Dirk M. Elston, MD

To the Editor:

Cutaneous collagenous vasculopathy (CCV) is an uncommon microangiopathy that presents with progressive telangiectases on the lower extremities that can eventually spread to involve the upper extremities and trunk. Systemic involvement is uncommon. The diagnosis is confirmed by biopsy, which demonstrates dilated capillaries and postcapillary venules with eosinophilic hyalinized walls. Treatment generally has focused on the use of vascular lasers.¹ We report a patient with advanced CCV and ocular involvement that responded to a combination of pulsed dye laser (PDL) therapy and sclerotherapy for cutaneous lesions.

A 63-year-old woman presented with partially blanchable, purple-black patches on the lower extremities (Figure 1). The upper extremities had minimal involvement at the time of presentation. A medical history revealed the lesions presented on the legs 10 years prior but were beginning to form on the arms. She had a history of hypertension and bleeding in the retina.

Histopathology revealed prominent dilation of postcapillary venules with eosinophilic collagenous materials in the vessel walls that was positive on periodic acid–Schiff stain, confirming the diagnosis of CCV. The perivascular collagenous material failed to stain with Congo red. Laboratory testing for serum protein electrophoresis, antinuclear antibodies, and baseline hematologic and metabolic panels revealed no abnormalities.

Over 3 years of treatment with PDL, most of the black patches resolved, but prominent telangiectatic vessels remained (Figure 2). Sclerotherapy with polidocanol (10 mg/mL) resulted in clearance of the majority of telangiectatic vessels. After each sclerotherapy treatment, Unna boots were applied for a minimum of 24 hours. The patient had no adverse effects from either PDL or sclerotherapy and was pleased with the results (Figure 3). An ophthalmologist had attributed the retinal bleeding to central serous chorioretinopathy, but tortuosity of superficial scleral and episcleral vessels progressed, suggesting CCV as the more likely cause (Figure 4). Currently, she is being followed for visual changes and further retinal bleeding.

Early CCV typically appears as blanchable pink or red macules, telangiectases, or petechiae on the lower extremities, progressing to involve the trunk and upper extremity.^1-3 In rare cases, CCV presents in a papular or annular variant instead of the typical telangiectatic form.^4,5 As the lesions progress, they often darken in appearance. Bleeding can occur, and the progressive patches are disfiguring.^6,7 Middle-aged to older adults typically present with CCV (range, 16–83 years), with a mean age of 62 years.^1,2,6 This disease affects both males and females, predominantly in White individuals.¹ Extracutaneous manifestations are rare.^1,2,6 One case of mucosal involvement was described in a patient with glossitis and oral erosions.⁸ We found no prior reports of nail or eye changes.^1,2

The etiology of CCV is unknown, but different theories have been proposed. One is that CCV is due to a genetic defect that changes collagen synthesis in the cutaneous microvasculature. Another more widely held belief is that CCV originates from an injury that occurs to the microvasculature endothelial cells. Regardless of the cause of the triggering injury, the result is induced intravascular occlusive microthrombi that cause perivascular fibrosis and endothelial hyperplasia.^2,6,7,9

Cutaneous collagenous vasculopathy may be influenced by systemic diseases. The most common comorbidities are hypertension, cardiovascular disease, diabetes mellitus, and hyperlipidemia.^1,3,6-8 The presentation of CCV with a malignancy is rare; 1 patient was diagnosed with multiple myeloma 18 months after CCV, and another patient’s cutaneous presentation led to discovery of pancreatic cancer with metastasis.^8,10 In this setting, the increased growth factors or hypercoagulability of malignancy may play a role in endothelial cell damage and hyperplasia. Autoimmune vascular injury also has been suggested to trigger CCV; 1 case involved antiribonucleoprotein antibodies, while another case involved anti–endothelial cell antibody assays.¹¹ In addition, CCV has been reported in hypercoagulable patients, demonstrating another route for endothelial damage, with 1 patient being heterozygous for prothrombin G20210A, a report of CCV in a patient with cryofibrinogenemia, and another patient being found positive for lupus anticoagulant.^11,12 Drugs also have been thought to influence CCV, including corticosteroids, lithium, thiothixene, interferon, isotretinoin, calcium channel blockers, antibiotics, hydroxyurea, and antidepressants.^7,11

The diagnosis of CCV is confirmed using light microscopy and collagen-specific immunostaining. Examination shows hyaline eosinophilic deposition of type IV collagen around the affected vessels, with the postcapillary venules showing characteristic duplication of the basal lamina.^3,9 The material stains positive with periodic acid-Schiff and Masson trichrome.³

Underreporting may contribute to the low incidence of CCV. The clinical presentation of CCV is similar to generalized essential telangiectasia, with biopsy distinguishing the two. Other diagnoses in the differential include hereditary hemorrhagic telangiectasia, which typically would have mucosal involvement; radiating telangiectatic mats and a strong family history; and hereditary benign telangiectasia, which typically presents in younger patients aged 1 year to adolescence.¹

Treatment with vascular lasers has been the main focus, using either the 595-nm PDL or the 1064-nm Nd:YAG laser.^6,13 Pulsed dye laser or intense pulsed light devices can improve patient well-being^1,2; intense pulsed light allows for a larger spot size and may be preferred in patients with a larger body surface area involved.¹³ However, a few other treatments have been proposed. One case report noted poor response to sclerotherapy.¹ In another case, a patient treated with a chemotherapy agent, bortezomib, for their concurrent multiple myeloma showed notable CCV cutaneous improvement. The proposed mechanism for bortezomib improving CCV is through its antiproliferative effect on endothelial cells of the superficial dermal vessels.⁸ Our patient did not achieve an adequate response with PDL, but the addition of sclerotherapy with polidocanol induced a successful response.

Patients should be examined for evidence of ocular involvement and referred to an ophthalmologist for appropriate care. Although there is no definite association with systemic illnesses or mediation, recent associations with an autoimmune disorder or underlying malignancy have been noted.^8,10,11 Age-appropriate cancer screening and attention to associated signs and symptoms are recommended.

To the Editor:

Cutaneous collagenous vasculopathy (CCV) is an uncommon microangiopathy that presents with progressive telangiectases on the lower extremities that can eventually spread to involve the upper extremities and trunk. Systemic involvement is uncommon. The diagnosis is confirmed by biopsy, which demonstrates dilated capillaries and postcapillary venules with eosinophilic hyalinized walls. Treatment generally has focused on the use of vascular lasers.¹ We report a patient with advanced CCV and ocular involvement that responded to a combination of pulsed dye laser (PDL) therapy and sclerotherapy for cutaneous lesions.

A 63-year-old woman presented with partially blanchable, purple-black patches on the lower extremities (Figure 1). The upper extremities had minimal involvement at the time of presentation. A medical history revealed the lesions presented on the legs 10 years prior but were beginning to form on the arms. She had a history of hypertension and bleeding in the retina.

Histopathology revealed prominent dilation of postcapillary venules with eosinophilic collagenous materials in the vessel walls that was positive on periodic acid–Schiff stain, confirming the diagnosis of CCV. The perivascular collagenous material failed to stain with Congo red. Laboratory testing for serum protein electrophoresis, antinuclear antibodies, and baseline hematologic and metabolic panels revealed no abnormalities.

Over 3 years of treatment with PDL, most of the black patches resolved, but prominent telangiectatic vessels remained (Figure 2). Sclerotherapy with polidocanol (10 mg/mL) resulted in clearance of the majority of telangiectatic vessels. After each sclerotherapy treatment, Unna boots were applied for a minimum of 24 hours. The patient had no adverse effects from either PDL or sclerotherapy and was pleased with the results (Figure 3). An ophthalmologist had attributed the retinal bleeding to central serous chorioretinopathy, but tortuosity of superficial scleral and episcleral vessels progressed, suggesting CCV as the more likely cause (Figure 4). Currently, she is being followed for visual changes and further retinal bleeding.

Early CCV typically appears as blanchable pink or red macules, telangiectases, or petechiae on the lower extremities, progressing to involve the trunk and upper extremity.^1-3 In rare cases, CCV presents in a papular or annular variant instead of the typical telangiectatic form.^4,5 As the lesions progress, they often darken in appearance. Bleeding can occur, and the progressive patches are disfiguring.^6,7 Middle-aged to older adults typically present with CCV (range, 16–83 years), with a mean age of 62 years.^1,2,6 This disease affects both males and females, predominantly in White individuals.¹ Extracutaneous manifestations are rare.^1,2,6 One case of mucosal involvement was described in a patient with glossitis and oral erosions.⁸ We found no prior reports of nail or eye changes.^1,2

The etiology of CCV is unknown, but different theories have been proposed. One is that CCV is due to a genetic defect that changes collagen synthesis in the cutaneous microvasculature. Another more widely held belief is that CCV originates from an injury that occurs to the microvasculature endothelial cells. Regardless of the cause of the triggering injury, the result is induced intravascular occlusive microthrombi that cause perivascular fibrosis and endothelial hyperplasia.^2,6,7,9

Cutaneous collagenous vasculopathy may be influenced by systemic diseases. The most common comorbidities are hypertension, cardiovascular disease, diabetes mellitus, and hyperlipidemia.^1,3,6-8 The presentation of CCV with a malignancy is rare; 1 patient was diagnosed with multiple myeloma 18 months after CCV, and another patient’s cutaneous presentation led to discovery of pancreatic cancer with metastasis.^8,10 In this setting, the increased growth factors or hypercoagulability of malignancy may play a role in endothelial cell damage and hyperplasia. Autoimmune vascular injury also has been suggested to trigger CCV; 1 case involved antiribonucleoprotein antibodies, while another case involved anti–endothelial cell antibody assays.¹¹ In addition, CCV has been reported in hypercoagulable patients, demonstrating another route for endothelial damage, with 1 patient being heterozygous for prothrombin G20210A, a report of CCV in a patient with cryofibrinogenemia, and another patient being found positive for lupus anticoagulant.^11,12 Drugs also have been thought to influence CCV, including corticosteroids, lithium, thiothixene, interferon, isotretinoin, calcium channel blockers, antibiotics, hydroxyurea, and antidepressants.^7,11

The diagnosis of CCV is confirmed using light microscopy and collagen-specific immunostaining. Examination shows hyaline eosinophilic deposition of type IV collagen around the affected vessels, with the postcapillary venules showing characteristic duplication of the basal lamina.^3,9 The material stains positive with periodic acid-Schiff and Masson trichrome.³

Underreporting may contribute to the low incidence of CCV. The clinical presentation of CCV is similar to generalized essential telangiectasia, with biopsy distinguishing the two. Other diagnoses in the differential include hereditary hemorrhagic telangiectasia, which typically would have mucosal involvement; radiating telangiectatic mats and a strong family history; and hereditary benign telangiectasia, which typically presents in younger patients aged 1 year to adolescence.¹

Treatment with vascular lasers has been the main focus, using either the 595-nm PDL or the 1064-nm Nd:YAG laser.^6,13 Pulsed dye laser or intense pulsed light devices can improve patient well-being^1,2; intense pulsed light allows for a larger spot size and may be preferred in patients with a larger body surface area involved.¹³ However, a few other treatments have been proposed. One case report noted poor response to sclerotherapy.¹ In another case, a patient treated with a chemotherapy agent, bortezomib, for their concurrent multiple myeloma showed notable CCV cutaneous improvement. The proposed mechanism for bortezomib improving CCV is through its antiproliferative effect on endothelial cells of the superficial dermal vessels.⁸ Our patient did not achieve an adequate response with PDL, but the addition of sclerotherapy with polidocanol induced a successful response.

Patients should be examined for evidence of ocular involvement and referred to an ophthalmologist for appropriate care. Although there is no definite association with systemic illnesses or mediation, recent associations with an autoimmune disorder or underlying malignancy have been noted.^8,10,11 Age-appropriate cancer screening and attention to associated signs and symptoms are recommended.

To the Editor:

Cutaneous collagenous vasculopathy (CCV) is an uncommon microangiopathy that presents with progressive telangiectases on the lower extremities that can eventually spread to involve the upper extremities and trunk. Systemic involvement is uncommon. The diagnosis is confirmed by biopsy, which demonstrates dilated capillaries and postcapillary venules with eosinophilic hyalinized walls. Treatment generally has focused on the use of vascular lasers.¹ We report a patient with advanced CCV and ocular involvement that responded to a combination of pulsed dye laser (PDL) therapy and sclerotherapy for cutaneous lesions.

A 63-year-old woman presented with partially blanchable, purple-black patches on the lower extremities (Figure 1). The upper extremities had minimal involvement at the time of presentation. A medical history revealed the lesions presented on the legs 10 years prior but were beginning to form on the arms. She had a history of hypertension and bleeding in the retina.

Histopathology revealed prominent dilation of postcapillary venules with eosinophilic collagenous materials in the vessel walls that was positive on periodic acid–Schiff stain, confirming the diagnosis of CCV. The perivascular collagenous material failed to stain with Congo red. Laboratory testing for serum protein electrophoresis, antinuclear antibodies, and baseline hematologic and metabolic panels revealed no abnormalities.

Over 3 years of treatment with PDL, most of the black patches resolved, but prominent telangiectatic vessels remained (Figure 2). Sclerotherapy with polidocanol (10 mg/mL) resulted in clearance of the majority of telangiectatic vessels. After each sclerotherapy treatment, Unna boots were applied for a minimum of 24 hours. The patient had no adverse effects from either PDL or sclerotherapy and was pleased with the results (Figure 3). An ophthalmologist had attributed the retinal bleeding to central serous chorioretinopathy, but tortuosity of superficial scleral and episcleral vessels progressed, suggesting CCV as the more likely cause (Figure 4). Currently, she is being followed for visual changes and further retinal bleeding.

Early CCV typically appears as blanchable pink or red macules, telangiectases, or petechiae on the lower extremities, progressing to involve the trunk and upper extremity.^1-3 In rare cases, CCV presents in a papular or annular variant instead of the typical telangiectatic form.^4,5 As the lesions progress, they often darken in appearance. Bleeding can occur, and the progressive patches are disfiguring.^6,7 Middle-aged to older adults typically present with CCV (range, 16–83 years), with a mean age of 62 years.^1,2,6 This disease affects both males and females, predominantly in White individuals.¹ Extracutaneous manifestations are rare.^1,2,6 One case of mucosal involvement was described in a patient with glossitis and oral erosions.⁸ We found no prior reports of nail or eye changes.^1,2

The etiology of CCV is unknown, but different theories have been proposed. One is that CCV is due to a genetic defect that changes collagen synthesis in the cutaneous microvasculature. Another more widely held belief is that CCV originates from an injury that occurs to the microvasculature endothelial cells. Regardless of the cause of the triggering injury, the result is induced intravascular occlusive microthrombi that cause perivascular fibrosis and endothelial hyperplasia.^2,6,7,9

Cutaneous collagenous vasculopathy may be influenced by systemic diseases. The most common comorbidities are hypertension, cardiovascular disease, diabetes mellitus, and hyperlipidemia.^1,3,6-8 The presentation of CCV with a malignancy is rare; 1 patient was diagnosed with multiple myeloma 18 months after CCV, and another patient’s cutaneous presentation led to discovery of pancreatic cancer with metastasis.^8,10 In this setting, the increased growth factors or hypercoagulability of malignancy may play a role in endothelial cell damage and hyperplasia. Autoimmune vascular injury also has been suggested to trigger CCV; 1 case involved antiribonucleoprotein antibodies, while another case involved anti–endothelial cell antibody assays.¹¹ In addition, CCV has been reported in hypercoagulable patients, demonstrating another route for endothelial damage, with 1 patient being heterozygous for prothrombin G20210A, a report of CCV in a patient with cryofibrinogenemia, and another patient being found positive for lupus anticoagulant.^11,12 Drugs also have been thought to influence CCV, including corticosteroids, lithium, thiothixene, interferon, isotretinoin, calcium channel blockers, antibiotics, hydroxyurea, and antidepressants.^7,11

The diagnosis of CCV is confirmed using light microscopy and collagen-specific immunostaining. Examination shows hyaline eosinophilic deposition of type IV collagen around the affected vessels, with the postcapillary venules showing characteristic duplication of the basal lamina.^3,9 The material stains positive with periodic acid-Schiff and Masson trichrome.³

Underreporting may contribute to the low incidence of CCV. The clinical presentation of CCV is similar to generalized essential telangiectasia, with biopsy distinguishing the two. Other diagnoses in the differential include hereditary hemorrhagic telangiectasia, which typically would have mucosal involvement; radiating telangiectatic mats and a strong family history; and hereditary benign telangiectasia, which typically presents in younger patients aged 1 year to adolescence.¹

Treatment with vascular lasers has been the main focus, using either the 595-nm PDL or the 1064-nm Nd:YAG laser.^6,13 Pulsed dye laser or intense pulsed light devices can improve patient well-being^1,2; intense pulsed light allows for a larger spot size and may be preferred in patients with a larger body surface area involved.¹³ However, a few other treatments have been proposed. One case report noted poor response to sclerotherapy.¹ In another case, a patient treated with a chemotherapy agent, bortezomib, for their concurrent multiple myeloma showed notable CCV cutaneous improvement. The proposed mechanism for bortezomib improving CCV is through its antiproliferative effect on endothelial cells of the superficial dermal vessels.⁸ Our patient did not achieve an adequate response with PDL, but the addition of sclerotherapy with polidocanol induced a successful response.

Patients should be examined for evidence of ocular involvement and referred to an ophthalmologist for appropriate care. Although there is no definite association with systemic illnesses or mediation, recent associations with an autoimmune disorder or underlying malignancy have been noted.^8,10,11 Age-appropriate cancer screening and attention to associated signs and symptoms are recommended.

Classification

Triatomine bugs (Triatoma) and the wheel bug (Arilus cristatus) are part of the family Reduviidae (order Hemiptera, a name that describes the sucking proboscis on the front of the insect’s head).^1,2 Both arthropods are found in multiple countries and are especially common in warmer areas, including in the United States, where they can be seen from Texas to California.^3,4 Because blood-feeding triatomines need a blood meal to survive while laying eggs and then throughout their 5 developmental nymph stages to undergo molting, they feed on mammals, such as opossums, raccoons, pack rats, and armadillos, whereas wheel bugs mainly prey on soft-bodied insects.^1,4-6

Triatoma bugs seek cutaneous blood vessels using thermosensors in their antennae to locate blood flow under the skin for feeding. After inserting the proboscis, they release nitric oxide and an anticoagulant that allows for continuous blood flow while feeding.⁷ It has been reported that triatomine bugs are not able to bite through clothing, instead seeking exposed skin, particularly near mucous membranes, such as the hands, arms, feet, head, and trunk. The name kissing bug for triatomines was coined because bites near the mouth are common.⁶ The bite typically is painless and occurs mainly at night when the insect is most active. After obtaining a blood meal, triatomine bugs seek shelter and hide in mud and daub structures, cracks, crevices, and furniture.^1,8

Unlike Triatoma species, A cristatus does not require a blood meal for development and survival, leading it to prey on soft-bodied insects. Piercing prey with the proboscis, wheel bugs inject a toxin to digest the contents and suck the digested contents through this apparatus.⁴ Because the wheel bug does not require a blood meal, it typically bites a human only for defense if it feels threatened. Unlike the painless bite of a triatomine bug, the bite of A cristatus is extremely painful; it has been described as the worst arthropod bite—worse than a hornet’s sting. The pain from the bite is caused by the toxin being injected into the skin; possible retention of the proboscis makes the pain worse.^4,9 In addition, when A cristatus is disturbed, it exudes pungent material from a pair of bright orange subrectal glands while stridulating to repulse predators.⁹

Although Triatoma species and A cristatus have separate roles in nature and vastly different impacts on health, they often are mistaken for the same arthropod when seen in nature. Features that members of Reduviidae share include large bodies (relative to their overall length); long thin legs; a narrow head; wings; and a long sucking proboscis on the front of the head.¹⁰

Characteristics that differentiate Triatoma and A cristatus species include size, color, and distinctive markings. Most triatomine bugs are 12- to 36-mm long; are dark brown or black; and have what are called tiger-stripe orange markings on the peripheral two-thirds of the body (Figure 1).¹¹ In contrast, wheel bugs commonly are bigger—measuring longer than 1.25 inches—and gray, with a cogwheel-like structure on the thorax (Figure 2).¹⁰

Dermatologic Presentation and Clinical Symptoms

The area of involved skin on patients presenting with Triatoma or A cristatus bites may resemble other insect bites. Many bites from Triatoma bugs and A cristatus initially present as an erythematous, raised, pruritic papule with a central punctum that is visible because of the involvement of the proboscis. However, other presentations of bites from both arthropods have been reported^4,6,7: grouped vesicles on an erythematous base; indurated, giant, urticarial-type wheels measuring 10 to 15 mm in diameter; and hemorrhagic bullous nodules (Figure 3). Associated lymphangitis or lymphadenitis is typical of the latter 2 variations.⁶ These variations in presentation can be mistaken for other causes of similarly presenting lesions, such as shingles or spider bites, leading to delayed or missed diagnosis.

Patients may present with a single bite or multiple bites due to the feeding pattern of Triatoma bugs; if the host moves or disrupts its feeding, the arthropod takes multiple bites to finish feeding.⁸ In comparison, 4 common variations of wheel bug bites have been reported: (1) a painful bite without complications; (2) a cutaneous horn and papilloma at the site of toxin injection; (3) a necrotic ulcer around the central punctum caused by injected toxin; and (4) an abscess under the central punctum due to secondary infection.⁴

Anaphylaxis—Although the bites of Triatoma and A cristatus present differently, both can cause anaphylaxis. Triatoma is implicated more often than A cristatus as the cause of anaphylaxis.¹² In fact, Triatoma bites are among the more common causes of anaphylaxis from bug bites, with multiple cases of these reactions reported in the literature.^12,13

Symptoms of Triatoma anaphylaxis include acute-onset urticarial rash, flushing, dyspnea, wheezing, nausea, vomiting, and localized edema.² The cause of anaphylaxis is proteins in Triatoma saliva, including 20-kDa procalin, which incites the systemic reaction. Other potential causes of anaphylaxis include serine protease, which has similarities to salivary protein and desmoglein in humans.¹¹

The degree of reaction to a bite depends on the patient's sensitization to antigenic proteins in each insect’s saliva.^4,6 Patients who have a bite from a triatomine bug are at risk for subsequent bites, as household infestation is likely due to the pliability of the insect, allowing it to hide in small spaces unnoticed.⁸ In the case of a bite from Triatoma or A cristatus, sensitization may lead to severe and worsening reactions with subsequent bites, which ultimately can result in life-threatening anaphylaxis.^1,6

Treatment and Prevention

Treatment of Triatoma and A cristatus bites depends on the severity of the patient’s reaction to the bite. A local reaction to a bite from either insect can be treated supportively with local corticosteroids and antihistamines.³ If the patient is sensitized to proteins associated with a bite, standard anaphylaxis treatment such as epinephrine and intravenous antihistamines may be indicated.¹⁴ Secondary infection can be treated with antibiotics; a formed abscess might need to be drained or debrided.¹⁵

There’s No Place Like Home—Because Triatoma bugs have a pliable exoskeleton and can squeeze into small spaces, they commonly infest dwellings where they find multiple attractants: light, heat, carbon dioxide, and lactic acid.⁸ The more household occupants (including pets), the higher the levels of carbon dioxide and lactic acid, thus the greater the attraction. Infestation of a home can lead to the spread of diseases harbored by Triatoma, including Chagas disease, which is caused by the parasite Trypanosoma cruzi.⁵

Preventive measures can be taken to reduce the risk and extent of home infestation by Triatoma bugs, including insecticides, a solid foundation, window screens, air conditioning, sealing of cracks and crevices, outdoor light management, and removal of clutter throughout the house.⁸ Because Triatoma bugs cannot bite through clothing, protective clothing and bug repellent on exposed skin can be employed. Another degree of protection is offered by pest management, especially control of rodents by removing food, water, and nests in areas where triatomine bugs feed off of that population.^8,14

Unlike triatomine bugs, wheel bugs tend not to invade houses; therefore, these preventive measures are unnecessary. If a wheel bug is identified, do not engage the arthropod due to the defensive nature of its attack.^4,9 Such deliberate avoidance should ensure protection from the wheel bug’s painful bite.

