise, which tend to occur within 3 to 5 days of the tick bite. Some cases may be accompanied by a nonspecific rash that may be morbilliform or petechial in appearance. Notably, approximately half of all patients will experience transient resolution of symptoms for 24 to 48 hours followed by a recurrence of fever, a phenomenon that has been referred to as saddleback fever. Routine laboratory findings may include leukopenia, thrombocytopenia, and a peripheral smear with atypical lymphocytes. Reverse transcription polymerase chain reaction is both sensitive and specific for detecting viral loads in the blood during the first week of infection, though testing does not alter management, which is largely supportive.⁸

Tularemia

Tularemia is a relatively rare disease but has been documented in every US state except Hawaii.⁹ The disease is caused by Francisella tularensis, a small, aerobic, gram-negative coccobacillus transmitted via inhalation, bitingflies, or tick bites; the most common ticks to transmit the disease include D andersoni, D variabilis, and A americanum.¹⁰ Clinical manifestations depend on the form of exposure, with tick bites most often resulting in an ulcerated skin lesion at the site of the vector bite accompanied by regional lymphadenopathy and systemic symptoms such as fever, chills, myalgia, and headache.¹¹ Mucosal manifestations such as pharyngitis, conjunctivitis, and other ocular lesions also are commonly seen. Diagnosis most frequently is made using serology because F tularensis is both challenging and dangerous to culture; in fact, because of the high risk of contagion, F tularensis should only be cultured in biosafety level 3 laboratories. Polymerase chain reaction assays can be used on tissue samples with decent sensitivity (78%) and specificity (96%); however, these assays cannot distinguish between Francisella subspecies and are not readily available to most clinicians.¹² First-line therapy for the treatment of tularemia is streptomycin given as twice-daily intramuscular injections over the course of 7 to 10 days. Alternative agents include gentamicin, ciprofloxacin, imipenem, doxycycline, and chloramphenicol.¹⁰ Because tularemia is relatively rare, a high index of suspicion is necessary to reduce the morbidity and mortality associated with the disease.

Tick Paralysis

More than 40 different species of ticks have been implicated worldwide as causes of tick paralysis, though D andersoni has been the most common in North America. Female patients account for most cases, possibly because long hair conceals ticks on the scalp or neck, the preferred attachment locations for Dermacentor ticks.¹³ The classic presentation of tick paralysis is an acute, flaccid, ascending paralysis that occurs from a neurotoxin in the tick saliva that impairs afferent nerve signal propagation.^14,15 The paralysis progresses over hours to days and typically occurs 5 to 6 days after attachment of the tick. Notably, there is no associated fever with tick paralysis, and without intervention, patients may die of respiratory failure. Overall, the condition carries a fatality rate of nearly 10%¹⁶ but reverses rapidly if the tick is identified and removed.

Protection against tick bites and tick-borne illnesses includes avoidance of infested areas, treatment of populated habitats with insecticide sprays, use of topical repellants prior to outdoor activities, and diligent full-body tick checks upon return from tick-heavy areas. Permethrin can be used to treat clothing and remains protective through multiple washings. Ticks typically survive washing of untreated clothing but are killed by prolonged drying in a dryer. Pets may be treated with oral, intramuscular, or topical agents prescribed by a veterinarian to prevent tick attachments.

Conclusion

Accurate identification of Dermacentor ticks allows for appropriate surveillance for associated diseases and can improve patient outcomes. Patients who engage in outdoor activities in endemic areas should take steps to avoid exposure, use appropriate acaricides and repellents, and perform tick checks after returning indoors.

Background and Distribution

The Dermacentor ticks belong to the family Ixodidae (hard ticks). The 2 best-known ticks of the genus are Dermacentor andersoni (Rocky Mountain wood tick)(Figure, A) and Dermacentor variabilis (American dog tick)(Figure, B). The Dermacentor ticks are large ticks with small anterior mouthparts that attach to a rectangular basis capituli (Figure, A). Both ticks exhibit widely spaced eyes and posterior festoons as well as bifid coxa 1 (the attachment site for the first pair of legs) and enlarged coxa 4. As adults, these ticks display an ornate hard dorsal plate, or scutum, with numerous pits. Female ticks have a much smaller scutum, allowing for abdominal engorgement during feeding.¹ Although D andersoni tends to have a brown to yellow hue, the specimens of D variabilis display a somewhat silver color pattern.

Dermacentor ticks can be found throughout most of North America, with the northern distribution limits of both species previously occurring in the province of Saskatchewan, Canada. Although the range of D andersoni has remained relatively stable within this distribution, the distribution of D variabilis recently has expanded westward and northward of these limits.² The ranges of the 2 species overlap in certain areas, though D andersoni primarily is found in the Rocky Mountain and northwestern states as well as southwestern Canada, whereas D variabilis can be found throughout most parts of the United States, except in the Rocky Mountain states.³ Within these regions the ticks can be found in heavily wooded areas, but they most commonly inhabit fields with tall grass, crops, bushes, and shrubbery, often clustering where these types of vegetation form clearly defined edges.⁴ The diseases transmitted by the Dermacentor ticks include Rocky Mountain spotted fever (RMSF), Colorado tick fever, tularemia, tick paralysis, and even human monocytic erlichiosis, though Amblyomma americanum is the major vector for human monocytic erlichiosis.