Medical Complications

Although triatomine bugs and wheel bugs are in the same taxonomic family, subsequent infection is unique to Triatoma bugs because they need a blood meal to survive. Because Triatoma bugs feed on mammals, they present an increased opportunity for transmitting the causative agents of infection from hosts on which they have fed.¹² The principal parasite transmitted by triatomines is T cruzi, which causes Chagas disease and lives in the gastrointestinal (GI) tract of the insect.⁵ When a triatomine bug seeks out a mucosal surface to bite, including the mouth, it defecates and urinates during or shortly after feeding, leading to contamination of the initial wound or mucosal surfaces. In addition, Triatoma bugs are vectors for transmission of Serratia marcescans, Bartonella henselae, and Mycobacterium leprae.¹⁶

Chagas Disease—This infection has 3 stages: acute, intermediate, and chronic.⁵ The acute stage can present with symptoms of conjunctivitis, fever, lymphadenopathy, hepatosplenomegaly, and anemia. The intermediate stage typically is asymptomatic. The chronic stage usually involves the heart and GI tract and causes cardiac aneurysms, cardiomegaly, megacolon, and megaesophagus. Initial symptoms can be a localized nodule (chagoma) at the inoculation site, fever, fatigue, lymphadenopathy, and hepatosplenomegaly.² Unilateral palpebral edema with associated lymphadenopathy (Romaña sign) also can be seen—not to be confused with bilateral swelling in an acute reaction to an insect bite. Romaña sign is pathognomonic of T cruzi infection; bilateral palpebral swelling is typical of an allergic reaction.¹²

Identification of a triatomine bite is the first step in diagnosing Chagas disease, which can be life-threatening. Among chronic carriers of Chagas disease, 30% develop GI and cardiac symptoms, of which 20% to 30% develop cardiomyopathy, with serious symptoms that present 10 to 20 years after the asymptomatic intermediate phase.²

Chagas disease is endemic to Central and South America but is also seen in North America; 28,000 new cases are reported annually in South America and North America combined. Human migration from endemic areas and from rural to urban areas has promoted the spread of Chagas disease.² However, patients in the United States have a relatively low risk for Chagas disease, largely because of the quality of housing construction and use of insecticides.

Treatment options for Chagas disease include nifurtimox and benznidazole. Without treatment, the host immune response typically controls acute replication of the parasite but will lead to a chronic state, ultimately involving the heart and GI tract.⁵

Classification

Triatomine bugs (Triatoma) and the wheel bug (Arilus cristatus) are part of the family Reduviidae (order Hemiptera, a name that describes the sucking proboscis on the front of the insect’s head).^1,2 Both arthropods are found in multiple countries and are especially common in warmer areas, including in the United States, where they can be seen from Texas to California.^3,4 Because blood-feeding triatomines need a blood meal to survive while laying eggs and then throughout their 5 developmental nymph stages to undergo molting, they feed on mammals, such as opossums, raccoons, pack rats, and armadillos, whereas wheel bugs mainly prey on soft-bodied insects.^1,4-6

Triatoma bugs seek cutaneous blood vessels using thermosensors in their antennae to locate blood flow under the skin for feeding. After inserting the proboscis, they release nitric oxide and an anticoagulant that allows for continuous blood flow while feeding.⁷ It has been reported that triatomine bugs are not able to bite through clothing, instead seeking exposed skin, particularly near mucous membranes, such as the hands, arms, feet, head, and trunk. The name kissing bug for triatomines was coined because bites near the mouth are common.⁶ The bite typically is painless and occurs mainly at night when the insect is most active. After obtaining a blood meal, triatomine bugs seek shelter and hide in mud and daub structures, cracks, crevices, and furniture.^1,8

Unlike Triatoma species, A cristatus does not require a blood meal for development and survival, leading it to prey on soft-bodied insects. Piercing prey with the proboscis, wheel bugs inject a toxin to digest the contents and suck the digested contents through this apparatus.⁴ Because the wheel bug does not require a blood meal, it typically bites a human only for defense if it feels threatened. Unlike the painless bite of a triatomine bug, the bite of A cristatus is extremely painful; it has been described as the worst arthropod bite—worse than a hornet’s sting. The pain from the bite is caused by the toxin being injected into the skin; possible retention of the proboscis makes the pain worse.^4,9 In addition, when A cristatus is disturbed, it exudes pungent material from a pair of bright orange subrectal glands while stridulating to repulse predators.⁹

Although Triatoma species and A cristatus have separate roles in nature and vastly different impacts on health, they often are mistaken for the same arthropod when seen in nature. Features that members of Reduviidae share include large bodies (relative to their overall length); long thin legs; a narrow head; wings; and a long sucking proboscis on the front of the head.¹⁰

Characteristics that differentiate Triatoma and A cristatus species include size, color, and distinctive markings. Most triatomine bugs are 12- to 36-mm long; are dark brown or black; and have what are called tiger-stripe orange markings on the peripheral two-thirds of the body (Figure 1).¹¹ In contrast, wheel bugs commonly are bigger—measuring longer than 1.25 inches—and gray, with a cogwheel-like structure on the thorax (Figure 2).¹⁰

Dermatologic Presentation and Clinical Symptoms

The area of involved skin on patients presenting with Triatoma or A cristatus bites may resemble other insect bites. Many bites from Triatoma bugs and A cristatus initially present as an erythematous, raised, pruritic papule with a central punctum that is visible because of the involvement of the proboscis. However, other presentations of bites from both arthropods have been reported^4,6,7: grouped vesicles on an erythematous base; indurated, giant, urticarial-type wheels measuring 10 to 15 mm in diameter; and hemorrhagic bullous nodules (Figure 3). Associated lymphangitis or lymphadenitis is typical of the latter 2 variations.⁶ These variations in presentation can be mistaken for other causes of similarly presenting lesions, such as shingles or spider bites, leading to delayed or missed diagnosis.

Patients may present with a single bite or multiple bites due to the feeding pattern of Triatoma bugs; if the host moves or disrupts its feeding, the arthropod takes multiple bites to finish feeding.⁸ In comparison, 4 common variations of wheel bug bites have been reported: (1) a painful bite without complications; (2) a cutaneous horn and papilloma at the site of toxin injection; (3) a necrotic ulcer around the central punctum caused by injected toxin; and (4) an abscess under the central punctum due to secondary infection.⁴

Anaphylaxis—Although the bites of Triatoma and A cristatus present differently, both can cause anaphylaxis. Triatoma is implicated more often than A cristatus as the cause of anaphylaxis.¹² In fact, Triatoma bites are among the more common causes of anaphylaxis from bug bites, with multiple cases of these reactions reported in the literature.^12,13

Symptoms of Triatoma anaphylaxis include acute-onset urticarial rash, flushing, dyspnea, wheezing, nausea, vomiting, and localized edema.² The cause of anaphylaxis is proteins in Triatoma saliva, including 20-kDa procalin, which incites the systemic reaction. Other potential causes of anaphylaxis include serine protease, which has similarities to salivary protein and desmoglein in humans.¹¹

The degree of reaction to a bite depends on the patient's sensitization to antigenic proteins in each insect’s saliva.^4,6 Patients who have a bite from a triatomine bug are at risk for subsequent bites, as household infestation is likely due to the pliability of the insect, allowing it to hide in small spaces unnoticed.⁸ In the case of a bite from Triatoma or A cristatus, sensitization may lead to severe and worsening reactions with subsequent bites, which ultimately can result in life-threatening anaphylaxis.^1,6

Treatment and Prevention

Treatment of Triatoma and A cristatus bites depends on the severity of the patient’s reaction to the bite. A local reaction to a bite from either insect can be treated supportively with local corticosteroids and antihistamines.³ If the patient is sensitized to proteins associated with a bite, standard anaphylaxis treatment such as epinephrine and intravenous antihistamines may be indicated.¹⁴ Secondary infection can be treated with antibiotics; a formed abscess might need to be drained or debrided.¹⁵

There’s No Place Like Home—Because Triatoma bugs have a pliable exoskeleton and can squeeze into small spaces, they commonly infest dwellings where they find multiple attractants: light, heat, carbon dioxide, and lactic acid.⁸ The more household occupants (including pets), the higher the levels of carbon dioxide and lactic acid, thus the greater the attraction. Infestation of a home can lead to the spread of diseases harbored by Triatoma, including Chagas disease, which is caused by the parasite Trypanosoma cruzi.⁵

Preventive measures can be taken to reduce the risk and extent of home infestation by Triatoma bugs, including insecticides, a solid foundation, window screens, air conditioning, sealing of cracks and crevices, outdoor light management, and removal of clutter throughout the house.⁸ Because Triatoma bugs cannot bite through clothing, protective clothing and bug repellent on exposed skin can be employed. Another degree of protection is offered by pest management, especially control of rodents by removing food, water, and nests in areas where triatomine bugs feed off of that population.^8,14

Unlike triatomine bugs, wheel bugs tend not to invade houses; therefore, these preventive measures are unnecessary. If a wheel bug is identified, do not engage the arthropod due to the defensive nature of its attack.^4,9 Such deliberate avoidance should ensure protection from the wheel bug’s painful bite.

Medical Complications

Although triatomine bugs and wheel bugs are in the same taxonomic family, subsequent infection is unique to Triatoma bugs because they need a blood meal to survive. Because Triatoma bugs feed on mammals, they present an increased opportunity for transmitting the causative agents of infection from hosts on which they have fed.¹² The principal parasite transmitted by triatomines is T cruzi, which causes Chagas disease and lives in the gastrointestinal (GI) tract of the insect.⁵ When a triatomine bug seeks out a mucosal surface to bite, including the mouth, it defecates and urinates during or shortly after feeding, leading to contamination of the initial wound or mucosal surfaces. In addition, Triatoma bugs are vectors for transmission of Serratia marcescans, Bartonella henselae, and Mycobacterium leprae.¹⁶

Chagas Disease—This infection has 3 stages: acute, intermediate, and chronic.⁵ The acute stage can present with symptoms of conjunctivitis, fever, lymphadenopathy, hepatosplenomegaly, and anemia. The intermediate stage typically is asymptomatic. The chronic stage usually involves the heart and GI tract and causes cardiac aneurysms, cardiomegaly, megacolon, and megaesophagus. Initial symptoms can be a localized nodule (chagoma) at the inoculation site, fever, fatigue, lymphadenopathy, and hepatosplenomegaly.² Unilateral palpebral edema with associated lymphadenopathy (Romaña sign) also can be seen—not to be confused with bilateral swelling in an acute reaction to an insect bite. Romaña sign is pathognomonic of T cruzi infection; bilateral palpebral swelling is typical of an allergic reaction.¹²

Identification of a triatomine bite is the first step in diagnosing Chagas disease, which can be life-threatening. Among chronic carriers of Chagas disease, 30% develop GI and cardiac symptoms, of which 20% to 30% develop cardiomyopathy, with serious symptoms that present 10 to 20 years after the asymptomatic intermediate phase.²

Chagas disease is endemic to Central and South America but is also seen in North America; 28,000 new cases are reported annually in South America and North America combined. Human migration from endemic areas and from rural to urban areas has promoted the spread of Chagas disease.² However, patients in the United States have a relatively low risk for Chagas disease, largely because of the quality of housing construction and use of insecticides.

Treatment options for Chagas disease include nifurtimox and benznidazole. Without treatment, the host immune response typically controls acute replication of the parasite but will lead to a chronic state, ultimately involving the heart and GI tract.⁵

Classification

Triatomine bugs (Triatoma) and the wheel bug (Arilus cristatus) are part of the family Reduviidae (order Hemiptera, a name that describes the sucking proboscis on the front of the insect’s head).^1,2 Both arthropods are found in multiple countries and are especially common in warmer areas, including in the United States, where they can be seen from Texas to California.^3,4 Because blood-feeding triatomines need a blood meal to survive while laying eggs and then throughout their 5 developmental nymph stages to undergo molting, they feed on mammals, such as opossums, raccoons, pack rats, and armadillos, whereas wheel bugs mainly prey on soft-bodied insects.^1,4-6

Triatoma bugs seek cutaneous blood vessels using thermosensors in their antennae to locate blood flow under the skin for feeding. After inserting the proboscis, they release nitric oxide and an anticoagulant that allows for continuous blood flow while feeding.⁷ It has been reported that triatomine bugs are not able to bite through clothing, instead seeking exposed skin, particularly near mucous membranes, such as the hands, arms, feet, head, and trunk. The name kissing bug for triatomines was coined because bites near the mouth are common.⁶ The bite typically is painless and occurs mainly at night when the insect is most active. After obtaining a blood meal, triatomine bugs seek shelter and hide in mud and daub structures, cracks, crevices, and furniture.^1,8

Unlike Triatoma species, A cristatus does not require a blood meal for development and survival, leading it to prey on soft-bodied insects. Piercing prey with the proboscis, wheel bugs inject a toxin to digest the contents and suck the digested contents through this apparatus.⁴ Because the wheel bug does not require a blood meal, it typically bites a human only for defense if it feels threatened. Unlike the painless bite of a triatomine bug, the bite of A cristatus is extremely painful; it has been described as the worst arthropod bite—worse than a hornet’s sting. The pain from the bite is caused by the toxin being injected into the skin; possible retention of the proboscis makes the pain worse.^4,9 In addition, when A cristatus is disturbed, it exudes pungent material from a pair of bright orange subrectal glands while stridulating to repulse predators.⁹

Although Triatoma species and A cristatus have separate roles in nature and vastly different impacts on health, they often are mistaken for the same arthropod when seen in nature. Features that members of Reduviidae share include large bodies (relative to their overall length); long thin legs; a narrow head; wings; and a long sucking proboscis on the front of the head.¹⁰

Characteristics that differentiate Triatoma and A cristatus species include size, color, and distinctive markings. Most triatomine bugs are 12- to 36-mm long; are dark brown or black; and have what are called tiger-stripe orange markings on the peripheral two-thirds of the body (Figure 1).¹¹ In contrast, wheel bugs commonly are bigger—measuring longer than 1.25 inches—and gray, with a cogwheel-like structure on the thorax (Figure 2).¹⁰

Dermatologic Presentation and Clinical Symptoms

The area of involved skin on patients presenting with Triatoma or A cristatus bites may resemble other insect bites. Many bites from Triatoma bugs and A cristatus initially present as an erythematous, raised, pruritic papule with a central punctum that is visible because of the involvement of the proboscis. However, other presentations of bites from both arthropods have been reported^4,6,7: grouped vesicles on an erythematous base; indurated, giant, urticarial-type wheels measuring 10 to 15 mm in diameter; and hemorrhagic bullous nodules (Figure 3). Associated lymphangitis or lymphadenitis is typical of the latter 2 variations.⁶ These variations in presentation can be mistaken for other causes of similarly presenting lesions, such as shingles or spider bites, leading to delayed or missed diagnosis.

Patients may present with a single bite or multiple bites due to the feeding pattern of Triatoma bugs; if the host moves or disrupts its feeding, the arthropod takes multiple bites to finish feeding.⁸ In comparison, 4 common variations of wheel bug bites have been reported: (1) a painful bite without complications; (2) a cutaneous horn and papilloma at the site of toxin injection; (3) a necrotic ulcer around the central punctum caused by injected toxin; and (4) an abscess under the central punctum due to secondary infection.⁴

Anaphylaxis—Although the bites of Triatoma and A cristatus present differently, both can cause anaphylaxis. Triatoma is implicated more often than A cristatus as the cause of anaphylaxis.¹² In fact, Triatoma bites are among the more common causes of anaphylaxis from bug bites, with multiple cases of these reactions reported in the literature.^12,13

Symptoms of Triatoma anaphylaxis include acute-onset urticarial rash, flushing, dyspnea, wheezing, nausea, vomiting, and localized edema.² The cause of anaphylaxis is proteins in Triatoma saliva, including 20-kDa procalin, which incites the systemic reaction. Other potential causes of anaphylaxis include serine protease, which has similarities to salivary protein and desmoglein in humans.¹¹

The degree of reaction to a bite depends on the patient's sensitization to antigenic proteins in each insect’s saliva.^4,6 Patients who have a bite from a triatomine bug are at risk for subsequent bites, as household infestation is likely due to the pliability of the insect, allowing it to hide in small spaces unnoticed.⁸ In the case of a bite from Triatoma or A cristatus, sensitization may lead to severe and worsening reactions with subsequent bites, which ultimately can result in life-threatening anaphylaxis.^1,6

Treatment and Prevention

Treatment of Triatoma and A cristatus bites depends on the severity of the patient’s reaction to the bite. A local reaction to a bite from either insect can be treated supportively with local corticosteroids and antihistamines.³ If the patient is sensitized to proteins associated with a bite, standard anaphylaxis treatment such as epinephrine and intravenous antihistamines may be indicated.¹⁴ Secondary infection can be treated with antibiotics; a formed abscess might need to be drained or debrided.¹⁵

There’s No Place Like Home—Because Triatoma bugs have a pliable exoskeleton and can squeeze into small spaces, they commonly infest dwellings where they find multiple attractants: light, heat, carbon dioxide, and lactic acid.⁸ The more household occupants (including pets), the higher the levels of carbon dioxide and lactic acid, thus the greater the attraction. Infestation of a home can lead to the spread of diseases harbored by Triatoma, including Chagas disease, which is caused by the parasite Trypanosoma cruzi.⁵

Preventive measures can be taken to reduce the risk and extent of home infestation by Triatoma bugs, including insecticides, a solid foundation, window screens, air conditioning, sealing of cracks and crevices, outdoor light management, and removal of clutter throughout the house.⁸ Because Triatoma bugs cannot bite through clothing, protective clothing and bug repellent on exposed skin can be employed. Another degree of protection is offered by pest management, especially control of rodents by removing food, water, and nests in areas where triatomine bugs feed off of that population.^8,14

Unlike triatomine bugs, wheel bugs tend not to invade houses; therefore, these preventive measures are unnecessary. If a wheel bug is identified, do not engage the arthropod due to the defensive nature of its attack.^4,9 Such deliberate avoidance should ensure protection from the wheel bug’s painful bite.

Medical Complications

Although triatomine bugs and wheel bugs are in the same taxonomic family, subsequent infection is unique to Triatoma bugs because they need a blood meal to survive. Because Triatoma bugs feed on mammals, they present an increased opportunity for transmitting the causative agents of infection from hosts on which they have fed.¹² The principal parasite transmitted by triatomines is T cruzi, which causes Chagas disease and lives in the gastrointestinal (GI) tract of the insect.⁵ When a triatomine bug seeks out a mucosal surface to bite, including the mouth, it defecates and urinates during or shortly after feeding, leading to contamination of the initial wound or mucosal surfaces. In addition, Triatoma bugs are vectors for transmission of Serratia marcescans, Bartonella henselae, and Mycobacterium leprae.¹⁶

Chagas Disease—This infection has 3 stages: acute, intermediate, and chronic.⁵ The acute stage can present with symptoms of conjunctivitis, fever, lymphadenopathy, hepatosplenomegaly, and anemia. The intermediate stage typically is asymptomatic. The chronic stage usually involves the heart and GI tract and causes cardiac aneurysms, cardiomegaly, megacolon, and megaesophagus. Initial symptoms can be a localized nodule (chagoma) at the inoculation site, fever, fatigue, lymphadenopathy, and hepatosplenomegaly.² Unilateral palpebral edema with associated lymphadenopathy (Romaña sign) also can be seen—not to be confused with bilateral swelling in an acute reaction to an insect bite. Romaña sign is pathognomonic of T cruzi infection; bilateral palpebral swelling is typical of an allergic reaction.¹²

Identification of a triatomine bite is the first step in diagnosing Chagas disease, which can be life-threatening. Among chronic carriers of Chagas disease, 30% develop GI and cardiac symptoms, of which 20% to 30% develop cardiomyopathy, with serious symptoms that present 10 to 20 years after the asymptomatic intermediate phase.²

Chagas disease is endemic to Central and South America but is also seen in North America; 28,000 new cases are reported annually in South America and North America combined. Human migration from endemic areas and from rural to urban areas has promoted the spread of Chagas disease.² However, patients in the United States have a relatively low risk for Chagas disease, largely because of the quality of housing construction and use of insecticides.

Treatment options for Chagas disease include nifurtimox and benznidazole. Without treatment, the host immune response typically controls acute replication of the parasite but will lead to a chronic state, ultimately involving the heart and GI tract.⁵

Cutaneous Manifestations

Capsicum peppers are used worldwide in preparing spicy dishes. Their active ingredient—capsaicin—is used as a topical medicine to treat localized pain. Capsicum peppers can cause irritant contact dermatitis with symptoms of erythema, cutaneous burning, and itch.¹

Irritant contact dermatitis is a common occupational skin disorder. Many cooks have experienced the sting of a chili pepper after contact with the hands or eyes. Cases of chronic exposure to Capsicum peppers with persistent burning and pain have been called Hunan hand syndrome.² Capsicum peppers also have induced allergic contact dermatitis in a food production worker.³

Capsicum peppers also are used in pepper spray, tear gas, and animal repellents because of their stinging properties. These agents usually cause cutaneous tingling and burning that soon resolves; however, a review of 31 studies showed that crowd-control methods with Capsicum-containing tear gas and pepper spray can cause moderate to severe skin damage such as a persistent skin rash or erythema, or even first-, second-, or third-degree burns.⁴

Topical application of capsaicin isolate is meant to cause burning and deplete local neuropeptides, with a cutaneous reaction that ranges from mild to intolerable.^5,6 Capsaicin also is found in other products. In one published case report, a 3-year-old boy broke out in facial urticaria when his mother kissed him on the cheek after she applied lip plumper containing capsaicin to her lips.⁷ Dermatologists should consider capsaicin an active ingredient that can irritate the skin in the garden, in the kitchen, and in topical products.

Obtaining Relief

Capsaicin-induced dermatitis can be relieved by washing the area with soap, detergent, baking soda, or oily compounds that act as solvents for the nonpolar capsaicin.⁸ Application of ice water or a high-potency topical steroid also may help. If the reaction is severe and persistent, a continuous stellate ganglion block may alleviate the pain of capsaicin-induced contact dermatitis.⁹

Identifying Features and Plant Facts

The Capsicum genus includes chili peppers, paprika, and red peppers. Capsicum peppers are native to tropical regions of the Americas (Figure). The use of Capsicum peppers in food can be traced to Indigenous peoples of Mexico as early as 7000 bc.¹⁰ On the Scoville scale, which was developed to quantify the hotness of foods and spices, Capsicum peppers are rated at approximately 2 million units; by comparison, jalapeño peppers have a Scoville score of 4500¹¹ and capsaicin isolate has a score of 16 million units. Capsicum species rank among the hottest peppers in the world.

Capsicum belongs to the family Solanaceae, which includes tobacco, tomatoes, potatoes, and nightshade plants. There are many varieties of peppers in the Capsicum genus, with 5 domesticated species: Capsicum annuum, Capsicum baccatum, Capsicum chinense, Capsicum frutescens, and Capsicum pubescens. These include bell, poblano, cayenne, tabasco, habanero, and ají peppers, among others. Capsicum species grow as a shrub with flowers that rotate to stellate corollas and rounded berries of different sizes and colors.¹² Capsaicin and other alkaloids are concentrated in the fruit; therefore, Capsicum dermatitis is most commonly induced by contact with the flesh of peppers.

 

 

Irritant Chemicals

Capsaicin (8-methyl-6-nonanoyl vanillylamide) is a nonpolar phenol, which is why washing skin that has come in contact with capsaicin with water or vinegar alone is insufficient to solubilize it.¹³ Capsaicin binds to the transient receptor potential vanilloid 1 (TRPV1), a calcium channel on neurons that opens in response to heat. When bound, the channel opens at a lower temperature threshold and depolarizes nerve endings, leading to vasodilation and activation of sensory nerves.¹⁴ Substance P is released and the individual experiences a painful burning sensation. When purified capsaicin is frequently applied at an appropriate dose, synthesis of substance P is diminished, resulting in reduced local pain overall.¹⁵

Capsaicin does not affect neurons without TRPV1, and administration of capsaicin is not painful if given with anesthesia. An inappropriately high dose of capsaicin destroys cells in the epidermal barrier, resulting in water loss and inducing release of vasoactive peptides and inflammatory cytokines.¹ Careful handling of Capsicum peppers and capsaicin products can reduce the risk for irritation.

Medicinal Use

On-/Off-Label and Potential Uses—Capsaicin is US Food and Drug Administration approved for use in arthritis and musculoskeletal pain. It also is used to treat diabetic neuropathy,⁵ postherpetic neuralgia,⁶ psoriasis,¹⁶ and other conditions. Studies have shown that capsaicin might be useful in treating trigeminal neuralgia,¹⁷ fibromyalgia,¹⁸ migraines,¹⁴ cluster headaches,⁹ and HIV-associated distal sensory neuropathy.⁵

Delivery of Capsaicin—Capsaicin preferentially acts on C-fibers, which transmit dull, aching, chronic pain.¹⁹ The compound is available as a cream, lotion, and large bandage (for the lower back), as well as low- and high-dose patches. Capsaicin creams, lotions, and the low-dose patch are uncomfortable and must be applied for 4 to 6 weeks to take effect, which may impact patient adherence. The high-dose patch, which requires administration under local anesthesia by a health care worker, brings pain relief with a single use and improves adherence.¹¹ Synthetic TRPV1-agonist injectables based on capsaicin have undergone clinical trials for localized pain (eg, postoperative musculoskeletal pain); many patients experience pain relief, though benefit fades over weeks to months.^20,21

Use in Traditional Medicine—Capsicum peppers have been used to aid digestion and promote healing in gastrointestinal conditions, such as dyspepsia.²² The peppers are a source of important vitamins and minerals, including vitamins A, C, and E; many of the B complex vitamins; and magnesium, calcium, and iron.²³

Use as Cancer Therapy—Studies of the use of capsaicin in treating cancer have produced controversial results. In cell and animal models, capsaicin induces apoptosis through downregulation of the Bcl-2 protein; upregulation of oxidative stress, tribbles-related protein 3 (TRIB3), and caspase-3; and other pathways.^19,24-26 On the other hand, consumption of Capsicum peppers has been associated with cancer of the stomach and gallbladder.²⁷ Capsaicin might have anticarcinogenic properties, but its mechanism of action varies, depending on variables not fully understood.

Final Thoughts

Capsaicin is a neuropeptide-active compound found in Capsicum peppers that has many promising applications for use. However, dermatologists should be aware of the possibility of a skin reaction to this compound from handling peppers and using topical medicines. Exposure to capsaicin can cause irritant contact dermatitis that may require clinical care.

Cutaneous Manifestations

Capsicum peppers are used worldwide in preparing spicy dishes. Their active ingredient—capsaicin—is used as a topical medicine to treat localized pain. Capsicum peppers can cause irritant contact dermatitis with symptoms of erythema, cutaneous burning, and itch.¹

Irritant contact dermatitis is a common occupational skin disorder. Many cooks have experienced the sting of a chili pepper after contact with the hands or eyes. Cases of chronic exposure to Capsicum peppers with persistent burning and pain have been called Hunan hand syndrome.² Capsicum peppers also have induced allergic contact dermatitis in a food production worker.³

Capsicum peppers also are used in pepper spray, tear gas, and animal repellents because of their stinging properties. These agents usually cause cutaneous tingling and burning that soon resolves; however, a review of 31 studies showed that crowd-control methods with Capsicum-containing tear gas and pepper spray can cause moderate to severe skin damage such as a persistent skin rash or erythema, or even first-, second-, or third-degree burns.⁴

Topical application of capsaicin isolate is meant to cause burning and deplete local neuropeptides, with a cutaneous reaction that ranges from mild to intolerable.^5,6 Capsaicin also is found in other products. In one published case report, a 3-year-old boy broke out in facial urticaria when his mother kissed him on the cheek after she applied lip plumper containing capsaicin to her lips.⁷ Dermatologists should consider capsaicin an active ingredient that can irritate the skin in the garden, in the kitchen, and in topical products.

Obtaining Relief

Capsaicin-induced dermatitis can be relieved by washing the area with soap, detergent, baking soda, or oily compounds that act as solvents for the nonpolar capsaicin.⁸ Application of ice water or a high-potency topical steroid also may help. If the reaction is severe and persistent, a continuous stellate ganglion block may alleviate the pain of capsaicin-induced contact dermatitis.⁹

Identifying Features and Plant Facts

The Capsicum genus includes chili peppers, paprika, and red peppers. Capsicum peppers are native to tropical regions of the Americas (Figure). The use of Capsicum peppers in food can be traced to Indigenous peoples of Mexico as early as 7000 bc.¹⁰ On the Scoville scale, which was developed to quantify the hotness of foods and spices, Capsicum peppers are rated at approximately 2 million units; by comparison, jalapeño peppers have a Scoville score of 4500¹¹ and capsaicin isolate has a score of 16 million units. Capsicum species rank among the hottest peppers in the world.

Capsicum belongs to the family Solanaceae, which includes tobacco, tomatoes, potatoes, and nightshade plants. There are many varieties of peppers in the Capsicum genus, with 5 domesticated species: Capsicum annuum, Capsicum baccatum, Capsicum chinense, Capsicum frutescens, and Capsicum pubescens. These include bell, poblano, cayenne, tabasco, habanero, and ají peppers, among others. Capsicum species grow as a shrub with flowers that rotate to stellate corollas and rounded berries of different sizes and colors.¹² Capsaicin and other alkaloids are concentrated in the fruit; therefore, Capsicum dermatitis is most commonly induced by contact with the flesh of peppers.

 

 

Irritant Chemicals

Capsaicin (8-methyl-6-nonanoyl vanillylamide) is a nonpolar phenol, which is why washing skin that has come in contact with capsaicin with water or vinegar alone is insufficient to solubilize it.¹³ Capsaicin binds to the transient receptor potential vanilloid 1 (TRPV1), a calcium channel on neurons that opens in response to heat. When bound, the channel opens at a lower temperature threshold and depolarizes nerve endings, leading to vasodilation and activation of sensory nerves.¹⁴ Substance P is released and the individual experiences a painful burning sensation. When purified capsaicin is frequently applied at an appropriate dose, synthesis of substance P is diminished, resulting in reduced local pain overall.¹⁵

Capsaicin does not affect neurons without TRPV1, and administration of capsaicin is not painful if given with anesthesia. An inappropriately high dose of capsaicin destroys cells in the epidermal barrier, resulting in water loss and inducing release of vasoactive peptides and inflammatory cytokines.¹ Careful handling of Capsicum peppers and capsaicin products can reduce the risk for irritation.

Medicinal Use

On-/Off-Label and Potential Uses—Capsaicin is US Food and Drug Administration approved for use in arthritis and musculoskeletal pain. It also is used to treat diabetic neuropathy,⁵ postherpetic neuralgia,⁶ psoriasis,¹⁶ and other conditions. Studies have shown that capsaicin might be useful in treating trigeminal neuralgia,¹⁷ fibromyalgia,¹⁸ migraines,¹⁴ cluster headaches,⁹ and HIV-associated distal sensory neuropathy.⁵

Delivery of Capsaicin—Capsaicin preferentially acts on C-fibers, which transmit dull, aching, chronic pain.¹⁹ The compound is available as a cream, lotion, and large bandage (for the lower back), as well as low- and high-dose patches. Capsaicin creams, lotions, and the low-dose patch are uncomfortable and must be applied for 4 to 6 weeks to take effect, which may impact patient adherence. The high-dose patch, which requires administration under local anesthesia by a health care worker, brings pain relief with a single use and improves adherence.¹¹ Synthetic TRPV1-agonist injectables based on capsaicin have undergone clinical trials for localized pain (eg, postoperative musculoskeletal pain); many patients experience pain relief, though benefit fades over weeks to months.^20,21

Use in Traditional Medicine—Capsicum peppers have been used to aid digestion and promote healing in gastrointestinal conditions, such as dyspepsia.²² The peppers are a source of important vitamins and minerals, including vitamins A, C, and E; many of the B complex vitamins; and magnesium, calcium, and iron.²³

Use as Cancer Therapy—Studies of the use of capsaicin in treating cancer have produced controversial results. In cell and animal models, capsaicin induces apoptosis through downregulation of the Bcl-2 protein; upregulation of oxidative stress, tribbles-related protein 3 (TRIB3), and caspase-3; and other pathways.^19,24-26 On the other hand, consumption of Capsicum peppers has been associated with cancer of the stomach and gallbladder.²⁷ Capsaicin might have anticarcinogenic properties, but its mechanism of action varies, depending on variables not fully understood.

Final Thoughts

Capsaicin is a neuropeptide-active compound found in Capsicum peppers that has many promising applications for use. However, dermatologists should be aware of the possibility of a skin reaction to this compound from handling peppers and using topical medicines. Exposure to capsaicin can cause irritant contact dermatitis that may require clinical care.

Cutaneous Manifestations

Capsicum peppers are used worldwide in preparing spicy dishes. Their active ingredient—capsaicin—is used as a topical medicine to treat localized pain. Capsicum peppers can cause irritant contact dermatitis with symptoms of erythema, cutaneous burning, and itch.¹

Irritant contact dermatitis is a common occupational skin disorder. Many cooks have experienced the sting of a chili pepper after contact with the hands or eyes. Cases of chronic exposure to Capsicum peppers with persistent burning and pain have been called Hunan hand syndrome.² Capsicum peppers also have induced allergic contact dermatitis in a food production worker.³

Capsicum peppers also are used in pepper spray, tear gas, and animal repellents because of their stinging properties. These agents usually cause cutaneous tingling and burning that soon resolves; however, a review of 31 studies showed that crowd-control methods with Capsicum-containing tear gas and pepper spray can cause moderate to severe skin damage such as a persistent skin rash or erythema, or even first-, second-, or third-degree burns.⁴

Topical application of capsaicin isolate is meant to cause burning and deplete local neuropeptides, with a cutaneous reaction that ranges from mild to intolerable.^5,6 Capsaicin also is found in other products. In one published case report, a 3-year-old boy broke out in facial urticaria when his mother kissed him on the cheek after she applied lip plumper containing capsaicin to her lips.⁷ Dermatologists should consider capsaicin an active ingredient that can irritate the skin in the garden, in the kitchen, and in topical products.

Obtaining Relief

Capsaicin-induced dermatitis can be relieved by washing the area with soap, detergent, baking soda, or oily compounds that act as solvents for the nonpolar capsaicin.⁸ Application of ice water or a high-potency topical steroid also may help. If the reaction is severe and persistent, a continuous stellate ganglion block may alleviate the pain of capsaicin-induced contact dermatitis.⁹

Identifying Features and Plant Facts

The Capsicum genus includes chili peppers, paprika, and red peppers. Capsicum peppers are native to tropical regions of the Americas (Figure). The use of Capsicum peppers in food can be traced to Indigenous peoples of Mexico as early as 7000 bc.¹⁰ On the Scoville scale, which was developed to quantify the hotness of foods and spices, Capsicum peppers are rated at approximately 2 million units; by comparison, jalapeño peppers have a Scoville score of 4500¹¹ and capsaicin isolate has a score of 16 million units. Capsicum species rank among the hottest peppers in the world.

Capsicum belongs to the family Solanaceae, which includes tobacco, tomatoes, potatoes, and nightshade plants. There are many varieties of peppers in the Capsicum genus, with 5 domesticated species: Capsicum annuum, Capsicum baccatum, Capsicum chinense, Capsicum frutescens, and Capsicum pubescens. These include bell, poblano, cayenne, tabasco, habanero, and ají peppers, among others. Capsicum species grow as a shrub with flowers that rotate to stellate corollas and rounded berries of different sizes and colors.¹² Capsaicin and other alkaloids are concentrated in the fruit; therefore, Capsicum dermatitis is most commonly induced by contact with the flesh of peppers.

 

 

Irritant Chemicals

Capsaicin (8-methyl-6-nonanoyl vanillylamide) is a nonpolar phenol, which is why washing skin that has come in contact with capsaicin with water or vinegar alone is insufficient to solubilize it.¹³ Capsaicin binds to the transient receptor potential vanilloid 1 (TRPV1), a calcium channel on neurons that opens in response to heat. When bound, the channel opens at a lower temperature threshold and depolarizes nerve endings, leading to vasodilation and activation of sensory nerves.¹⁴ Substance P is released and the individual experiences a painful burning sensation. When purified capsaicin is frequently applied at an appropriate dose, synthesis of substance P is diminished, resulting in reduced local pain overall.¹⁵

Capsaicin does not affect neurons without TRPV1, and administration of capsaicin is not painful if given with anesthesia. An inappropriately high dose of capsaicin destroys cells in the epidermal barrier, resulting in water loss and inducing release of vasoactive peptides and inflammatory cytokines.¹ Careful handling of Capsicum peppers and capsaicin products can reduce the risk for irritation.

Medicinal Use

On-/Off-Label and Potential Uses—Capsaicin is US Food and Drug Administration approved for use in arthritis and musculoskeletal pain. It also is used to treat diabetic neuropathy,⁵ postherpetic neuralgia,⁶ psoriasis,¹⁶ and other conditions. Studies have shown that capsaicin might be useful in treating trigeminal neuralgia,¹⁷ fibromyalgia,¹⁸ migraines,¹⁴ cluster headaches,⁹ and HIV-associated distal sensory neuropathy.⁵

Delivery of Capsaicin—Capsaicin preferentially acts on C-fibers, which transmit dull, aching, chronic pain.¹⁹ The compound is available as a cream, lotion, and large bandage (for the lower back), as well as low- and high-dose patches. Capsaicin creams, lotions, and the low-dose patch are uncomfortable and must be applied for 4 to 6 weeks to take effect, which may impact patient adherence. The high-dose patch, which requires administration under local anesthesia by a health care worker, brings pain relief with a single use and improves adherence.¹¹ Synthetic TRPV1-agonist injectables based on capsaicin have undergone clinical trials for localized pain (eg, postoperative musculoskeletal pain); many patients experience pain relief, though benefit fades over weeks to months.^20,21

Use in Traditional Medicine—Capsicum peppers have been used to aid digestion and promote healing in gastrointestinal conditions, such as dyspepsia.²² The peppers are a source of important vitamins and minerals, including vitamins A, C, and E; many of the B complex vitamins; and magnesium, calcium, and iron.²³

Use as Cancer Therapy—Studies of the use of capsaicin in treating cancer have produced controversial results. In cell and animal models, capsaicin induces apoptosis through downregulation of the Bcl-2 protein; upregulation of oxidative stress, tribbles-related protein 3 (TRIB3), and caspase-3; and other pathways.^19,24-26 On the other hand, consumption of Capsicum peppers has been associated with cancer of the stomach and gallbladder.²⁷ Capsaicin might have anticarcinogenic properties, but its mechanism of action varies, depending on variables not fully understood.

Final Thoughts

Capsaicin is a neuropeptide-active compound found in Capsicum peppers that has many promising applications for use. However, dermatologists should be aware of the possibility of a skin reaction to this compound from handling peppers and using topical medicines. Exposure to capsaicin can cause irritant contact dermatitis that may require clinical care.

Contact dermatitis is a common problem in the floral bulb industry and is considered an occupational disease. Daffodils (Narcissus species)(Figure) are thought to be the most common cause of irritant contact dermatitis among florists.¹

Clinical Importance

Picking daffodils can start as early as October, when the flowers are still closed. The picker’s hand slides down the stem to snap the stalk at the base. This potentially traumatic maneuver to the web of the fingers leads to abrasions, which are irritated by the sap and cause granulomatous sores and paronychia. An experienced picker can pick 20,000 flowers a day, leading to extensive contact with sap.²

Eczematous or granulomatous rash on the arms also is seen as the sap irritates the wrist and forearm. The pickers often hold the flowers until a bunch of 10 has been collected. The 10 flowers are held together by a rubber band and stacked along the arm, the chin, and the axilla, causing the rash to extend to those areas. Sap also can be transferred by the hand to other parts of the body, such as the face. In men, sap can be transferred to the genitalia as the men urinate in the field.

Narcissus also can cause poisoning if ingested by humans or animals. Researchers who analyzed calls made to the New Zealand Natural Poisons Centre between 2003 and 2010 determined that daffodil was the 11th most common call for plant-related poisoning.³

Although the severity of plant poisoning often is low due to the small amount of plant material usually consumed, more severe poisoning can occur when the plant is eaten for medicinal purposes or mistaken for an edible plant.³ Vomiting, respiratory symptoms, abdominal pain, diarrhea, trembling, and convulsions can occur when daffodils are ingested. Death has been reported due to ingestion of the bulbs.⁴

In February 2010, 10 children aged 10 and 11 years and their 22-year-old guide presented to an emergency department in Israel after ingesting Narcissus bulbs, which were mistakenly believed to be the bulbs of onions.⁴ Eight children and the guide vomited. One child and the guide reported abdominal pain. All were discharged in stable condition after 4 hours of observation.⁴

Clinical Manifestations

Daffodil rash or lily rash was first described in 1910.⁵ The typical rash presents as dryness, fissures, scaling, and erythema of the fingertips, hands, and forearms, often with subungual hyperkeratosis. Vesicles and pustules may be seen. The rash may extend to other areas of the body, including the face.⁶

 

 

Prevention and Treatment

Use of protective gloves and clothing to avoid contact with the plant is recommended.² Treatment includes stopping contact with the irritant, eye irrigation, and supportive measures (airway, breathing, and circulation). Activated charcoal can be helpful if used within 1 hour after ingestion but is contraindicated in vomiting patients.⁴

Identifying Features

The genus Narcissus is in the family Amaryllidaceae and contains ornamental plants, including daffodil (trumpet Narcissus, Narcissus pseudonarcissus), jonquil (Narcissus jonquilla), and poet’s narcissus (Narcissus poeticus). Most species are perennial; the plant emerges from a bulb in spring. Leaves originate from the base of the plant and range from 5-cm to 1.2-meters long, depending on the species. The flowers span a range of shapes and colors—from a trumpet (the daffodil) to a ringlike cup (poet’s Narcissus) and in yellow, white, and pink.⁷

Distribution and Plant Facts

Distribution—There are approximately 80 to 100 wild Narcissus species, which are found in southwestern Europe, North Africa, the Balkan Peninsula, Italy, and France. There are more than 27,000 Narcissus cultivars registered in the International Daffodil Register.⁸

Plant Facts—The daffodil is the national flower of Wales. It also is often used to depict hope and joy and is the symbol of cancer charities in many countries.⁹

The name Narcissus is believed to have originated from Greek mythology. A handsome youth, Narcissus, fell in love with his own reflection, for which the gods punished him by turning him into a flower.¹⁰

Another theory states that Narcissus is derived from the Greek word narkao (to benumb) due to its narcotic properties. When an open wound is subjected to an extract of the bulb, numbness of the entire nervous system is said to occur as well as paralysis of the heart. This narcotic effect led Socrates to refer to the Narcissus plant as the “chaplet of the infernal gods.”¹¹

Narcissus is an important flower in various ethnic rituals. The Greeks often planted daffodils near tombs. In Muslim culture, white is believed to be the symbol of good and purity; Narcissus was one of the most common white-flowered plants found in Muslim graveyards.¹²

Medicinal Qualities and Uses—Narcissus species have been used as medicinal plants for a variety of ailments. For example, Narcissus tazetta contains flavonoids, alkaloids, saponins, tannins, cardiac glycosides, oil, steroids, terpenoids, and anthraquinones that contribute to its antibacterial, antifungal, antiviral, antimalarial, anticancer, antioxidant, dermatologic, cardiovascular, immunomodulatory, and acetylcholinesterase inhibitory effects.¹³ In a study, chloroform extracts from N tazetta bulbs were found to be more active than doxorubicin against hepatocellular and colon cancer cell lines.¹⁴

More than 500 alkaloids have been isolated from the Narcissus genus.¹⁵ In 2001, the US Food and Drug Administration approved one of the alkaloids, galantamine, for the treatment of mild to moderate stages of Alzheimer disease.¹⁶ Galantamine selectively and reversibly inhibits acetylcholinesterase, the enzyme believed responsible for neurodegeneration seen in Alzheimer disease. Plants are the main source of galantamine, despite the ability of pharmaceutical companies to synthesize the compound. Galantamine hydrobromide is sold by prescription (Razadyne [Janssen Pharmaceuticals, Inc]); generic formulations approved by the US Food and Drug Administration have been produced by more than 15 pharmaceutical companies.^17,18

Irritant and Allergen

Sap found in the bulbs and hollow stems of Narcissus contains calcium oxalate crystals, or raphides. The minute, needle-shaped calcium oxalate crystals are believed to be a waste product of cellular metabolism.¹⁹ When the plant structure is compromised by pickers snapping the stalk, the sharp crystals penetrate the skin to cause an irritant contact dermatitis.