Rocky Mountain Spotted Fever

Both species of ticks are known to serve as vectors for RMSF, but D variabilis is the major vector in the United States, especially in the eastern and southeastern parts of the United States. Overall, the majority of cases occur in North Carolina, South Carolina, Tennessee, and Oklahoma,⁵ with North Carolina having the highest incidence. In endemic areas, RMSF should be suspected in any patient with fever and headache, and empiric treatment with antibiotics should be started while awaiting the results of diagnostic tests. Serologic testing with indirect fluorescent antibodies is widely available and is considered the best method for detection; although the sensitivity is poor during the first 10 to 12 days of infection, it increases to 94% during days 14 to 21.⁶ Therapeutic decisions should be influenced by clinical suspicion and epidemiologic data. Treatment should be started promptly and should never be delayed until confirmatory tests are available. Doxycycline is considered the gold standard therapy in both adults and children, with a typical treatment duration of 10 days. The only other recommended agent for pregnant women in the first or second trimesters or patients with severe hypersensitivity reactions to tetracyclines is chloramphenicol.⁷

Colorado Tick Fever

Colorado tick fever, also known as mountain fever, is an arboviral infection transmitted by D andersoni. Its distribution coincides with the tick’s natural geographic range in the western United States and Rocky Mountains. Colorado tick fever causes an acute febrile illness consisting of chills, headaches, myalgia, retro-orbital pain, and malaise, which tend to occur within 3 to 5 days of the tick bite. Some cases may be accompanied by a nonspecific rash that may be morbilliform or petechial in appearance. Notably, approximately half of all patients will experience transient resolution of symptoms for 24 to 48 hours followed by a recurrence of fever, a phenomenon that has been referred to as saddleback fever. Routine laboratory findings may include leukopenia, thrombocytopenia, and a peripheral smear with atypical lymphocytes. Reverse transcription polymerase chain reaction is both sensitive and specific for detecting viral loads in the blood during the first week of infection, though testing does not alter management, which is largely supportive.⁸

Tularemia

Tularemia is a relatively rare disease but has been documented in every US state except Hawaii.⁹ The disease is caused by Francisella tularensis, a small, aerobic, gram-negative coccobacillus transmitted via inhalation, bitingflies, or tick bites; the most common ticks to transmit the disease include D andersoni, D variabilis, and A americanum.¹⁰ Clinical manifestations depend on the form of exposure, with tick bites most often resulting in an ulcerated skin lesion at the site of the vector bite accompanied by regional lymphadenopathy and systemic symptoms such as fever, chills, myalgia, and headache.¹¹ Mucosal manifestations such as pharyngitis, conjunctivitis, and other ocular lesions also are commonly seen. Diagnosis most frequently is made using serology because F tularensis is both challenging and dangerous to culture; in fact, because of the high risk of contagion, F tularensis should only be cultured in biosafety level 3 laboratories. Polymerase chain reaction assays can be used on tissue samples with decent sensitivity (78%) and specificity (96%); however, these assays cannot distinguish between Francisella subspecies and are not readily available to most clinicians.¹² First-line therapy for the treatment of tularemia is streptomycin given as twice-daily intramuscular injections over the course of 7 to 10 days. Alternative agents include gentamicin, ciprofloxacin, imipenem, doxycycline, and chloramphenicol.¹⁰ Because tularemia is relatively rare, a high index of suspicion is necessary to reduce the morbidity and mortality associated with the disease.

Tick Paralysis

More than 40 different species of ticks have been implicated worldwide as causes of tick paralysis, though D andersoni has been the most common in North America. Female patients account for most cases, possibly because long hair conceals ticks on the scalp or neck, the preferred attachment locations for Dermacentor ticks.¹³ The classic presentation of tick paralysis is an acute, flaccid, ascending paralysis that occurs from a neurotoxin in the tick saliva that impairs afferent nerve signal propagation.^14,15 The paralysis progresses over hours to days and typically occurs 5 to 6 days after attachment of the tick. Notably, there is no associated fever with tick paralysis, and without intervention, patients may die of respiratory failure. Overall, the condition carries a fatality rate of nearly 10%¹⁶ but reverses rapidly if the tick is identified and removed.

Protection against tick bites and tick-borne illnesses includes avoidance of infested areas, treatment of populated habitats with insecticide sprays, use of topical repellants prior to outdoor activities, and diligent full-body tick checks upon return from tick-heavy areas. Permethrin can be used to treat clothing and remains protective through multiple washings. Ticks typically survive washing of untreated clothing but are killed by prolonged drying in a dryer. Pets may be treated with oral, intramuscular, or topical agents prescribed by a veterinarian to prevent tick attachments.

Conclusion

Accurate identification of Dermacentor ticks allows for appropriate surveillance for associated diseases and can improve patient outcomes. Patients who engage in outdoor activities in endemic areas should take steps to avoid exposure, use appropriate acaricides and repellents, and perform tick checks after returning indoors.