Relevant Research—A study used electron microscopy to characterize the structure of raphides from various plants,² though not from Narcissus species; the structure of each raphide was then compared to the degree of irritation it produced. The researchers concluded that more elongated crystals (those containing barbs) produce a greater degree of irritation. Narcissus species are known to cause varying degrees of skin irritation: For example, N tazetta rarely causes skin irritation, whereas N pseudonarcissi (daffodil) tends to cause remarkably more skin irritation.²

Allergic reactions to and strong toxicity from Narcissus species are not well understood. In a study, only 2 alkaloids—homolycorine and masonin—produced a weakly positive reaction in patch tests on sensitized guinea pigs, which correlates with the finding of a different study, in which only 2 of 12 patients whose findings were examined over 14 years had a positive patch test for Narcissus.^20,21

However, IgE-mediated allergies indicative of an allergic response to Narcissus have been reported. A study isolated an allergenic protein, narcin, from bulbs of N tazetta. Narcin is a 13-kDa protein with potent allergenic effects capable of inducing production of proinflammatory cytokines and increasing IgE levels in mononuclear cells in peripheral blood.²²

More research is required to find and understand the compounds responsible for causing an allergic reaction to Narcissus.

Contact dermatitis is a common problem in the floral bulb industry and is considered an occupational disease. Daffodils (Narcissus species)(Figure) are thought to be the most common cause of irritant contact dermatitis among florists.¹

Clinical Importance

Picking daffodils can start as early as October, when the flowers are still closed. The picker’s hand slides down the stem to snap the stalk at the base. This potentially traumatic maneuver to the web of the fingers leads to abrasions, which are irritated by the sap and cause granulomatous sores and paronychia. An experienced picker can pick 20,000 flowers a day, leading to extensive contact with sap.²

Eczematous or granulomatous rash on the arms also is seen as the sap irritates the wrist and forearm. The pickers often hold the flowers until a bunch of 10 has been collected. The 10 flowers are held together by a rubber band and stacked along the arm, the chin, and the axilla, causing the rash to extend to those areas. Sap also can be transferred by the hand to other parts of the body, such as the face. In men, sap can be transferred to the genitalia as the men urinate in the field.

Narcissus also can cause poisoning if ingested by humans or animals. Researchers who analyzed calls made to the New Zealand Natural Poisons Centre between 2003 and 2010 determined that daffodil was the 11th most common call for plant-related poisoning.³

Although the severity of plant poisoning often is low due to the small amount of plant material usually consumed, more severe poisoning can occur when the plant is eaten for medicinal purposes or mistaken for an edible plant.³ Vomiting, respiratory symptoms, abdominal pain, diarrhea, trembling, and convulsions can occur when daffodils are ingested. Death has been reported due to ingestion of the bulbs.⁴

In February 2010, 10 children aged 10 and 11 years and their 22-year-old guide presented to an emergency department in Israel after ingesting Narcissus bulbs, which were mistakenly believed to be the bulbs of onions.⁴ Eight children and the guide vomited. One child and the guide reported abdominal pain. All were discharged in stable condition after 4 hours of observation.⁴

Clinical Manifestations

Daffodil rash or lily rash was first described in 1910.⁵ The typical rash presents as dryness, fissures, scaling, and erythema of the fingertips, hands, and forearms, often with subungual hyperkeratosis. Vesicles and pustules may be seen. The rash may extend to other areas of the body, including the face.⁶

 

 

Prevention and Treatment

Use of protective gloves and clothing to avoid contact with the plant is recommended.² Treatment includes stopping contact with the irritant, eye irrigation, and supportive measures (airway, breathing, and circulation). Activated charcoal can be helpful if used within 1 hour after ingestion but is contraindicated in vomiting patients.⁴

Identifying Features

The genus Narcissus is in the family Amaryllidaceae and contains ornamental plants, including daffodil (trumpet Narcissus, Narcissus pseudonarcissus), jonquil (Narcissus jonquilla), and poet’s narcissus (Narcissus poeticus). Most species are perennial; the plant emerges from a bulb in spring. Leaves originate from the base of the plant and range from 5-cm to 1.2-meters long, depending on the species. The flowers span a range of shapes and colors—from a trumpet (the daffodil) to a ringlike cup (poet’s Narcissus) and in yellow, white, and pink.⁷

Distribution and Plant Facts

Distribution—There are approximately 80 to 100 wild Narcissus species, which are found in southwestern Europe, North Africa, the Balkan Peninsula, Italy, and France. There are more than 27,000 Narcissus cultivars registered in the International Daffodil Register.⁸

Plant Facts—The daffodil is the national flower of Wales. It also is often used to depict hope and joy and is the symbol of cancer charities in many countries.⁹

The name Narcissus is believed to have originated from Greek mythology. A handsome youth, Narcissus, fell in love with his own reflection, for which the gods punished him by turning him into a flower.¹⁰

Another theory states that Narcissus is derived from the Greek word narkao (to benumb) due to its narcotic properties. When an open wound is subjected to an extract of the bulb, numbness of the entire nervous system is said to occur as well as paralysis of the heart. This narcotic effect led Socrates to refer to the Narcissus plant as the “chaplet of the infernal gods.”¹¹

Narcissus is an important flower in various ethnic rituals. The Greeks often planted daffodils near tombs. In Muslim culture, white is believed to be the symbol of good and purity; Narcissus was one of the most common white-flowered plants found in Muslim graveyards.¹²

Medicinal Qualities and Uses—Narcissus species have been used as medicinal plants for a variety of ailments. For example, Narcissus tazetta contains flavonoids, alkaloids, saponins, tannins, cardiac glycosides, oil, steroids, terpenoids, and anthraquinones that contribute to its antibacterial, antifungal, antiviral, antimalarial, anticancer, antioxidant, dermatologic, cardiovascular, immunomodulatory, and acetylcholinesterase inhibitory effects.¹³ In a study, chloroform extracts from N tazetta bulbs were found to be more active than doxorubicin against hepatocellular and colon cancer cell lines.¹⁴

More than 500 alkaloids have been isolated from the Narcissus genus.¹⁵ In 2001, the US Food and Drug Administration approved one of the alkaloids, galantamine, for the treatment of mild to moderate stages of Alzheimer disease.¹⁶ Galantamine selectively and reversibly inhibits acetylcholinesterase, the enzyme believed responsible for neurodegeneration seen in Alzheimer disease. Plants are the main source of galantamine, despite the ability of pharmaceutical companies to synthesize the compound. Galantamine hydrobromide is sold by prescription (Razadyne [Janssen Pharmaceuticals, Inc]); generic formulations approved by the US Food and Drug Administration have been produced by more than 15 pharmaceutical companies.^17,18

Irritant and Allergen

Sap found in the bulbs and hollow stems of Narcissus contains calcium oxalate crystals, or raphides. The minute, needle-shaped calcium oxalate crystals are believed to be a waste product of cellular metabolism.¹⁹ When the plant structure is compromised by pickers snapping the stalk, the sharp crystals penetrate the skin to cause an irritant contact dermatitis.

Relevant Research—A study used electron microscopy to characterize the structure of raphides from various plants,² though not from Narcissus species; the structure of each raphide was then compared to the degree of irritation it produced. The researchers concluded that more elongated crystals (those containing barbs) produce a greater degree of irritation. Narcissus species are known to cause varying degrees of skin irritation: For example, N tazetta rarely causes skin irritation, whereas N pseudonarcissi (daffodil) tends to cause remarkably more skin irritation.²

Allergic reactions to and strong toxicity from Narcissus species are not well understood. In a study, only 2 alkaloids—homolycorine and masonin—produced a weakly positive reaction in patch tests on sensitized guinea pigs, which correlates with the finding of a different study, in which only 2 of 12 patients whose findings were examined over 14 years had a positive patch test for Narcissus.^20,21

However, IgE-mediated allergies indicative of an allergic response to Narcissus have been reported. A study isolated an allergenic protein, narcin, from bulbs of N tazetta. Narcin is a 13-kDa protein with potent allergenic effects capable of inducing production of proinflammatory cytokines and increasing IgE levels in mononuclear cells in peripheral blood.²²

More research is required to find and understand the compounds responsible for causing an allergic reaction to Narcissus.

Contact dermatitis is a common problem in the floral bulb industry and is considered an occupational disease. Daffodils (Narcissus species)(Figure) are thought to be the most common cause of irritant contact dermatitis among florists.¹

Clinical Importance

Picking daffodils can start as early as October, when the flowers are still closed. The picker’s hand slides down the stem to snap the stalk at the base. This potentially traumatic maneuver to the web of the fingers leads to abrasions, which are irritated by the sap and cause granulomatous sores and paronychia. An experienced picker can pick 20,000 flowers a day, leading to extensive contact with sap.²

Eczematous or granulomatous rash on the arms also is seen as the sap irritates the wrist and forearm. The pickers often hold the flowers until a bunch of 10 has been collected. The 10 flowers are held together by a rubber band and stacked along the arm, the chin, and the axilla, causing the rash to extend to those areas. Sap also can be transferred by the hand to other parts of the body, such as the face. In men, sap can be transferred to the genitalia as the men urinate in the field.

Narcissus also can cause poisoning if ingested by humans or animals. Researchers who analyzed calls made to the New Zealand Natural Poisons Centre between 2003 and 2010 determined that daffodil was the 11th most common call for plant-related poisoning.³

Although the severity of plant poisoning often is low due to the small amount of plant material usually consumed, more severe poisoning can occur when the plant is eaten for medicinal purposes or mistaken for an edible plant.³ Vomiting, respiratory symptoms, abdominal pain, diarrhea, trembling, and convulsions can occur when daffodils are ingested. Death has been reported due to ingestion of the bulbs.⁴

In February 2010, 10 children aged 10 and 11 years and their 22-year-old guide presented to an emergency department in Israel after ingesting Narcissus bulbs, which were mistakenly believed to be the bulbs of onions.⁴ Eight children and the guide vomited. One child and the guide reported abdominal pain. All were discharged in stable condition after 4 hours of observation.⁴

Clinical Manifestations

Daffodil rash or lily rash was first described in 1910.⁵ The typical rash presents as dryness, fissures, scaling, and erythema of the fingertips, hands, and forearms, often with subungual hyperkeratosis. Vesicles and pustules may be seen. The rash may extend to other areas of the body, including the face.⁶

 

 

Prevention and Treatment

Use of protective gloves and clothing to avoid contact with the plant is recommended.² Treatment includes stopping contact with the irritant, eye irrigation, and supportive measures (airway, breathing, and circulation). Activated charcoal can be helpful if used within 1 hour after ingestion but is contraindicated in vomiting patients.⁴

Identifying Features

The genus Narcissus is in the family Amaryllidaceae and contains ornamental plants, including daffodil (trumpet Narcissus, Narcissus pseudonarcissus), jonquil (Narcissus jonquilla), and poet’s narcissus (Narcissus poeticus). Most species are perennial; the plant emerges from a bulb in spring. Leaves originate from the base of the plant and range from 5-cm to 1.2-meters long, depending on the species. The flowers span a range of shapes and colors—from a trumpet (the daffodil) to a ringlike cup (poet’s Narcissus) and in yellow, white, and pink.⁷

Distribution and Plant Facts

Distribution—There are approximately 80 to 100 wild Narcissus species, which are found in southwestern Europe, North Africa, the Balkan Peninsula, Italy, and France. There are more than 27,000 Narcissus cultivars registered in the International Daffodil Register.⁸

Plant Facts—The daffodil is the national flower of Wales. It also is often used to depict hope and joy and is the symbol of cancer charities in many countries.⁹

The name Narcissus is believed to have originated from Greek mythology. A handsome youth, Narcissus, fell in love with his own reflection, for which the gods punished him by turning him into a flower.¹⁰

Another theory states that Narcissus is derived from the Greek word narkao (to benumb) due to its narcotic properties. When an open wound is subjected to an extract of the bulb, numbness of the entire nervous system is said to occur as well as paralysis of the heart. This narcotic effect led Socrates to refer to the Narcissus plant as the “chaplet of the infernal gods.”¹¹

Narcissus is an important flower in various ethnic rituals. The Greeks often planted daffodils near tombs. In Muslim culture, white is believed to be the symbol of good and purity; Narcissus was one of the most common white-flowered plants found in Muslim graveyards.¹²

Medicinal Qualities and Uses—Narcissus species have been used as medicinal plants for a variety of ailments. For example, Narcissus tazetta contains flavonoids, alkaloids, saponins, tannins, cardiac glycosides, oil, steroids, terpenoids, and anthraquinones that contribute to its antibacterial, antifungal, antiviral, antimalarial, anticancer, antioxidant, dermatologic, cardiovascular, immunomodulatory, and acetylcholinesterase inhibitory effects.¹³ In a study, chloroform extracts from N tazetta bulbs were found to be more active than doxorubicin against hepatocellular and colon cancer cell lines.¹⁴

More than 500 alkaloids have been isolated from the Narcissus genus.¹⁵ In 2001, the US Food and Drug Administration approved one of the alkaloids, galantamine, for the treatment of mild to moderate stages of Alzheimer disease.¹⁶ Galantamine selectively and reversibly inhibits acetylcholinesterase, the enzyme believed responsible for neurodegeneration seen in Alzheimer disease. Plants are the main source of galantamine, despite the ability of pharmaceutical companies to synthesize the compound. Galantamine hydrobromide is sold by prescription (Razadyne [Janssen Pharmaceuticals, Inc]); generic formulations approved by the US Food and Drug Administration have been produced by more than 15 pharmaceutical companies.^17,18

Irritant and Allergen

Sap found in the bulbs and hollow stems of Narcissus contains calcium oxalate crystals, or raphides. The minute, needle-shaped calcium oxalate crystals are believed to be a waste product of cellular metabolism.¹⁹ When the plant structure is compromised by pickers snapping the stalk, the sharp crystals penetrate the skin to cause an irritant contact dermatitis.

Relevant Research—A study used electron microscopy to characterize the structure of raphides from various plants,² though not from Narcissus species; the structure of each raphide was then compared to the degree of irritation it produced. The researchers concluded that more elongated crystals (those containing barbs) produce a greater degree of irritation. Narcissus species are known to cause varying degrees of skin irritation: For example, N tazetta rarely causes skin irritation, whereas N pseudonarcissi (daffodil) tends to cause remarkably more skin irritation.²

Allergic reactions to and strong toxicity from Narcissus species are not well understood. In a study, only 2 alkaloids—homolycorine and masonin—produced a weakly positive reaction in patch tests on sensitized guinea pigs, which correlates with the finding of a different study, in which only 2 of 12 patients whose findings were examined over 14 years had a positive patch test for Narcissus.^20,21

However, IgE-mediated allergies indicative of an allergic response to Narcissus have been reported. A study isolated an allergenic protein, narcin, from bulbs of N tazetta. Narcin is a 13-kDa protein with potent allergenic effects capable of inducing production of proinflammatory cytokines and increasing IgE levels in mononuclear cells in peripheral blood.²²

More research is required to find and understand the compounds responsible for causing an allergic reaction to Narcissus.

Reactions to poison ivy, poison oak, and poison sumac, which affect 10 to 50 million Americans a year,¹ are classified as Toxicodendron dermatitis; 50% to 75% of US adults are clinically sensitive to these plants.² Furthermore, people of all ethnicities, skin types, and ages residing in most US geographical regions are at risk.³ Allergenicity is caused by urushiol, which is found in members of the Anacardiaceae family.⁴ Once absorbed, urushiol causes a type IV hypersensitivity reaction in those who are susceptible.⁵

Cutaneous Manifestations

Toxicodendron dermatitis presents with an acute eczematous eruption characterized by streaks of intensely pruritic and erythematous papules and vesicles (Figure 1). Areas of involvement are characterized by sharp margins that follow the pattern of contact made by the plant’s leaves, berries, stems, and vines.⁶ The fluid content of the vesicles is not antigenic and cannot cause subsequent transmission to oneself or others.³ A person with prior contact to the plant who becomes sensitized develops an eruption 24 to 48 hours after subsequent contact with the plant; peak severity manifests 1 to 14 days later.⁷

When left untreated, the eruption can last 3 weeks. If the plant is burned, urushiol can be aerosolized in smoke, causing respiratory tract inflammation and generalized dermatitis, which has been reported among wildland firefighters.² Long-term complications from an outbreak are limited but can include postinflammatory hyperpigmentation and secondary bacterial infection.⁸ Rare reports of nephrotic syndrome also have appeared in the literature.⁹ Toxicodendron dermatitis can present distinctively as so-called black dot dermatitis.⁶

Nomenclature

Poison ivy, poison oak, and poison sumac are members of the family Anacardiaceae and genus Toxicodendron,⁶ derived from the Greek words toxikos (poison) and dendron (tree).¹⁰

Distribution

Toxicodendron plants characteristically are found in various regions of the United States. Poison ivy is the most common and is comprised of 2 species: Toxicodendron rydbergii and Toxicodendron radicans. Toxicodendron rydbergii is a nonclimbing dwarf shrub typically found in the northern and western United States. Toxicodendron radicans is a climbing vine found in the eastern United States. Poison oak also is comprised of 2 species—Toxicodendron toxicarium and Toxicodendron diversilobum—and is more common in the western United States. Poison sumac (also known as Toxicodendron vernix) is a small shrub that grows in moist swampy areas. It has a predilection for marshes of the eastern and southeastern United States.^6,11

Identifying Features

Educating patients on how to identify poison ivy can play a key role in avoidance, which is the most important step in preventing Toxicodendron dermatitis. A challenge in identification of poison ivy is the plant’s variable appearance; it grows as a small shrub, low-lying vine, or vine that climbs other trees.

As the vine matures, it develops tiny, rough, “hairy” rootlets—hence the saying, “Hairy vine, no friend of mine!” Rootlets help the plant attach to trees growing near a water source. Vines can reach a diameter of 3 inches. From mature vines, solitary stems extend 1 to 2 inches with 3 characteristic leaves at the terminus (Figure 2), prompting another classic saying, “Leaves of 3, let it be!”¹²

Poison oak is characterized by 3 to 5 leaflets. Poison sumac has 7 to 13 pointed, smooth-edged leaves.⁶

Dermatitis-Inducing Plant Parts

The primary allergenic component of Toxicodendron plants is urushiol, a resinous sap found in stems, roots, leaves, and skins of the fruits. These components must be damaged or bruised to release the allergen; slight contact with an uninjured plant part might not lead to harm.^2,13 Some common forms of transmission include skin contact, ingestion, inhalation of smoke from burning plants, and contact with skin through contaminated items, such as clothing, animals, and tools.¹⁴

Allergens

The catecholic ring and aliphatic chain of the urushiol molecule are allergenic.¹⁵ The degree of saturation and length of the side chains vary with different catechols. Urushiol displays cross-reactivity with poison ivy, poison oak, and poison sumac. Urushiol from these plants differs only slightly in structure; therefore, sensitization to one causes sensitization to all. There also is cross-reactivity between different members of the Anacardiaceae family, including Anacardium occidentale (tropical cashew nut), Mangifera indica (tropical mango tree), Ginkgo biloba (ginkgo tree), and Semecarpus anacardium (Indian marking nut tree).¹²

Poison ivy, poison oak, and poison sumac cause allergic contact dermatitis as a type IV hypersensitivity reaction. First, urushiol binds and penetrates the skin, where it is oxidized to quinone intermediates and bound to haptens. Then, the intermediates bind surface proteins on antigen-presenting cells, specifically Langerhans cells in the epidermis and dermis.⁵

Presentation of nonpeptide antigens, such as urushiol, to T cells requires expression of langerin (also known as CD207) and CD1a.¹⁶ Langerin is a C-type lectin that causes formation of Birbeck granules; CD1a is a major histocompatibility complex class I molecule found in Birbeck granules.^5,17 After Langerhans cells internalize and process the urushiol self-hapten neoantigen, it is presented to CD4⁺ T cells.⁶ These cells then expand to form circulating activated T-effector and T-memory lymphocytes.¹⁸

The molecular link that occurs between the hapten and carrier protein determines the response. When linked by an amino nucleophile, selective induction of T-effector cells ensues, resulting in allergic contact dermatitis. When linked by a sulfhydryl bond, selective induction of suppressor cells occurs, resulting in a reduced allergic contact dermatitis response.¹⁹ In the case of activation of T-effector cells, a cell-mediated cytotoxic immune response is generated that destroys epidermal cells and dermal vasculature.² The incidence and intensity of poison ivy sensitivity decline proportionally with age and the absence of continued exposure.²⁰

Preventive Action—Patients should be counseled that if contact between plant and skin occurs, it is important to remove contaminated clothing or objects and wash them with soap to prevent additional exposure.^14,21 Areas of the skin that made contact with the plant should be washed with water as soon as possible; after 30 minutes, urushiol has sufficiently penetrated to cause a reaction.² Forceful unidirectional washing with a damp washcloth and liquid dishwashing soap is recommended.²²

Several barrier creams are commercially available to help prevent absorption or to deactivate the urushiol antigen. These products are used widely by forestry workers and wildland firefighters.²³ One such barrier cream is bentoquatam (sold as various trade names), an organoclay compound made of quaternium-18 bentonite that interferes with absorption of the allergen by acting as a physical blocker.²⁴

Treatment

After Toxicodendron dermatitis develops, several treatments are available to help manage symptoms. Calamine lotion can be used to help dry weeping lesions.^25,26 Topical steroids can be used to help control pruritus and alleviate inflammation. High-potency topical corticosteroids such as clobetasol and mid-potency steroids such as triamcinolone can be used. Topical anesthetics (eg, benzocaine, pramoxine, benzyl alcohol) might provide symptomatic relief.^27,28

Oral antihistamines can allow for better sleep by providing sedation but do not target the pruritus of poison ivy dermatitis, which is not histamine mediated.^29,30 Systemic corticosteroids usually are considered in more severe dermatitis—when 20% or more of the body surface area is involved; blistering and itching are severe; or the face, hands, or genitalia are involved.^31,32

Clinical Uses

Therapeutic uses for poison ivy have been explored extensively. In 1892, Dakin³³ reported that ingestion of leaves by Native Americans reduced the incidence and severity of skin lesions after contact with poison ivy. Consumption of poison ivy was further studied by Epstein and colleagues³⁴ in 1974; they concluded that ingestion of a large amount of urushiol over a period of 3 months or longer may help with hyposensitization—but not complete desensitization—to contact with poison ivy. However, the risk for adverse effects is thought to outweigh benefits because ingestion can cause perianal dermatitis, mucocutaneous sequelae, and systemic contact dermatitis.²

Although the use of Toxicodendron plants in modern-day medicine is limited, development of a vaccine (immunotherapy) against Toxicodendron dermatitis offers an exciting opportunity for further research.

Reactions to poison ivy, poison oak, and poison sumac, which affect 10 to 50 million Americans a year,¹ are classified as Toxicodendron dermatitis; 50% to 75% of US adults are clinically sensitive to these plants.² Furthermore, people of all ethnicities, skin types, and ages residing in most US geographical regions are at risk.³ Allergenicity is caused by urushiol, which is found in members of the Anacardiaceae family.⁴ Once absorbed, urushiol causes a type IV hypersensitivity reaction in those who are susceptible.⁵

Cutaneous Manifestations

Toxicodendron dermatitis presents with an acute eczematous eruption characterized by streaks of intensely pruritic and erythematous papules and vesicles (Figure 1). Areas of involvement are characterized by sharp margins that follow the pattern of contact made by the plant’s leaves, berries, stems, and vines.⁶ The fluid content of the vesicles is not antigenic and cannot cause subsequent transmission to oneself or others.³ A person with prior contact to the plant who becomes sensitized develops an eruption 24 to 48 hours after subsequent contact with the plant; peak severity manifests 1 to 14 days later.⁷

When left untreated, the eruption can last 3 weeks. If the plant is burned, urushiol can be aerosolized in smoke, causing respiratory tract inflammation and generalized dermatitis, which has been reported among wildland firefighters.² Long-term complications from an outbreak are limited but can include postinflammatory hyperpigmentation and secondary bacterial infection.⁸ Rare reports of nephrotic syndrome also have appeared in the literature.⁹ Toxicodendron dermatitis can present distinctively as so-called black dot dermatitis.⁶

Nomenclature

Poison ivy, poison oak, and poison sumac are members of the family Anacardiaceae and genus Toxicodendron,⁶ derived from the Greek words toxikos (poison) and dendron (tree).¹⁰

Distribution

Toxicodendron plants characteristically are found in various regions of the United States. Poison ivy is the most common and is comprised of 2 species: Toxicodendron rydbergii and Toxicodendron radicans. Toxicodendron rydbergii is a nonclimbing dwarf shrub typically found in the northern and western United States. Toxicodendron radicans is a climbing vine found in the eastern United States. Poison oak also is comprised of 2 species—Toxicodendron toxicarium and Toxicodendron diversilobum—and is more common in the western United States. Poison sumac (also known as Toxicodendron vernix) is a small shrub that grows in moist swampy areas. It has a predilection for marshes of the eastern and southeastern United States.^6,11

Identifying Features

Educating patients on how to identify poison ivy can play a key role in avoidance, which is the most important step in preventing Toxicodendron dermatitis. A challenge in identification of poison ivy is the plant’s variable appearance; it grows as a small shrub, low-lying vine, or vine that climbs other trees.

As the vine matures, it develops tiny, rough, “hairy” rootlets—hence the saying, “Hairy vine, no friend of mine!” Rootlets help the plant attach to trees growing near a water source. Vines can reach a diameter of 3 inches. From mature vines, solitary stems extend 1 to 2 inches with 3 characteristic leaves at the terminus (Figure 2), prompting another classic saying, “Leaves of 3, let it be!”¹²

Poison oak is characterized by 3 to 5 leaflets. Poison sumac has 7 to 13 pointed, smooth-edged leaves.⁶

Dermatitis-Inducing Plant Parts

The primary allergenic component of Toxicodendron plants is urushiol, a resinous sap found in stems, roots, leaves, and skins of the fruits. These components must be damaged or bruised to release the allergen; slight contact with an uninjured plant part might not lead to harm.^2,13 Some common forms of transmission include skin contact, ingestion, inhalation of smoke from burning plants, and contact with skin through contaminated items, such as clothing, animals, and tools.¹⁴

Allergens

The catecholic ring and aliphatic chain of the urushiol molecule are allergenic.¹⁵ The degree of saturation and length of the side chains vary with different catechols. Urushiol displays cross-reactivity with poison ivy, poison oak, and poison sumac. Urushiol from these plants differs only slightly in structure; therefore, sensitization to one causes sensitization to all. There also is cross-reactivity between different members of the Anacardiaceae family, including Anacardium occidentale (tropical cashew nut), Mangifera indica (tropical mango tree), Ginkgo biloba (ginkgo tree), and Semecarpus anacardium (Indian marking nut tree).¹²

Poison ivy, poison oak, and poison sumac cause allergic contact dermatitis as a type IV hypersensitivity reaction. First, urushiol binds and penetrates the skin, where it is oxidized to quinone intermediates and bound to haptens. Then, the intermediates bind surface proteins on antigen-presenting cells, specifically Langerhans cells in the epidermis and dermis.⁵

Presentation of nonpeptide antigens, such as urushiol, to T cells requires expression of langerin (also known as CD207) and CD1a.¹⁶ Langerin is a C-type lectin that causes formation of Birbeck granules; CD1a is a major histocompatibility complex class I molecule found in Birbeck granules.^5,17 After Langerhans cells internalize and process the urushiol self-hapten neoantigen, it is presented to CD4⁺ T cells.⁶ These cells then expand to form circulating activated T-effector and T-memory lymphocytes.¹⁸

The molecular link that occurs between the hapten and carrier protein determines the response. When linked by an amino nucleophile, selective induction of T-effector cells ensues, resulting in allergic contact dermatitis. When linked by a sulfhydryl bond, selective induction of suppressor cells occurs, resulting in a reduced allergic contact dermatitis response.¹⁹ In the case of activation of T-effector cells, a cell-mediated cytotoxic immune response is generated that destroys epidermal cells and dermal vasculature.² The incidence and intensity of poison ivy sensitivity decline proportionally with age and the absence of continued exposure.²⁰

Preventive Action—Patients should be counseled that if contact between plant and skin occurs, it is important to remove contaminated clothing or objects and wash them with soap to prevent additional exposure.^14,21 Areas of the skin that made contact with the plant should be washed with water as soon as possible; after 30 minutes, urushiol has sufficiently penetrated to cause a reaction.² Forceful unidirectional washing with a damp washcloth and liquid dishwashing soap is recommended.²²

Several barrier creams are commercially available to help prevent absorption or to deactivate the urushiol antigen. These products are used widely by forestry workers and wildland firefighters.²³ One such barrier cream is bentoquatam (sold as various trade names), an organoclay compound made of quaternium-18 bentonite that interferes with absorption of the allergen by acting as a physical blocker.²⁴

Treatment

After Toxicodendron dermatitis develops, several treatments are available to help manage symptoms. Calamine lotion can be used to help dry weeping lesions.^25,26 Topical steroids can be used to help control pruritus and alleviate inflammation. High-potency topical corticosteroids such as clobetasol and mid-potency steroids such as triamcinolone can be used. Topical anesthetics (eg, benzocaine, pramoxine, benzyl alcohol) might provide symptomatic relief.^27,28

Oral antihistamines can allow for better sleep by providing sedation but do not target the pruritus of poison ivy dermatitis, which is not histamine mediated.^29,30 Systemic corticosteroids usually are considered in more severe dermatitis—when 20% or more of the body surface area is involved; blistering and itching are severe; or the face, hands, or genitalia are involved.^31,32

Clinical Uses

Therapeutic uses for poison ivy have been explored extensively. In 1892, Dakin³³ reported that ingestion of leaves by Native Americans reduced the incidence and severity of skin lesions after contact with poison ivy. Consumption of poison ivy was further studied by Epstein and colleagues³⁴ in 1974; they concluded that ingestion of a large amount of urushiol over a period of 3 months or longer may help with hyposensitization—but not complete desensitization—to contact with poison ivy. However, the risk for adverse effects is thought to outweigh benefits because ingestion can cause perianal dermatitis, mucocutaneous sequelae, and systemic contact dermatitis.²

Although the use of Toxicodendron plants in modern-day medicine is limited, development of a vaccine (immunotherapy) against Toxicodendron dermatitis offers an exciting opportunity for further research.

Reactions to poison ivy, poison oak, and poison sumac, which affect 10 to 50 million Americans a year,¹ are classified as Toxicodendron dermatitis; 50% to 75% of US adults are clinically sensitive to these plants.² Furthermore, people of all ethnicities, skin types, and ages residing in most US geographical regions are at risk.³ Allergenicity is caused by urushiol, which is found in members of the Anacardiaceae family.⁴ Once absorbed, urushiol causes a type IV hypersensitivity reaction in those who are susceptible.⁵

Cutaneous Manifestations

Toxicodendron dermatitis presents with an acute eczematous eruption characterized by streaks of intensely pruritic and erythematous papules and vesicles (Figure 1). Areas of involvement are characterized by sharp margins that follow the pattern of contact made by the plant’s leaves, berries, stems, and vines.⁶ The fluid content of the vesicles is not antigenic and cannot cause subsequent transmission to oneself or others.³ A person with prior contact to the plant who becomes sensitized develops an eruption 24 to 48 hours after subsequent contact with the plant; peak severity manifests 1 to 14 days later.⁷

When left untreated, the eruption can last 3 weeks. If the plant is burned, urushiol can be aerosolized in smoke, causing respiratory tract inflammation and generalized dermatitis, which has been reported among wildland firefighters.² Long-term complications from an outbreak are limited but can include postinflammatory hyperpigmentation and secondary bacterial infection.⁸ Rare reports of nephrotic syndrome also have appeared in the literature.⁹ Toxicodendron dermatitis can present distinctively as so-called black dot dermatitis.⁶

Nomenclature

Poison ivy, poison oak, and poison sumac are members of the family Anacardiaceae and genus Toxicodendron,⁶ derived from the Greek words toxikos (poison) and dendron (tree).¹⁰

Distribution

Toxicodendron plants characteristically are found in various regions of the United States. Poison ivy is the most common and is comprised of 2 species: Toxicodendron rydbergii and Toxicodendron radicans. Toxicodendron rydbergii is a nonclimbing dwarf shrub typically found in the northern and western United States. Toxicodendron radicans is a climbing vine found in the eastern United States. Poison oak also is comprised of 2 species—Toxicodendron toxicarium and Toxicodendron diversilobum—and is more common in the western United States. Poison sumac (also known as Toxicodendron vernix) is a small shrub that grows in moist swampy areas. It has a predilection for marshes of the eastern and southeastern United States.^6,11

Identifying Features

Educating patients on how to identify poison ivy can play a key role in avoidance, which is the most important step in preventing Toxicodendron dermatitis. A challenge in identification of poison ivy is the plant’s variable appearance; it grows as a small shrub, low-lying vine, or vine that climbs other trees.

As the vine matures, it develops tiny, rough, “hairy” rootlets—hence the saying, “Hairy vine, no friend of mine!” Rootlets help the plant attach to trees growing near a water source. Vines can reach a diameter of 3 inches. From mature vines, solitary stems extend 1 to 2 inches with 3 characteristic leaves at the terminus (Figure 2), prompting another classic saying, “Leaves of 3, let it be!”¹²

Poison oak is characterized by 3 to 5 leaflets. Poison sumac has 7 to 13 pointed, smooth-edged leaves.⁶

Dermatitis-Inducing Plant Parts

The primary allergenic component of Toxicodendron plants is urushiol, a resinous sap found in stems, roots, leaves, and skins of the fruits. These components must be damaged or bruised to release the allergen; slight contact with an uninjured plant part might not lead to harm.^2,13 Some common forms of transmission include skin contact, ingestion, inhalation of smoke from burning plants, and contact with skin through contaminated items, such as clothing, animals, and tools.¹⁴

Allergens

The catecholic ring and aliphatic chain of the urushiol molecule are allergenic.¹⁵ The degree of saturation and length of the side chains vary with different catechols. Urushiol displays cross-reactivity with poison ivy, poison oak, and poison sumac. Urushiol from these plants differs only slightly in structure; therefore, sensitization to one causes sensitization to all. There also is cross-reactivity between different members of the Anacardiaceae family, including Anacardium occidentale (tropical cashew nut), Mangifera indica (tropical mango tree), Ginkgo biloba (ginkgo tree), and Semecarpus anacardium (Indian marking nut tree).¹²

Poison ivy, poison oak, and poison sumac cause allergic contact dermatitis as a type IV hypersensitivity reaction. First, urushiol binds and penetrates the skin, where it is oxidized to quinone intermediates and bound to haptens. Then, the intermediates bind surface proteins on antigen-presenting cells, specifically Langerhans cells in the epidermis and dermis.⁵

Presentation of nonpeptide antigens, such as urushiol, to T cells requires expression of langerin (also known as CD207) and CD1a.¹⁶ Langerin is a C-type lectin that causes formation of Birbeck granules; CD1a is a major histocompatibility complex class I molecule found in Birbeck granules.^5,17 After Langerhans cells internalize and process the urushiol self-hapten neoantigen, it is presented to CD4⁺ T cells.⁶ These cells then expand to form circulating activated T-effector and T-memory lymphocytes.¹⁸

The molecular link that occurs between the hapten and carrier protein determines the response. When linked by an amino nucleophile, selective induction of T-effector cells ensues, resulting in allergic contact dermatitis. When linked by a sulfhydryl bond, selective induction of suppressor cells occurs, resulting in a reduced allergic contact dermatitis response.¹⁹ In the case of activation of T-effector cells, a cell-mediated cytotoxic immune response is generated that destroys epidermal cells and dermal vasculature.² The incidence and intensity of poison ivy sensitivity decline proportionally with age and the absence of continued exposure.²⁰

Preventive Action—Patients should be counseled that if contact between plant and skin occurs, it is important to remove contaminated clothing or objects and wash them with soap to prevent additional exposure.^14,21 Areas of the skin that made contact with the plant should be washed with water as soon as possible; after 30 minutes, urushiol has sufficiently penetrated to cause a reaction.² Forceful unidirectional washing with a damp washcloth and liquid dishwashing soap is recommended.²²

Several barrier creams are commercially available to help prevent absorption or to deactivate the urushiol antigen. These products are used widely by forestry workers and wildland firefighters.²³ One such barrier cream is bentoquatam (sold as various trade names), an organoclay compound made of quaternium-18 bentonite that interferes with absorption of the allergen by acting as a physical blocker.²⁴

Treatment

After Toxicodendron dermatitis develops, several treatments are available to help manage symptoms. Calamine lotion can be used to help dry weeping lesions.^25,26 Topical steroids can be used to help control pruritus and alleviate inflammation. High-potency topical corticosteroids such as clobetasol and mid-potency steroids such as triamcinolone can be used. Topical anesthetics (eg, benzocaine, pramoxine, benzyl alcohol) might provide symptomatic relief.^27,28

Oral antihistamines can allow for better sleep by providing sedation but do not target the pruritus of poison ivy dermatitis, which is not histamine mediated.^29,30 Systemic corticosteroids usually are considered in more severe dermatitis—when 20% or more of the body surface area is involved; blistering and itching are severe; or the face, hands, or genitalia are involved.^31,32

Clinical Uses

Therapeutic uses for poison ivy have been explored extensively. In 1892, Dakin³³ reported that ingestion of leaves by Native Americans reduced the incidence and severity of skin lesions after contact with poison ivy. Consumption of poison ivy was further studied by Epstein and colleagues³⁴ in 1974; they concluded that ingestion of a large amount of urushiol over a period of 3 months or longer may help with hyposensitization—but not complete desensitization—to contact with poison ivy. However, the risk for adverse effects is thought to outweigh benefits because ingestion can cause perianal dermatitis, mucocutaneous sequelae, and systemic contact dermatitis.²

Although the use of Toxicodendron plants in modern-day medicine is limited, development of a vaccine (immunotherapy) against Toxicodendron dermatitis offers an exciting opportunity for further research.

Cutaneous Manifestations

Contact dermatitis is a common problem for individuals who work in the floral industry. Hand dermatitis has been reported in as many as 26% of floral employees.¹Tulipa species have been identified as one of the most common causes of hand dermatitis. Tulipalin A (α-methylene-γ-butyrolactone) is the main sensitizer in tulips (Figure 1) and its precursor tuliposide A also occurs both in tulips and the Peruvian lily (Alstroemeria).

In a 1996 study, 18% (9/51) of tulip workers were found to be allergic to tulipalin A.² In a more recent study of 164 tulip workers, 48 (29.3%) had clinical evidence of contact dermatitis and subsequently underwent patch testing; 17 (35.4%) showed a positive reaction to either tulipalin A or to tulip-bulb extract.³ Itching was the most common symptom (39 workers [81.3%]) and hand eczema at the tip of the thumb and index finger was the most common finding. In 9 (18.8%) workers, eczema had spread to other body parts including the forearm, face, legs, and abdomen.³

Peruvian lily is widely used in floral arrangements and has become a leading cause of hand dermatitis in florists (Figure 2). Large amounts of free tulipalin A are present in bulb scales of tulips, along with a small amount of tuliposide A. In young developing shoots, the situation is reversed: Both compounds are found in all parts of the plant to some degree, though tulipalin A is the major allergen, and more mature parts of the plant and bulb are most allergenic.

Cultural Considerations

In traditional Kurdish cuisine, raw herbs are part of snacking or are served as a side dish (sawza). Snacks often are consumed raw on the spot. Tulipa montana, Tulipa armena, and possibly other Tulipa species are consumed as a snack.⁴ Traditionally, Tulipa systola is consumed by the Kurds as an anti-inflammatory medicine and for pain relief. It also has been proposed that T systola has antioxidant properties.⁵ Cooked tulip also has been consumed in time of famine in Europe, though none of these dietary practices are recommended.⁴

Clinical Presentation

“Tulip fingers” describes the most common presentation of contact dermatitis caused by tulip bulbs. Erythematous scaling plaques are seen in the periungual skin and first and second fingertips of the dominant hand. Other manifestations include diffuse dry dermatitis of the hand; paronychia; pulpitis; and secondary spread to the face, neck, arms, and genitalia, with eczematous papules and plaques.⁶ Clinical signs include erythema, vesicles, hyperkeratosis, and exfoliation of the fingertips. The allergen also can cause airborne contact dermatitis and manifest as conjunctivitis, rhinitis, and asthma.² A considerable number of tulip workers develop paresthesia and tenderness in the fingertips within several hours after working with tulip bulbs, known as “tulip fire.”⁷

Plant Facts

There are approximately 250 genera of bulbous plants. Tulips are members of the genus Tulipa and family Liliaceae. Tulips often are thought of as native to southwest central Asia and Turkey⁸; however, Tulipa sylvestris is native to Portugal, Spain, and North Africa.

Etymology and Symbolism—The word tulip is derived from the Turkish word türbent meaning a turban, possibly because the flower is compared to turbans worn by men of the Ottoman Empire in the 16th century. In Turkish culture, the tulip is a symbol of paradise on earth and can have divine status. In the Netherlands, on the other hand, the tulip represents the briefness of life.

History—By 1562, tulip bulbs had already been introduced to Holland by merchants. However, the first shipment of tulip bulbs was mistaken by the Dutch for onions and were either roasted over a fire or perished when planted in gardens with vegetables. Carolus Clusius—botanist, director of the imperial medical garden in Vienna and recipient of many plants through diplomatic channels—was particularly fond of flower bulbs and contributed to the popularity of the tulip in Europe by sending bulbs and seeds to other European countries.

In the early 17th century, the tulip craze began in France, fueled by a viral disease of tulips that produced variegated color patterns on the petals; entire properties were sold in exchange for a single tulip bulb. The tulip craze drifted from France to Holland in 1634 for 3 years before the tulip market collapsed.

More recently, in 2003 investors started a multimillion-euro tulip fund in the Netherlands to develop new varieties of tulip. Tulip bulbs were used to create money with high percentages over the selling price. With exorbitant pricing and ever-changing ownership of bulbs—bulbs were bought and sold as many as 10 times—the tulip fund collapsed 1 year later and investors lost their money. Bulb speculators then took their profit abroad. In 2006, bulb owners were charged with fraud; the tulip craze often is cited as one of the early major stock market collapses.

Tulips continue to grow in popularity. Today, nearly 6000 cultivars are registered, with 40 new cultivars registered every 5 years.⁹

Identifying Features

At the base of the erect tulip plant is a cluster of 2 or 3 thick bluish-green leaves. Three petals and 3 sepals make up the solitary bell-shaped flower. Many tulips can propagate only by means of their scaly bulbs. The flowers arise from the tips of stems in different solid colors, except true blue—from pure white to all shades of yellow, red, and a deep purple that is almost black. Solid-color tulips are called “self-colored.” So-called broken tulips are individual flowers with multiple colors, a condition caused by a viral disease transmitted by aphids.¹⁰

Tulip Allergen

Tuliposide A is found in many species of the genera Tulipa, Alstroemeria, and Erythronium.⁶ So far, 7 analogs have been identified: 1-tuliposide A and B; 6-tuliposide A and B; and tuliposides D, E, and F. 6-Tuliposide A and B are the principal tuliposides found in tulip cultivars.¹¹ With trauma and maturation, tuliposides A and B are hydrolyzed to tulipalin A and tulipalin B, respectively.

Tulipalin A and tulipalin B have antimicrobial properties against bacteria and fungi; tulipalin A is mostly an antifungal agent, and tulipalin B has mostly bacteriostatic characteristics.¹² The highest concentration of tulipalin A is found in the outer layer of the bulb, followed by (in descending order) the stem, leaves, and petals.¹³

The prevalence of tulipalin A allergy led the German Federal Institute for Risk Assessment to assign tuliposide A and tulipalin A to category B, which is a “solid-based indication for contact allergenic effects”; both chemicals also are considered skin sensitizers, defined by the Globally Harmonized System of Classification and Labelling of Chemicals of the United Nations as a substance that will induce an allergic response following skin contact.¹⁴ Patients who are allergic to tulips have cross-sensitivity to Alstroemeria because tuliposide A and its metabolites are found in both plants.¹⁵

Symptoms of an allergic response to tulipalin A can be immediate or delayed.¹⁴ The most common allergic contact dermatitis caused by tulip bulbs is type IV hypersensitivity, though type I reactions can occur. Symptoms of a type I reaction including contact urticaria, rhinitis, hoarseness, and dyspnea have been reported.¹⁴

The variety of tulip handled also contributes to the severity of dermatitis. Handling bulbs of Rose Copeland variety tulips and cutting the flowers of Preludium tulips have been associated with more severe allergic dermatitis presentations, whereas the Red Emperor tulip was found to have less tuliposide A and thus provoke a weaker patch-test reaction.⁷

A Word About Garlic—Garlic is in the subfamily Allioideae (formerly Alliaceae) taxonomically related to the tulip family (Liliaceae). Garlic also can cause hand dermatitis in cooks, with a similar clinical appearance as tulip fingers. Gas chromatography has shown that garlic contains predominantly tuliposide B, which has been found to be much less allergenic than tuliposide A.^7,16

Prevention of Tulipa Dermatitis

Tuliposide A and its metabolites can be found in storehouses and trucks used to transport tulips, in clothing, and in any other place where dust containing the allergen has settled. The best prevention against contact dermatitis is to avoid the inciting plants. Gloves may prevent contact dermatitis due to tuliposide A, which penetrates vinyl but not nitrile gloves. Barrier creams have been proposed, but data are scant.¹

Cutaneous Manifestations

Contact dermatitis is a common problem for individuals who work in the floral industry. Hand dermatitis has been reported in as many as 26% of floral employees.¹Tulipa species have been identified as one of the most common causes of hand dermatitis. Tulipalin A (α-methylene-γ-butyrolactone) is the main sensitizer in tulips (Figure 1) and its precursor tuliposide A also occurs both in tulips and the Peruvian lily (Alstroemeria).

In a 1996 study, 18% (9/51) of tulip workers were found to be allergic to tulipalin A.² In a more recent study of 164 tulip workers, 48 (29.3%) had clinical evidence of contact dermatitis and subsequently underwent patch testing; 17 (35.4%) showed a positive reaction to either tulipalin A or to tulip-bulb extract.³ Itching was the most common symptom (39 workers [81.3%]) and hand eczema at the tip of the thumb and index finger was the most common finding. In 9 (18.8%) workers, eczema had spread to other body parts including the forearm, face, legs, and abdomen.³

Peruvian lily is widely used in floral arrangements and has become a leading cause of hand dermatitis in florists (Figure 2). Large amounts of free tulipalin A are present in bulb scales of tulips, along with a small amount of tuliposide A. In young developing shoots, the situation is reversed: Both compounds are found in all parts of the plant to some degree, though tulipalin A is the major allergen, and more mature parts of the plant and bulb are most allergenic.

Cultural Considerations

In traditional Kurdish cuisine, raw herbs are part of snacking or are served as a side dish (sawza). Snacks often are consumed raw on the spot. Tulipa montana, Tulipa armena, and possibly other Tulipa species are consumed as a snack.⁴ Traditionally, Tulipa systola is consumed by the Kurds as an anti-inflammatory medicine and for pain relief. It also has been proposed that T systola has antioxidant properties.⁵ Cooked tulip also has been consumed in time of famine in Europe, though none of these dietary practices are recommended.⁴

Clinical Presentation

“Tulip fingers” describes the most common presentation of contact dermatitis caused by tulip bulbs. Erythematous scaling plaques are seen in the periungual skin and first and second fingertips of the dominant hand. Other manifestations include diffuse dry dermatitis of the hand; paronychia; pulpitis; and secondary spread to the face, neck, arms, and genitalia, with eczematous papules and plaques.⁶ Clinical signs include erythema, vesicles, hyperkeratosis, and exfoliation of the fingertips. The allergen also can cause airborne contact dermatitis and manifest as conjunctivitis, rhinitis, and asthma.² A considerable number of tulip workers develop paresthesia and tenderness in the fingertips within several hours after working with tulip bulbs, known as “tulip fire.”⁷

Plant Facts

There are approximately 250 genera of bulbous plants. Tulips are members of the genus Tulipa and family Liliaceae. Tulips often are thought of as native to southwest central Asia and Turkey⁸; however, Tulipa sylvestris is native to Portugal, Spain, and North Africa.

Etymology and Symbolism—The word tulip is derived from the Turkish word türbent meaning a turban, possibly because the flower is compared to turbans worn by men of the Ottoman Empire in the 16th century. In Turkish culture, the tulip is a symbol of paradise on earth and can have divine status. In the Netherlands, on the other hand, the tulip represents the briefness of life.

History—By 1562, tulip bulbs had already been introduced to Holland by merchants. However, the first shipment of tulip bulbs was mistaken by the Dutch for onions and were either roasted over a fire or perished when planted in gardens with vegetables. Carolus Clusius—botanist, director of the imperial medical garden in Vienna and recipient of many plants through diplomatic channels—was particularly fond of flower bulbs and contributed to the popularity of the tulip in Europe by sending bulbs and seeds to other European countries.

In the early 17th century, the tulip craze began in France, fueled by a viral disease of tulips that produced variegated color patterns on the petals; entire properties were sold in exchange for a single tulip bulb. The tulip craze drifted from France to Holland in 1634 for 3 years before the tulip market collapsed.

More recently, in 2003 investors started a multimillion-euro tulip fund in the Netherlands to develop new varieties of tulip. Tulip bulbs were used to create money with high percentages over the selling price. With exorbitant pricing and ever-changing ownership of bulbs—bulbs were bought and sold as many as 10 times—the tulip fund collapsed 1 year later and investors lost their money. Bulb speculators then took their profit abroad. In 2006, bulb owners were charged with fraud; the tulip craze often is cited as one of the early major stock market collapses.

Tulips continue to grow in popularity. Today, nearly 6000 cultivars are registered, with 40 new cultivars registered every 5 years.⁹

Identifying Features

At the base of the erect tulip plant is a cluster of 2 or 3 thick bluish-green leaves. Three petals and 3 sepals make up the solitary bell-shaped flower. Many tulips can propagate only by means of their scaly bulbs. The flowers arise from the tips of stems in different solid colors, except true blue—from pure white to all shades of yellow, red, and a deep purple that is almost black. Solid-color tulips are called “self-colored.” So-called broken tulips are individual flowers with multiple colors, a condition caused by a viral disease transmitted by aphids.¹⁰

Tulip Allergen

Tuliposide A is found in many species of the genera Tulipa, Alstroemeria, and Erythronium.⁶ So far, 7 analogs have been identified: 1-tuliposide A and B; 6-tuliposide A and B; and tuliposides D, E, and F. 6-Tuliposide A and B are the principal tuliposides found in tulip cultivars.¹¹ With trauma and maturation, tuliposides A and B are hydrolyzed to tulipalin A and tulipalin B, respectively.

Tulipalin A and tulipalin B have antimicrobial properties against bacteria and fungi; tulipalin A is mostly an antifungal agent, and tulipalin B has mostly bacteriostatic characteristics.¹² The highest concentration of tulipalin A is found in the outer layer of the bulb, followed by (in descending order) the stem, leaves, and petals.¹³

The prevalence of tulipalin A allergy led the German Federal Institute for Risk Assessment to assign tuliposide A and tulipalin A to category B, which is a “solid-based indication for contact allergenic effects”; both chemicals also are considered skin sensitizers, defined by the Globally Harmonized System of Classification and Labelling of Chemicals of the United Nations as a substance that will induce an allergic response following skin contact.¹⁴ Patients who are allergic to tulips have cross-sensitivity to Alstroemeria because tuliposide A and its metabolites are found in both plants.¹⁵

Symptoms of an allergic response to tulipalin A can be immediate or delayed.¹⁴ The most common allergic contact dermatitis caused by tulip bulbs is type IV hypersensitivity, though type I reactions can occur. Symptoms of a type I reaction including contact urticaria, rhinitis, hoarseness, and dyspnea have been reported.¹⁴

The variety of tulip handled also contributes to the severity of dermatitis. Handling bulbs of Rose Copeland variety tulips and cutting the flowers of Preludium tulips have been associated with more severe allergic dermatitis presentations, whereas the Red Emperor tulip was found to have less tuliposide A and thus provoke a weaker patch-test reaction.⁷

A Word About Garlic—Garlic is in the subfamily Allioideae (formerly Alliaceae) taxonomically related to the tulip family (Liliaceae). Garlic also can cause hand dermatitis in cooks, with a similar clinical appearance as tulip fingers. Gas chromatography has shown that garlic contains predominantly tuliposide B, which has been found to be much less allergenic than tuliposide A.^7,16

Prevention of Tulipa Dermatitis

Tuliposide A and its metabolites can be found in storehouses and trucks used to transport tulips, in clothing, and in any other place where dust containing the allergen has settled. The best prevention against contact dermatitis is to avoid the inciting plants. Gloves may prevent contact dermatitis due to tuliposide A, which penetrates vinyl but not nitrile gloves. Barrier creams have been proposed, but data are scant.¹

Cutaneous Manifestations

Contact dermatitis is a common problem for individuals who work in the floral industry. Hand dermatitis has been reported in as many as 26% of floral employees.¹Tulipa species have been identified as one of the most common causes of hand dermatitis. Tulipalin A (α-methylene-γ-butyrolactone) is the main sensitizer in tulips (Figure 1) and its precursor tuliposide A also occurs both in tulips and the Peruvian lily (Alstroemeria).

In a 1996 study, 18% (9/51) of tulip workers were found to be allergic to tulipalin A.² In a more recent study of 164 tulip workers, 48 (29.3%) had clinical evidence of contact dermatitis and subsequently underwent patch testing; 17 (35.4%) showed a positive reaction to either tulipalin A or to tulip-bulb extract.³ Itching was the most common symptom (39 workers [81.3%]) and hand eczema at the tip of the thumb and index finger was the most common finding. In 9 (18.8%) workers, eczema had spread to other body parts including the forearm, face, legs, and abdomen.³

Peruvian lily is widely used in floral arrangements and has become a leading cause of hand dermatitis in florists (Figure 2). Large amounts of free tulipalin A are present in bulb scales of tulips, along with a small amount of tuliposide A. In young developing shoots, the situation is reversed: Both compounds are found in all parts of the plant to some degree, though tulipalin A is the major allergen, and more mature parts of the plant and bulb are most allergenic.

Cultural Considerations

In traditional Kurdish cuisine, raw herbs are part of snacking or are served as a side dish (sawza). Snacks often are consumed raw on the spot. Tulipa montana, Tulipa armena, and possibly other Tulipa species are consumed as a snack.⁴ Traditionally, Tulipa systola is consumed by the Kurds as an anti-inflammatory medicine and for pain relief. It also has been proposed that T systola has antioxidant properties.⁵ Cooked tulip also has been consumed in time of famine in Europe, though none of these dietary practices are recommended.⁴

Clinical Presentation

“Tulip fingers” describes the most common presentation of contact dermatitis caused by tulip bulbs. Erythematous scaling plaques are seen in the periungual skin and first and second fingertips of the dominant hand. Other manifestations include diffuse dry dermatitis of the hand; paronychia; pulpitis; and secondary spread to the face, neck, arms, and genitalia, with eczematous papules and plaques.⁶ Clinical signs include erythema, vesicles, hyperkeratosis, and exfoliation of the fingertips. The allergen also can cause airborne contact dermatitis and manifest as conjunctivitis, rhinitis, and asthma.² A considerable number of tulip workers develop paresthesia and tenderness in the fingertips within several hours after working with tulip bulbs, known as “tulip fire.”⁷

Plant Facts

There are approximately 250 genera of bulbous plants. Tulips are members of the genus Tulipa and family Liliaceae. Tulips often are thought of as native to southwest central Asia and Turkey⁸; however, Tulipa sylvestris is native to Portugal, Spain, and North Africa.

Etymology and Symbolism—The word tulip is derived from the Turkish word türbent meaning a turban, possibly because the flower is compared to turbans worn by men of the Ottoman Empire in the 16th century. In Turkish culture, the tulip is a symbol of paradise on earth and can have divine status. In the Netherlands, on the other hand, the tulip represents the briefness of life.

History—By 1562, tulip bulbs had already been introduced to Holland by merchants. However, the first shipment of tulip bulbs was mistaken by the Dutch for onions and were either roasted over a fire or perished when planted in gardens with vegetables. Carolus Clusius—botanist, director of the imperial medical garden in Vienna and recipient of many plants through diplomatic channels—was particularly fond of flower bulbs and contributed to the popularity of the tulip in Europe by sending bulbs and seeds to other European countries.

In the early 17th century, the tulip craze began in France, fueled by a viral disease of tulips that produced variegated color patterns on the petals; entire properties were sold in exchange for a single tulip bulb. The tulip craze drifted from France to Holland in 1634 for 3 years before the tulip market collapsed.

More recently, in 2003 investors started a multimillion-euro tulip fund in the Netherlands to develop new varieties of tulip. Tulip bulbs were used to create money with high percentages over the selling price. With exorbitant pricing and ever-changing ownership of bulbs—bulbs were bought and sold as many as 10 times—the tulip fund collapsed 1 year later and investors lost their money. Bulb speculators then took their profit abroad. In 2006, bulb owners were charged with fraud; the tulip craze often is cited as one of the early major stock market collapses.

Tulips continue to grow in popularity. Today, nearly 6000 cultivars are registered, with 40 new cultivars registered every 5 years.⁹

Identifying Features

At the base of the erect tulip plant is a cluster of 2 or 3 thick bluish-green leaves. Three petals and 3 sepals make up the solitary bell-shaped flower. Many tulips can propagate only by means of their scaly bulbs. The flowers arise from the tips of stems in different solid colors, except true blue—from pure white to all shades of yellow, red, and a deep purple that is almost black. Solid-color tulips are called “self-colored.” So-called broken tulips are individual flowers with multiple colors, a condition caused by a viral disease transmitted by aphids.¹⁰

Tulip Allergen

Tuliposide A is found in many species of the genera Tulipa, Alstroemeria, and Erythronium.⁶ So far, 7 analogs have been identified: 1-tuliposide A and B; 6-tuliposide A and B; and tuliposides D, E, and F. 6-Tuliposide A and B are the principal tuliposides found in tulip cultivars.¹¹ With trauma and maturation, tuliposides A and B are hydrolyzed to tulipalin A and tulipalin B, respectively.

Tulipalin A and tulipalin B have antimicrobial properties against bacteria and fungi; tulipalin A is mostly an antifungal agent, and tulipalin B has mostly bacteriostatic characteristics.¹² The highest concentration of tulipalin A is found in the outer layer of the bulb, followed by (in descending order) the stem, leaves, and petals.¹³

The prevalence of tulipalin A allergy led the German Federal Institute for Risk Assessment to assign tuliposide A and tulipalin A to category B, which is a “solid-based indication for contact allergenic effects”; both chemicals also are considered skin sensitizers, defined by the Globally Harmonized System of Classification and Labelling of Chemicals of the United Nations as a substance that will induce an allergic response following skin contact.¹⁴ Patients who are allergic to tulips have cross-sensitivity to Alstroemeria because tuliposide A and its metabolites are found in both plants.¹⁵

Symptoms of an allergic response to tulipalin A can be immediate or delayed.¹⁴ The most common allergic contact dermatitis caused by tulip bulbs is type IV hypersensitivity, though type I reactions can occur. Symptoms of a type I reaction including contact urticaria, rhinitis, hoarseness, and dyspnea have been reported.¹⁴

The variety of tulip handled also contributes to the severity of dermatitis. Handling bulbs of Rose Copeland variety tulips and cutting the flowers of Preludium tulips have been associated with more severe allergic dermatitis presentations, whereas the Red Emperor tulip was found to have less tuliposide A and thus provoke a weaker patch-test reaction.⁷

A Word About Garlic—Garlic is in the subfamily Allioideae (formerly Alliaceae) taxonomically related to the tulip family (Liliaceae). Garlic also can cause hand dermatitis in cooks, with a similar clinical appearance as tulip fingers. Gas chromatography has shown that garlic contains predominantly tuliposide B, which has been found to be much less allergenic than tuliposide A.^7,16

Prevention of Tulipa Dermatitis

Tuliposide A and its metabolites can be found in storehouses and trucks used to transport tulips, in clothing, and in any other place where dust containing the allergen has settled. The best prevention against contact dermatitis is to avoid the inciting plants. Gloves may prevent contact dermatitis due to tuliposide A, which penetrates vinyl but not nitrile gloves. Barrier creams have been proposed, but data are scant.¹

An ancient tree of the Ginkgoaceae family, Ginkgo biloba is known as a living fossil because its genome has been identified in fossils older than 200 million years.¹ An individual tree can live longer than 1000 years. Originating in China, G biloba (here, “ginkgo”) is cultivated worldwide for its attractive foliage (Figure 1). Ginkgo extract has long been used in traditional Chinese medicine; however, contact with the plant proper can provoke allergic contact dermatitis.

Dermatitis-Inducing Components

The allergenic component of the ginkgo tree is ginkgolic acid, which is structurally similar to urushiol and anacardic acid.^2,3 This compound can cause a cross-reaction in a person previously sensitized by contact with other plants. Urushiol is found in poison ivy(Toxicodendron radicans); anacardic acid is found in the cashew tree (Anacardium occidentale). Both plants belong to the family Anacardiaceae, commonly known as the cashew family.

Members of Anacardiaceae are the most common causes of plant-induced allergic contact dermatitis and include the cashew tree, mango tree, poison ivy, poison oak, and poison sumac. These plants can cross-react to cause contact dermatitis (Table).³ Patch tests have revealed that some individuals who are sensitive to components of the ginkgo tree also demonstrate sensitivity to poison ivy and poison sumac^4,5; countering this finding, Lepoittevin and colleagues⁶ demonstrated in animal studies that there was no cross-reactivity between ginkgo and urushiol, suggesting that patients with a reported cross-reaction might truly have been previously sensitized to both plants. In general, patients who have a history of a reaction to any Anacardiaceae plant should take precautions when handling them.

Therapeutic Benefit of Ginkgo

Ginkgo extract is sold as the herbal supplement EGB761, which acts as an antioxidant.⁷ In France, Germany, and China, it is a commonly prescribed herbal medicine.⁸ It is purported to support memory and attention; studies have shown improvement in cognition and in involvement with activities of daily living for patients with dementia.^9,10 Ginkgo extract might lessen peripheral vascular disease and cerebral circulatory disease, having been shown in vitro and in animal models to prevent platelet aggregation induced by platelet-activating factor and to stimulate vasodilation by increasing production of nitric oxide.^11,12

Furthermore, purified ginkgo extract might have beneficial effects on skin. A study in rats showed that when intraperitoneal ginkgo extract was given prior to radiation therapy, 100% of rats receiving placebo developed radiation dermatitis vs 13% of those that received ginkgo extract (P<.0001). An excisional skin biopsy showed a decrease in markers of oxidative stress in rats that received ginkgo extract prior to radiation.⁷

A randomized, double-blind clinical trial showed a significant reduction in disease progression in vitiligo patients assigned to receive ginkgo extract orally compared to placebo (P=.006).¹³ Research for many possible uses of ginkgo extract is ongoing.

Cutaneous Manifestations

Contact with the fruit of the ginkgo tree can induce allergic contact dermatitis,¹⁴ most often as erythematous papules, vesicles, and in some cases edema.^5,15

Exposures While Picking Berries—In 1939, Bolus¹⁵ reported the case of a patient who presented with edema, erythema, and vesicular lesions involving the hands and face after picking berries from a ginkgo tree. Later, patch testing on this patient, using ginkgo fruit, resulted in burning and stinging that necessitated removal of the patch, suggesting an irritant reaction. This was followed by a vesicular reaction that then developed within 24 hours, which was more consistent with allergy. Similarly, in 1988, a case series of contact dermatitis was reported in 3 patients after gathering ginkgo fruit.⁵

Incidental Exposure While Walking—In 1965, dermatitis broke out in 35 high school students, mainly affecting exposed portions of the leg, after ginkgo fruit fell and its pulp was exposed on a path at their school.⁴ Subsequently, patch testing was performed on 29 volunteers—some who had been exposed to ginkgo on that path, others without prior exposure. It was established that testing with ginkgo pulp directly caused an irritant reaction in all students, regardless of prior ginkgo exposure, but all prior ginkgo-exposed students in this study reacted positively to an acetone extract of ginkgo pulp and either poison ivy extract or pentadecylcatechol.⁴

Systemic Contact After Eating Fruit—An illustrative case of dermatitis, stomatitis, and proctitis was reported in a man with history of poison oak contact dermatitis who had eaten fruit from a ginkgo tree, suggesting systemic contact dermatitis. Weeks after resolution of symptoms, he reacted positively to ginkgo fruit and poison ivy extracts on patch testing.¹⁶

Ginkgo dermatitis tends to resolve upon removal of the inciting agent and application of a topical steroid.^8,17 Although many reported cases involve the fruit, allergic contact dermatitis can result from exposure to any part of the plant. In a reported case, a woman developed airborne contact dermatitis from working with sarcotesta of the ginkgo plant.¹⁸ Despite wearing rubber gloves, she broke out 1 week after exposure with erythema on the face and arms and severe facial edema.

Ginkgo leaves also can cause allergic contact dermatitis.¹⁹ Precautions should be taken when handling any component of the ginkgo tree.

Oral ginkgo supplementation has been implicated in a variety of other cutaneous reactions—from benign to life-threatening. When the ginkgo allergen concentration is too high within the supplement, as has been noted in some formulations, patients have presented with a diffuse morbilliform eruption within 1 or 2 weeks after taking ginkgo.²⁰ One patient—who was not taking any other medication—experienced an episode of acute generalized exanthematous pustulosis 48 hours after taking ginkgo.²¹ Ingestion of ginkgo extract also has been associated with Stevens-Johnson syndrome.^22-24

Other Adverse Reactions

The adverse effects of ginkgo supplement vary widely. In addition to dermatitis, ginkgo supplement can cause headaches, palpitations, tachycardia, vasculitis, nausea, and other symptoms.¹⁴

Metabolic Disturbance—One patient taking ginkgo who died after a seizure was found to have subtherapeutic levels of valproate and phenytoin,²⁵ which could be due to ginkgo’s effect on cytochrome p450 enzyme CYP2C19.²⁶ Ginkgo interactions with many cytochrome enzymes have been studied for potential drug interactions. Any other direct effects remain variable and controversial.^27,28

Hemorrhage—Another serious effect associated with taking ginkgo supplements is hemorrhage, often in conjunction with warfarin¹⁴; however, a meta-analysis indicated that ginkgo generally does not increase the risk of bleeding.²⁹ Other studies have shown that taking ginkgo with warfarin showed no difference in clotting status, and ginkgo with aspirin resulted in no clinically significant difference in bruising, bleeding, or platelet function in an analysis over a period of 1 month.^30,31 These findings notwithstanding, pregnant women, surgical patients, and those taking a blood thinner are advised as a general precaution not to take ginkgo extract.

Carcinogenesis—Ginkgo extract has antioxidant properties, but there is evidence that it might act as a carcinogen. An animal study reported by the US National Toxicology Program found that ginkgo induced mutagenic activity in the liver, thyroid, and nose of mice and rats. Over time, rodent liver underwent changes consistent with hepatic enzyme induction.³² More research is needed to clarify the role of ginkgo in this process.

Toxicity by Ingestion—Ginkgo seeds can cause food poisoning due to the compound 4’-O-methylpyridoxine (also known as ginkgotoxin).³³ Because methylpyridoxine can cause depletion of pyridoxal phosphate (a form of vitamin B₆ necessary for the synthesis of γ-aminobutyric acid), overconsumption of ginkgo seeds, even when fully cooked, might result in convulsions and even death.³³

Nomenclature and Distribution of Plants

Gingko biloba belongs to the Ginkgoaceae family (class Ginkgophytes). The tree originated in China but might no longer exist in a truly wild form. It is grown worldwide for its beauty and longevity. The female ginkgo tree is a gymnosperm, producing fruit with seeds that are not coated by an ovary wall¹⁵; male (nonfruiting) trees are preferentially planted because the fruit is surrounded by a pulp that, when dropped, emits a sour smell described variously as rancid butter, vomit, or excrement.⁵

Identifying Features and Plant Facts

The deciduous ginkgo tree has unique fan-shaped leaves and is cultivated for its beauty and resistance to disease (Figure 2).^4,34 It is nicknamed the maidenhair tree because the leaves are similar to the pinnae of the maidenhair fern.³⁴ Because G biloba is resistant to pollution, it often is planted along city streets.¹⁷ The leaf—5- to 8-cm wide and a symbol of the city of Tokyo, Japan³⁴—grows in clusters (Figure 3)⁵ and is green but turns yellow before it falls in autumn.³⁴ Leaf veins branch out into the blade without anastomosing.³⁴

Male flowers grow in a catkinlike pattern; female flowers grow on long stems.⁵ The fruit is small, dark, and shriveled, with a hint of silver⁴; it typically is 2 to 2.5 cm in diameter and contains the ginkgo nut or seed. The kernel of the ginkgo nut is edible when roasted and is used in traditional Chinese and Japanese cuisine as a dish served on special occasions in autumn.³³

Final Thoughts

Given that G biloba is a beautiful, commonly planted ornamental tree, gardeners and landscapers should be aware of the risk for allergic contact dermatitis and use proper protection. Dermatologists should be aware of its cross-reactivity with other common plants such as poison ivy and poison oak to help patients identify the cause of their reactions and avoid the inciting agent. Because ginkgo extract also can cause a cutaneous reaction or interact with other medications, providers should remember to take a thorough medication history that includes herbal medicines and supplements.

An ancient tree of the Ginkgoaceae family, Ginkgo biloba is known as a living fossil because its genome has been identified in fossils older than 200 million years.¹ An individual tree can live longer than 1000 years. Originating in China, G biloba (here, “ginkgo”) is cultivated worldwide for its attractive foliage (Figure 1). Ginkgo extract has long been used in traditional Chinese medicine; however, contact with the plant proper can provoke allergic contact dermatitis.

Dermatitis-Inducing Components

The allergenic component of the ginkgo tree is ginkgolic acid, which is structurally similar to urushiol and anacardic acid.^2,3 This compound can cause a cross-reaction in a person previously sensitized by contact with other plants. Urushiol is found in poison ivy(Toxicodendron radicans); anacardic acid is found in the cashew tree (Anacardium occidentale). Both plants belong to the family Anacardiaceae, commonly known as the cashew family.

Members of Anacardiaceae are the most common causes of plant-induced allergic contact dermatitis and include the cashew tree, mango tree, poison ivy, poison oak, and poison sumac. These plants can cross-react to cause contact dermatitis (Table).³ Patch tests have revealed that some individuals who are sensitive to components of the ginkgo tree also demonstrate sensitivity to poison ivy and poison sumac^4,5; countering this finding, Lepoittevin and colleagues⁶ demonstrated in animal studies that there was no cross-reactivity between ginkgo and urushiol, suggesting that patients with a reported cross-reaction might truly have been previously sensitized to both plants. In general, patients who have a history of a reaction to any Anacardiaceae plant should take precautions when handling them.

Therapeutic Benefit of Ginkgo

Ginkgo extract is sold as the herbal supplement EGB761, which acts as an antioxidant.⁷ In France, Germany, and China, it is a commonly prescribed herbal medicine.⁸ It is purported to support memory and attention; studies have shown improvement in cognition and in involvement with activities of daily living for patients with dementia.^9,10 Ginkgo extract might lessen peripheral vascular disease and cerebral circulatory disease, having been shown in vitro and in animal models to prevent platelet aggregation induced by platelet-activating factor and to stimulate vasodilation by increasing production of nitric oxide.^11,12

Furthermore, purified ginkgo extract might have beneficial effects on skin. A study in rats showed that when intraperitoneal ginkgo extract was given prior to radiation therapy, 100% of rats receiving placebo developed radiation dermatitis vs 13% of those that received ginkgo extract (P<.0001). An excisional skin biopsy showed a decrease in markers of oxidative stress in rats that received ginkgo extract prior to radiation.⁷

A randomized, double-blind clinical trial showed a significant reduction in disease progression in vitiligo patients assigned to receive ginkgo extract orally compared to placebo (P=.006).¹³ Research for many possible uses of ginkgo extract is ongoing.

Cutaneous Manifestations

Contact with the fruit of the ginkgo tree can induce allergic contact dermatitis,¹⁴ most often as erythematous papules, vesicles, and in some cases edema.^5,15

Exposures While Picking Berries—In 1939, Bolus¹⁵ reported the case of a patient who presented with edema, erythema, and vesicular lesions involving the hands and face after picking berries from a ginkgo tree. Later, patch testing on this patient, using ginkgo fruit, resulted in burning and stinging that necessitated removal of the patch, suggesting an irritant reaction. This was followed by a vesicular reaction that then developed within 24 hours, which was more consistent with allergy. Similarly, in 1988, a case series of contact dermatitis was reported in 3 patients after gathering ginkgo fruit.⁵

Incidental Exposure While Walking—In 1965, dermatitis broke out in 35 high school students, mainly affecting exposed portions of the leg, after ginkgo fruit fell and its pulp was exposed on a path at their school.⁴ Subsequently, patch testing was performed on 29 volunteers—some who had been exposed to ginkgo on that path, others without prior exposure. It was established that testing with ginkgo pulp directly caused an irritant reaction in all students, regardless of prior ginkgo exposure, but all prior ginkgo-exposed students in this study reacted positively to an acetone extract of ginkgo pulp and either poison ivy extract or pentadecylcatechol.⁴

Systemic Contact After Eating Fruit—An illustrative case of dermatitis, stomatitis, and proctitis was reported in a man with history of poison oak contact dermatitis who had eaten fruit from a ginkgo tree, suggesting systemic contact dermatitis. Weeks after resolution of symptoms, he reacted positively to ginkgo fruit and poison ivy extracts on patch testing.¹⁶

Ginkgo dermatitis tends to resolve upon removal of the inciting agent and application of a topical steroid.^8,17 Although many reported cases involve the fruit, allergic contact dermatitis can result from exposure to any part of the plant. In a reported case, a woman developed airborne contact dermatitis from working with sarcotesta of the ginkgo plant.¹⁸ Despite wearing rubber gloves, she broke out 1 week after exposure with erythema on the face and arms and severe facial edema.

Ginkgo leaves also can cause allergic contact dermatitis.¹⁹ Precautions should be taken when handling any component of the ginkgo tree.

Oral ginkgo supplementation has been implicated in a variety of other cutaneous reactions—from benign to life-threatening. When the ginkgo allergen concentration is too high within the supplement, as has been noted in some formulations, patients have presented with a diffuse morbilliform eruption within 1 or 2 weeks after taking ginkgo.²⁰ One patient—who was not taking any other medication—experienced an episode of acute generalized exanthematous pustulosis 48 hours after taking ginkgo.²¹ Ingestion of ginkgo extract also has been associated with Stevens-Johnson syndrome.^22-24

Other Adverse Reactions

The adverse effects of ginkgo supplement vary widely. In addition to dermatitis, ginkgo supplement can cause headaches, palpitations, tachycardia, vasculitis, nausea, and other symptoms.¹⁴

Metabolic Disturbance—One patient taking ginkgo who died after a seizure was found to have subtherapeutic levels of valproate and phenytoin,²⁵ which could be due to ginkgo’s effect on cytochrome p450 enzyme CYP2C19.²⁶ Ginkgo interactions with many cytochrome enzymes have been studied for potential drug interactions. Any other direct effects remain variable and controversial.^27,28

Hemorrhage—Another serious effect associated with taking ginkgo supplements is hemorrhage, often in conjunction with warfarin¹⁴; however, a meta-analysis indicated that ginkgo generally does not increase the risk of bleeding.²⁹ Other studies have shown that taking ginkgo with warfarin showed no difference in clotting status, and ginkgo with aspirin resulted in no clinically significant difference in bruising, bleeding, or platelet function in an analysis over a period of 1 month.^30,31 These findings notwithstanding, pregnant women, surgical patients, and those taking a blood thinner are advised as a general precaution not to take ginkgo extract.

Carcinogenesis—Ginkgo extract has antioxidant properties, but there is evidence that it might act as a carcinogen. An animal study reported by the US National Toxicology Program found that ginkgo induced mutagenic activity in the liver, thyroid, and nose of mice and rats. Over time, rodent liver underwent changes consistent with hepatic enzyme induction.³² More research is needed to clarify the role of ginkgo in this process.

Toxicity by Ingestion—Ginkgo seeds can cause food poisoning due to the compound 4’-O-methylpyridoxine (also known as ginkgotoxin).³³ Because methylpyridoxine can cause depletion of pyridoxal phosphate (a form of vitamin B₆ necessary for the synthesis of γ-aminobutyric acid), overconsumption of ginkgo seeds, even when fully cooked, might result in convulsions and even death.³³

Nomenclature and Distribution of Plants

Gingko biloba belongs to the Ginkgoaceae family (class Ginkgophytes). The tree originated in China but might no longer exist in a truly wild form. It is grown worldwide for its beauty and longevity. The female ginkgo tree is a gymnosperm, producing fruit with seeds that are not coated by an ovary wall¹⁵; male (nonfruiting) trees are preferentially planted because the fruit is surrounded by a pulp that, when dropped, emits a sour smell described variously as rancid butter, vomit, or excrement.⁵

Identifying Features and Plant Facts

The deciduous ginkgo tree has unique fan-shaped leaves and is cultivated for its beauty and resistance to disease (Figure 2).^4,34 It is nicknamed the maidenhair tree because the leaves are similar to the pinnae of the maidenhair fern.³⁴ Because G biloba is resistant to pollution, it often is planted along city streets.¹⁷ The leaf—5- to 8-cm wide and a symbol of the city of Tokyo, Japan³⁴—grows in clusters (Figure 3)⁵ and is green but turns yellow before it falls in autumn.³⁴ Leaf veins branch out into the blade without anastomosing.³⁴

Male flowers grow in a catkinlike pattern; female flowers grow on long stems.⁵ The fruit is small, dark, and shriveled, with a hint of silver⁴; it typically is 2 to 2.5 cm in diameter and contains the ginkgo nut or seed. The kernel of the ginkgo nut is edible when roasted and is used in traditional Chinese and Japanese cuisine as a dish served on special occasions in autumn.³³

Final Thoughts

Given that G biloba is a beautiful, commonly planted ornamental tree, gardeners and landscapers should be aware of the risk for allergic contact dermatitis and use proper protection. Dermatologists should be aware of its cross-reactivity with other common plants such as poison ivy and poison oak to help patients identify the cause of their reactions and avoid the inciting agent. Because ginkgo extract also can cause a cutaneous reaction or interact with other medications, providers should remember to take a thorough medication history that includes herbal medicines and supplements.

An ancient tree of the Ginkgoaceae family, Ginkgo biloba is known as a living fossil because its genome has been identified in fossils older than 200 million years.¹ An individual tree can live longer than 1000 years. Originating in China, G biloba (here, “ginkgo”) is cultivated worldwide for its attractive foliage (Figure 1). Ginkgo extract has long been used in traditional Chinese medicine; however, contact with the plant proper can provoke allergic contact dermatitis.

Dermatitis-Inducing Components

The allergenic component of the ginkgo tree is ginkgolic acid, which is structurally similar to urushiol and anacardic acid.^2,3 This compound can cause a cross-reaction in a person previously sensitized by contact with other plants. Urushiol is found in poison ivy(Toxicodendron radicans); anacardic acid is found in the cashew tree (Anacardium occidentale). Both plants belong to the family Anacardiaceae, commonly known as the cashew family.

Members of Anacardiaceae are the most common causes of plant-induced allergic contact dermatitis and include the cashew tree, mango tree, poison ivy, poison oak, and poison sumac. These plants can cross-react to cause contact dermatitis (Table).³ Patch tests have revealed that some individuals who are sensitive to components of the ginkgo tree also demonstrate sensitivity to poison ivy and poison sumac^4,5; countering this finding, Lepoittevin and colleagues⁶ demonstrated in animal studies that there was no cross-reactivity between ginkgo and urushiol, suggesting that patients with a reported cross-reaction might truly have been previously sensitized to both plants. In general, patients who have a history of a reaction to any Anacardiaceae plant should take precautions when handling them.

Therapeutic Benefit of Ginkgo

Ginkgo extract is sold as the herbal supplement EGB761, which acts as an antioxidant.⁷ In France, Germany, and China, it is a commonly prescribed herbal medicine.⁸ It is purported to support memory and attention; studies have shown improvement in cognition and in involvement with activities of daily living for patients with dementia.^9,10 Ginkgo extract might lessen peripheral vascular disease and cerebral circulatory disease, having been shown in vitro and in animal models to prevent platelet aggregation induced by platelet-activating factor and to stimulate vasodilation by increasing production of nitric oxide.^11,12

Furthermore, purified ginkgo extract might have beneficial effects on skin. A study in rats showed that when intraperitoneal ginkgo extract was given prior to radiation therapy, 100% of rats receiving placebo developed radiation dermatitis vs 13% of those that received ginkgo extract (P<.0001). An excisional skin biopsy showed a decrease in markers of oxidative stress in rats that received ginkgo extract prior to radiation.⁷

A randomized, double-blind clinical trial showed a significant reduction in disease progression in vitiligo patients assigned to receive ginkgo extract orally compared to placebo (P=.006).¹³ Research for many possible uses of ginkgo extract is ongoing.

Cutaneous Manifestations

Contact with the fruit of the ginkgo tree can induce allergic contact dermatitis,¹⁴ most often as erythematous papules, vesicles, and in some cases edema.^5,15

Exposures While Picking Berries—In 1939, Bolus¹⁵ reported the case of a patient who presented with edema, erythema, and vesicular lesions involving the hands and face after picking berries from a ginkgo tree. Later, patch testing on this patient, using ginkgo fruit, resulted in burning and stinging that necessitated removal of the patch, suggesting an irritant reaction. This was followed by a vesicular reaction that then developed within 24 hours, which was more consistent with allergy. Similarly, in 1988, a case series of contact dermatitis was reported in 3 patients after gathering ginkgo fruit.⁵

Incidental Exposure While Walking—In 1965, dermatitis broke out in 35 high school students, mainly affecting exposed portions of the leg, after ginkgo fruit fell and its pulp was exposed on a path at their school.⁴ Subsequently, patch testing was performed on 29 volunteers—some who had been exposed to ginkgo on that path, others without prior exposure. It was established that testing with ginkgo pulp directly caused an irritant reaction in all students, regardless of prior ginkgo exposure, but all prior ginkgo-exposed students in this study reacted positively to an acetone extract of ginkgo pulp and either poison ivy extract or pentadecylcatechol.⁴

Systemic Contact After Eating Fruit—An illustrative case of dermatitis, stomatitis, and proctitis was reported in a man with history of poison oak contact dermatitis who had eaten fruit from a ginkgo tree, suggesting systemic contact dermatitis. Weeks after resolution of symptoms, he reacted positively to ginkgo fruit and poison ivy extracts on patch testing.¹⁶

Ginkgo dermatitis tends to resolve upon removal of the inciting agent and application of a topical steroid.^8,17 Although many reported cases involve the fruit, allergic contact dermatitis can result from exposure to any part of the plant. In a reported case, a woman developed airborne contact dermatitis from working with sarcotesta of the ginkgo plant.¹⁸ Despite wearing rubber gloves, she broke out 1 week after exposure with erythema on the face and arms and severe facial edema.

Ginkgo leaves also can cause allergic contact dermatitis.¹⁹ Precautions should be taken when handling any component of the ginkgo tree.

Oral ginkgo supplementation has been implicated in a variety of other cutaneous reactions—from benign to life-threatening. When the ginkgo allergen concentration is too high within the supplement, as has been noted in some formulations, patients have presented with a diffuse morbilliform eruption within 1 or 2 weeks after taking ginkgo.²⁰ One patient—who was not taking any other medication—experienced an episode of acute generalized exanthematous pustulosis 48 hours after taking ginkgo.²¹ Ingestion of ginkgo extract also has been associated with Stevens-Johnson syndrome.^22-24

Other Adverse Reactions

The adverse effects of ginkgo supplement vary widely. In addition to dermatitis, ginkgo supplement can cause headaches, palpitations, tachycardia, vasculitis, nausea, and other symptoms.¹⁴

Metabolic Disturbance—One patient taking ginkgo who died after a seizure was found to have subtherapeutic levels of valproate and phenytoin,²⁵ which could be due to ginkgo’s effect on cytochrome p450 enzyme CYP2C19.²⁶ Ginkgo interactions with many cytochrome enzymes have been studied for potential drug interactions. Any other direct effects remain variable and controversial.^27,28

Hemorrhage—Another serious effect associated with taking ginkgo supplements is hemorrhage, often in conjunction with warfarin¹⁴; however, a meta-analysis indicated that ginkgo generally does not increase the risk of bleeding.²⁹ Other studies have shown that taking ginkgo with warfarin showed no difference in clotting status, and ginkgo with aspirin resulted in no clinically significant difference in bruising, bleeding, or platelet function in an analysis over a period of 1 month.^30,31 These findings notwithstanding, pregnant women, surgical patients, and those taking a blood thinner are advised as a general precaution not to take ginkgo extract.

Carcinogenesis—Ginkgo extract has antioxidant properties, but there is evidence that it might act as a carcinogen. An animal study reported by the US National Toxicology Program found that ginkgo induced mutagenic activity in the liver, thyroid, and nose of mice and rats. Over time, rodent liver underwent changes consistent with hepatic enzyme induction.³² More research is needed to clarify the role of ginkgo in this process.

Toxicity by Ingestion—Ginkgo seeds can cause food poisoning due to the compound 4’-O-methylpyridoxine (also known as ginkgotoxin).³³ Because methylpyridoxine can cause depletion of pyridoxal phosphate (a form of vitamin B₆ necessary for the synthesis of γ-aminobutyric acid), overconsumption of ginkgo seeds, even when fully cooked, might result in convulsions and even death.³³

Nomenclature and Distribution of Plants

Gingko biloba belongs to the Ginkgoaceae family (class Ginkgophytes). The tree originated in China but might no longer exist in a truly wild form. It is grown worldwide for its beauty and longevity. The female ginkgo tree is a gymnosperm, producing fruit with seeds that are not coated by an ovary wall¹⁵; male (nonfruiting) trees are preferentially planted because the fruit is surrounded by a pulp that, when dropped, emits a sour smell described variously as rancid butter, vomit, or excrement.⁵

Identifying Features and Plant Facts

The deciduous ginkgo tree has unique fan-shaped leaves and is cultivated for its beauty and resistance to disease (Figure 2).^4,34 It is nicknamed the maidenhair tree because the leaves are similar to the pinnae of the maidenhair fern.³⁴ Because G biloba is resistant to pollution, it often is planted along city streets.¹⁷ The leaf—5- to 8-cm wide and a symbol of the city of Tokyo, Japan³⁴—grows in clusters (Figure 3)⁵ and is green but turns yellow before it falls in autumn.³⁴ Leaf veins branch out into the blade without anastomosing.³⁴

Male flowers grow in a catkinlike pattern; female flowers grow on long stems.⁵ The fruit is small, dark, and shriveled, with a hint of silver⁴; it typically is 2 to 2.5 cm in diameter and contains the ginkgo nut or seed. The kernel of the ginkgo nut is edible when roasted and is used in traditional Chinese and Japanese cuisine as a dish served on special occasions in autumn.³³

Final Thoughts

Given that G biloba is a beautiful, commonly planted ornamental tree, gardeners and landscapers should be aware of the risk for allergic contact dermatitis and use proper protection. Dermatologists should be aware of its cross-reactivity with other common plants such as poison ivy and poison oak to help patients identify the cause of their reactions and avoid the inciting agent. Because ginkgo extract also can cause a cutaneous reaction or interact with other medications, providers should remember to take a thorough medication history that includes herbal medicines and supplements.

Incidence and Characteristics

Mosquitoes are insects categorized into the order of Diptera and family of Culicidae, and more than 3500 different species have been identified.¹ In the United States, the most common genus of mosquitoes is Aedes, with other common genera including Culex, Anopheles, Culiseta, and Coquillettidia. Most bites are performed by female rather than male mosquitoes, as it serves to complete their life cycle (Figure 1).¹

There are a variety of possible reactions to mosquito bites. Severe local reactions that are large (papules >30 mm in diameter) or are accompanied by systemic manifestations are referred to as hypersensitivity to mosquito bites (HMB).² These hypersensitivity reactions vary according to multiple factors, including comorbid conditions, genetic predisposition, and geographic location. The majority of the world’s population will exhibit local reactions to mosquito bites at some point during life, with the median age of onset of the first bite at 2 years of age.³ In a study by Arias-Cruz et al,⁴ the incidence of patient-reported large local reactions was 2.5%. Hypersensitivity to mosquito bites, perhaps the most rare reaction, is more common among Asian and Central American children.⁵ The median age of diagnosis for HMB is 7 years, and most reactions occur during the first 2 decades of life.^6,7

Clinical Presentation

Mosquitoes bite vertebrates in an attempt to feed and thus must locate the host’s blood vessels through a process known as probing, which often necessitates changing the bite site several times. Once the vessel is located and lacerated, the mosquito feeds either from the vessel directly or the hematoma around it. Not only does the bite cause trauma to the skin, but a cutaneous reaction also may occur in response to salivary gland secretions that concurrently are deposited in the host tissue.⁸ Mosquitoes’ salivary gland components are the primary cause of cutaneous reactions, as one study showed that bites from mosquitoes lacking salivary gland ducts were not associated with these reactions.⁹ Mosquito saliva contains a large number of compounds with biologic activities, including lysozymes, antibacterial glucosidases, anticoagulants, antiplatelet aggregating factors, and vasodilators, as well as a potentially large number of unknown allergenic proteins. As of 2016, 70 mosquito-derived allergens have been identified, but this number continues to grow.² After a bite from a mosquito, these compounds may result in host sensitization over time, though interestingly, sensitization to mosquito bites from a species different from the original offender does not occur due to lack of cross-reactivity between species.¹ 

Because mosquitoes reproduce by laying their eggs directly on or near water, people who live near bodies of water or wetlands are at the highest risk for mosquito bites. Patient factors that have been found to lead to increased rates of mosquito bites include lower microbial diversity on the skin, the presence of sweat or body odor, pregnancy, increased body temperature, type O blood, dark clothing, and perfumes.² Exaggerated bite reactions are associated with Epstein-Barr virus (EBV) infection and hematologic malignancies.¹⁰ 

Immediate hypersensitivity is mediated by a specific IgE antibody and is characterized by erythema and a wheal at the bite site that peaks within minutes of the bite. In contrast, delayed hypersensitivity is lymphocyte mediated; occurs 24 hours after the bite; and causes an indurated, pruritic, and erythematous 2- to 10-mm papule that may blister.¹¹ Although the evidence of immediate hypersensitivity disappears within hours, symptoms of delayed hypersensitivity may last days to weeks. Accompanying symptoms may include local swelling, pain, and warmth. The itch that often is experienced in conjunction with erythema and papule formation is elicited in 3 main ways: direct induction utilizing classic pruritic pathways, IgE-mediated hypersensitivity reaction to salivary components, and IgE-independent host immune response to salivary antigens. Papular urticaria is a common additional finding in children with mosquito bites.¹ As an individual is repeatedly bitten, they may undergo 5 stages of sensitization: stage I (neither immediate nor delayed reaction), stage II (delayed reaction), stage III (immediate and delayed reaction), stage IV (immediate reaction), and stage V (neither immediate or delayed reaction).¹¹

Although most mosquito bites cause common local reactions, patients rarely demonstrate systemic reactions that can be much more severe. Skeeter syndrome is a milder systemic response characterized by large local reactions (papules >30 mm in diameter) developing hours after a bite with accompanying fever.¹² The reaction typically peaks over days to weeks.² Although the reaction may resemble cellulitis clinically, a history of a preceding mosquito bite can help make the distinction.¹³ 

A more severe systemic reaction is HMB, which is characterized by intense local skin findings as well as generalized systemic symptoms. Initially, indurated, clear, or hemorrhagic bullae appear at the bite site (Figure 2). Later, there is progression to swelling, necrosis, and ulceration.¹⁰ Biopsies from the skin lesions associated with HMB reveal necrosis, interstitial and perivascular eosinophilic and lymphocytic infiltrates, and small vessels with fibrinoid necrosis.⁷ Systemically, high fever, general malaise, liver dysfunction, proteinuria, hematuria, hepatosplenomegaly, and lymph node enlargement may occur. Patients typically experience these severe symptoms each time they are bitten.¹⁰

The mechanism of the HMB reaction is complex but has a close association with natural killer (NK) cell lymphoproliferative disorder and EBV infection (Figure 3). In fact, it is not uncommon for HMB patients to develop malignant lymphomas during their clinical course, even those unrelated to EBV.¹⁴ Epstein-Barr virus, one of the human herpesviruses, produces latent infection in NK cells. It is hypothesized that after a mosquito bite, EBV may be reactivated within these cells by induced expression of the viral lytic-cycle transactivator gene BamHI Z fragment leftward open reading frame 1, BZLF1.⁶ In response to mosquito salivary gland components, CD4⁺ T cells proliferate and induce expression of the EBV oncogene latent membrane protein 1, LMP1, on NK cells, which then infiltrate the bite site.¹⁵ These EBV-infected NK cells also overexpress the Fas ligand, thus contributing to organ and tissue damage.⁶ In addition to activating oncogene expression on NK cells, T cells also activate the basophils and mast cells carrying mosquito-specific IgE, both of which also add to the severe skin reaction of HMB.¹⁵ The particular triad of HMB, chronic active EBV infection, and NK cell lymphoproliferative disorder commonly is known as HMB-EBV-NK or HEN disease.¹ Patients with HMB should be monitored for malignancy. The mortality of HMB is increased in patients in whom onset occurs when they are older than 9 years and with BZLF1 messenger RNA in skin lesions.⁶ 

Other rare reactions to mosquito bites include Wells syndrome, anaphylaxis, and superficial lymphangitis. Wells syndrome (also known as eosinophilic cellulitis) is characterized by erythematous or violaceous plaques and pruritic blisters. Although its etiology has not been defined, it is thought to be evoked or exacerbated by insect bites, with CD4⁺ T cells playing a primary role.¹ Anaphylaxis (angioedema, urticaria, and wheezing) rarely may occur due to mosquito salivary gland components but typically is caused by other stinging insects. Superficial lymphangitis, often misdiagnosed as an infection of the lymphatic system, presents within minutes as nontender pink streaks originating from the bite site. A biopsy with eosinophil and mast cell infiltrates consistent with an allergic-type reaction confirms the absence of infection. Patients respond well to glucocorticoid treatment.

Mosquitoes are vectors for many blood-borne diseases, including dengue hemorrhagic fever, malaria, Chikungunya virus, La Crosse encephalitis, St. Louis encephalitis, West Nile virus, and yellow fever.¹⁶ Additionally, scratching the bites may lead to superinfection and scarring.¹

Prevention and Treatment

Patients with known mosquito sensitivity should avoid areas of stagnant water and utilize preventative measures such as wearing protective clothing and using mosquito repellent containing DEET (N,N-diethyl-meta-toluamide), IR3535 (ethyl butylacetylaminopropionate), picaridin, or 2-undecanone (methyl nonyl ketone or IBI-246) when outdoors. Essential oils such as lemon, eucalyptus, citronella, and garlic are somewhat effective.¹ Additionally, prophylactic dosing of antihistamines may prevent milder reactions.

Although often supportive, treatment and management of mosquito bites depends on the extent of the reaction. For common local reactions, symptomatic management with topical anesthetics, calamine lotion, or corticosteroid creams is appropriate. If superinfection from scratching is a concern, antibiotics may be appropriate.

Management of more severe and systemic reactions such as HMB also is supportive, and the addition of oral corticosteroids to decrease inflammation is required.⁷ Severe HMB also has been treated with immunosuppressive and anticancer drugs, though the efficacy is limited. Venom immunotherapy is a preventative option for patients with mosquito-specific IgE antibodies, and hematopoietic stem cell transplant may be required in patients with HMB.^14,16

Conclusion

Mosquito allergens can cause a variety of reactions, ranging from those limited to the skin to those characterized by severe systemic effects. Although common local reactions can be symptomatically treated with topical medication, more severe reactions such as HMB require more involved clinical management. Hypersensitivity to mosquito bites is an important condition to recognize, as it is related to multiple organ impairment as well as later development of malignancy. Patients should be closely monitored during the entire clinical course and in the years following.

Incidence and Characteristics

Mosquitoes are insects categorized into the order of Diptera and family of Culicidae, and more than 3500 different species have been identified.¹ In the United States, the most common genus of mosquitoes is Aedes, with other common genera including Culex, Anopheles, Culiseta, and Coquillettidia. Most bites are performed by female rather than male mosquitoes, as it serves to complete their life cycle (Figure 1).¹

There are a variety of possible reactions to mosquito bites. Severe local reactions that are large (papules >30 mm in diameter) or are accompanied by systemic manifestations are referred to as hypersensitivity to mosquito bites (HMB).² These hypersensitivity reactions vary according to multiple factors, including comorbid conditions, genetic predisposition, and geographic location. The majority of the world’s population will exhibit local reactions to mosquito bites at some point during life, with the median age of onset of the first bite at 2 years of age.³ In a study by Arias-Cruz et al,⁴ the incidence of patient-reported large local reactions was 2.5%. Hypersensitivity to mosquito bites, perhaps the most rare reaction, is more common among Asian and Central American children.⁵ The median age of diagnosis for HMB is 7 years, and most reactions occur during the first 2 decades of life.^6,7

Clinical Presentation

Mosquitoes bite vertebrates in an attempt to feed and thus must locate the host’s blood vessels through a process known as probing, which often necessitates changing the bite site several times. Once the vessel is located and lacerated, the mosquito feeds either from the vessel directly or the hematoma around it. Not only does the bite cause trauma to the skin, but a cutaneous reaction also may occur in response to salivary gland secretions that concurrently are deposited in the host tissue.⁸ Mosquitoes’ salivary gland components are the primary cause of cutaneous reactions, as one study showed that bites from mosquitoes lacking salivary gland ducts were not associated with these reactions.⁹ Mosquito saliva contains a large number of compounds with biologic activities, including lysozymes, antibacterial glucosidases, anticoagulants, antiplatelet aggregating factors, and vasodilators, as well as a potentially large number of unknown allergenic proteins. As of 2016, 70 mosquito-derived allergens have been identified, but this number continues to grow.² After a bite from a mosquito, these compounds may result in host sensitization over time, though interestingly, sensitization to mosquito bites from a species different from the original offender does not occur due to lack of cross-reactivity between species.¹ 

Because mosquitoes reproduce by laying their eggs directly on or near water, people who live near bodies of water or wetlands are at the highest risk for mosquito bites. Patient factors that have been found to lead to increased rates of mosquito bites include lower microbial diversity on the skin, the presence of sweat or body odor, pregnancy, increased body temperature, type O blood, dark clothing, and perfumes.² Exaggerated bite reactions are associated with Epstein-Barr virus (EBV) infection and hematologic malignancies.¹⁰ 

Immediate hypersensitivity is mediated by a specific IgE antibody and is characterized by erythema and a wheal at the bite site that peaks within minutes of the bite. In contrast, delayed hypersensitivity is lymphocyte mediated; occurs 24 hours after the bite; and causes an indurated, pruritic, and erythematous 2- to 10-mm papule that may blister.¹¹ Although the evidence of immediate hypersensitivity disappears within hours, symptoms of delayed hypersensitivity may last days to weeks. Accompanying symptoms may include local swelling, pain, and warmth. The itch that often is experienced in conjunction with erythema and papule formation is elicited in 3 main ways: direct induction utilizing classic pruritic pathways, IgE-mediated hypersensitivity reaction to salivary components, and IgE-independent host immune response to salivary antigens. Papular urticaria is a common additional finding in children with mosquito bites.¹ As an individual is repeatedly bitten, they may undergo 5 stages of sensitization: stage I (neither immediate nor delayed reaction), stage II (delayed reaction), stage III (immediate and delayed reaction), stage IV (immediate reaction), and stage V (neither immediate or delayed reaction).¹¹

Although most mosquito bites cause common local reactions, patients rarely demonstrate systemic reactions that can be much more severe. Skeeter syndrome is a milder systemic response characterized by large local reactions (papules >30 mm in diameter) developing hours after a bite with accompanying fever.¹² The reaction typically peaks over days to weeks.² Although the reaction may resemble cellulitis clinically, a history of a preceding mosquito bite can help make the distinction.¹³ 

A more severe systemic reaction is HMB, which is characterized by intense local skin findings as well as generalized systemic symptoms. Initially, indurated, clear, or hemorrhagic bullae appear at the bite site (Figure 2). Later, there is progression to swelling, necrosis, and ulceration.¹⁰ Biopsies from the skin lesions associated with HMB reveal necrosis, interstitial and perivascular eosinophilic and lymphocytic infiltrates, and small vessels with fibrinoid necrosis.⁷ Systemically, high fever, general malaise, liver dysfunction, proteinuria, hematuria, hepatosplenomegaly, and lymph node enlargement may occur. Patients typically experience these severe symptoms each time they are bitten.¹⁰

The mechanism of the HMB reaction is complex but has a close association with natural killer (NK) cell lymphoproliferative disorder and EBV infection (Figure 3). In fact, it is not uncommon for HMB patients to develop malignant lymphomas during their clinical course, even those unrelated to EBV.¹⁴ Epstein-Barr virus, one of the human herpesviruses, produces latent infection in NK cells. It is hypothesized that after a mosquito bite, EBV may be reactivated within these cells by induced expression of the viral lytic-cycle transactivator gene BamHI Z fragment leftward open reading frame 1, BZLF1.⁶ In response to mosquito salivary gland components, CD4⁺ T cells proliferate and induce expression of the EBV oncogene latent membrane protein 1, LMP1, on NK cells, which then infiltrate the bite site.¹⁵ These EBV-infected NK cells also overexpress the Fas ligand, thus contributing to organ and tissue damage.⁶ In addition to activating oncogene expression on NK cells, T cells also activate the basophils and mast cells carrying mosquito-specific IgE, both of which also add to the severe skin reaction of HMB.¹⁵ The particular triad of HMB, chronic active EBV infection, and NK cell lymphoproliferative disorder commonly is known as HMB-EBV-NK or HEN disease.¹ Patients with HMB should be monitored for malignancy. The mortality of HMB is increased in patients in whom onset occurs when they are older than 9 years and with BZLF1 messenger RNA in skin lesions.⁶ 

Other rare reactions to mosquito bites include Wells syndrome, anaphylaxis, and superficial lymphangitis. Wells syndrome (also known as eosinophilic cellulitis) is characterized by erythematous or violaceous plaques and pruritic blisters. Although its etiology has not been defined, it is thought to be evoked or exacerbated by insect bites, with CD4⁺ T cells playing a primary role.¹ Anaphylaxis (angioedema, urticaria, and wheezing) rarely may occur due to mosquito salivary gland components but typically is caused by other stinging insects. Superficial lymphangitis, often misdiagnosed as an infection of the lymphatic system, presents within minutes as nontender pink streaks originating from the bite site. A biopsy with eosinophil and mast cell infiltrates consistent with an allergic-type reaction confirms the absence of infection. Patients respond well to glucocorticoid treatment.

Mosquitoes are vectors for many blood-borne diseases, including dengue hemorrhagic fever, malaria, Chikungunya virus, La Crosse encephalitis, St. Louis encephalitis, West Nile virus, and yellow fever.¹⁶ Additionally, scratching the bites may lead to superinfection and scarring.¹

Prevention and Treatment

Patients with known mosquito sensitivity should avoid areas of stagnant water and utilize preventative measures such as wearing protective clothing and using mosquito repellent containing DEET (N,N-diethyl-meta-toluamide), IR3535 (ethyl butylacetylaminopropionate), picaridin, or 2-undecanone (methyl nonyl ketone or IBI-246) when outdoors. Essential oils such as lemon, eucalyptus, citronella, and garlic are somewhat effective.¹ Additionally, prophylactic dosing of antihistamines may prevent milder reactions.

Although often supportive, treatment and management of mosquito bites depends on the extent of the reaction. For common local reactions, symptomatic management with topical anesthetics, calamine lotion, or corticosteroid creams is appropriate. If superinfection from scratching is a concern, antibiotics may be appropriate.

Management of more severe and systemic reactions such as HMB also is supportive, and the addition of oral corticosteroids to decrease inflammation is required.⁷ Severe HMB also has been treated with immunosuppressive and anticancer drugs, though the efficacy is limited. Venom immunotherapy is a preventative option for patients with mosquito-specific IgE antibodies, and hematopoietic stem cell transplant may be required in patients with HMB.^14,16

Conclusion

Mosquito allergens can cause a variety of reactions, ranging from those limited to the skin to those characterized by severe systemic effects. Although common local reactions can be symptomatically treated with topical medication, more severe reactions such as HMB require more involved clinical management. Hypersensitivity to mosquito bites is an important condition to recognize, as it is related to multiple organ impairment as well as later development of malignancy. Patients should be closely monitored during the entire clinical course and in the years following.

Incidence and Characteristics

Mosquitoes are insects categorized into the order of Diptera and family of Culicidae, and more than 3500 different species have been identified.¹ In the United States, the most common genus of mosquitoes is Aedes, with other common genera including Culex, Anopheles, Culiseta, and Coquillettidia. Most bites are performed by female rather than male mosquitoes, as it serves to complete their life cycle (Figure 1).¹

There are a variety of possible reactions to mosquito bites. Severe local reactions that are large (papules >30 mm in diameter) or are accompanied by systemic manifestations are referred to as hypersensitivity to mosquito bites (HMB).² These hypersensitivity reactions vary according to multiple factors, including comorbid conditions, genetic predisposition, and geographic location. The majority of the world’s population will exhibit local reactions to mosquito bites at some point during life, with the median age of onset of the first bite at 2 years of age.³ In a study by Arias-Cruz et al,⁴ the incidence of patient-reported large local reactions was 2.5%. Hypersensitivity to mosquito bites, perhaps the most rare reaction, is more common among Asian and Central American children.⁵ The median age of diagnosis for HMB is 7 years, and most reactions occur during the first 2 decades of life.^6,7

Clinical Presentation

Mosquitoes bite vertebrates in an attempt to feed and thus must locate the host’s blood vessels through a process known as probing, which often necessitates changing the bite site several times. Once the vessel is located and lacerated, the mosquito feeds either from the vessel directly or the hematoma around it. Not only does the bite cause trauma to the skin, but a cutaneous reaction also may occur in response to salivary gland secretions that concurrently are deposited in the host tissue.⁸ Mosquitoes’ salivary gland components are the primary cause of cutaneous reactions, as one study showed that bites from mosquitoes lacking salivary gland ducts were not associated with these reactions.⁹ Mosquito saliva contains a large number of compounds with biologic activities, including lysozymes, antibacterial glucosidases, anticoagulants, antiplatelet aggregating factors, and vasodilators, as well as a potentially large number of unknown allergenic proteins. As of 2016, 70 mosquito-derived allergens have been identified, but this number continues to grow.² After a bite from a mosquito, these compounds may result in host sensitization over time, though interestingly, sensitization to mosquito bites from a species different from the original offender does not occur due to lack of cross-reactivity between species.¹ 

Because mosquitoes reproduce by laying their eggs directly on or near water, people who live near bodies of water or wetlands are at the highest risk for mosquito bites. Patient factors that have been found to lead to increased rates of mosquito bites include lower microbial diversity on the skin, the presence of sweat or body odor, pregnancy, increased body temperature, type O blood, dark clothing, and perfumes.² Exaggerated bite reactions are associated with Epstein-Barr virus (EBV) infection and hematologic malignancies.¹⁰ 

Immediate hypersensitivity is mediated by a specific IgE antibody and is characterized by erythema and a wheal at the bite site that peaks within minutes of the bite. In contrast, delayed hypersensitivity is lymphocyte mediated; occurs 24 hours after the bite; and causes an indurated, pruritic, and erythematous 2- to 10-mm papule that may blister.¹¹ Although the evidence of immediate hypersensitivity disappears within hours, symptoms of delayed hypersensitivity may last days to weeks. Accompanying symptoms may include local swelling, pain, and warmth. The itch that often is experienced in conjunction with erythema and papule formation is elicited in 3 main ways: direct induction utilizing classic pruritic pathways, IgE-mediated hypersensitivity reaction to salivary components, and IgE-independent host immune response to salivary antigens. Papular urticaria is a common additional finding in children with mosquito bites.¹ As an individual is repeatedly bitten, they may undergo 5 stages of sensitization: stage I (neither immediate nor delayed reaction), stage II (delayed reaction), stage III (immediate and delayed reaction), stage IV (immediate reaction), and stage V (neither immediate or delayed reaction).¹¹

Although most mosquito bites cause common local reactions, patients rarely demonstrate systemic reactions that can be much more severe. Skeeter syndrome is a milder systemic response characterized by large local reactions (papules >30 mm in diameter) developing hours after a bite with accompanying fever.¹² The reaction typically peaks over days to weeks.² Although the reaction may resemble cellulitis clinically, a history of a preceding mosquito bite can help make the distinction.¹³ 

A more severe systemic reaction is HMB, which is characterized by intense local skin findings as well as generalized systemic symptoms. Initially, indurated, clear, or hemorrhagic bullae appear at the bite site (Figure 2). Later, there is progression to swelling, necrosis, and ulceration.¹⁰ Biopsies from the skin lesions associated with HMB reveal necrosis, interstitial and perivascular eosinophilic and lymphocytic infiltrates, and small vessels with fibrinoid necrosis.⁷ Systemically, high fever, general malaise, liver dysfunction, proteinuria, hematuria, hepatosplenomegaly, and lymph node enlargement may occur. Patients typically experience these severe symptoms each time they are bitten.¹⁰

The mechanism of the HMB reaction is complex but has a close association with natural killer (NK) cell lymphoproliferative disorder and EBV infection (Figure 3). In fact, it is not uncommon for HMB patients to develop malignant lymphomas during their clinical course, even those unrelated to EBV.¹⁴ Epstein-Barr virus, one of the human herpesviruses, produces latent infection in NK cells. It is hypothesized that after a mosquito bite, EBV may be reactivated within these cells by induced expression of the viral lytic-cycle transactivator gene BamHI Z fragment leftward open reading frame 1, BZLF1.⁶ In response to mosquito salivary gland components, CD4⁺ T cells proliferate and induce expression of the EBV oncogene latent membrane protein 1, LMP1, on NK cells, which then infiltrate the bite site.¹⁵ These EBV-infected NK cells also overexpress the Fas ligand, thus contributing to organ and tissue damage.⁶ In addition to activating oncogene expression on NK cells, T cells also activate the basophils and mast cells carrying mosquito-specific IgE, both of which also add to the severe skin reaction of HMB.¹⁵ The particular triad of HMB, chronic active EBV infection, and NK cell lymphoproliferative disorder commonly is known as HMB-EBV-NK or HEN disease.¹ Patients with HMB should be monitored for malignancy. The mortality of HMB is increased in patients in whom onset occurs when they are older than 9 years and with BZLF1 messenger RNA in skin lesions.⁶ 

Other rare reactions to mosquito bites include Wells syndrome, anaphylaxis, and superficial lymphangitis. Wells syndrome (also known as eosinophilic cellulitis) is characterized by erythematous or violaceous plaques and pruritic blisters. Although its etiology has not been defined, it is thought to be evoked or exacerbated by insect bites, with CD4⁺ T cells playing a primary role.¹ Anaphylaxis (angioedema, urticaria, and wheezing) rarely may occur due to mosquito salivary gland components but typically is caused by other stinging insects. Superficial lymphangitis, often misdiagnosed as an infection of the lymphatic system, presents within minutes as nontender pink streaks originating from the bite site. A biopsy with eosinophil and mast cell infiltrates consistent with an allergic-type reaction confirms the absence of infection. Patients respond well to glucocorticoid treatment.

Mosquitoes are vectors for many blood-borne diseases, including dengue hemorrhagic fever, malaria, Chikungunya virus, La Crosse encephalitis, St. Louis encephalitis, West Nile virus, and yellow fever.¹⁶ Additionally, scratching the bites may lead to superinfection and scarring.¹

Prevention and Treatment

Patients with known mosquito sensitivity should avoid areas of stagnant water and utilize preventative measures such as wearing protective clothing and using mosquito repellent containing DEET (N,N-diethyl-meta-toluamide), IR3535 (ethyl butylacetylaminopropionate), picaridin, or 2-undecanone (methyl nonyl ketone or IBI-246) when outdoors. Essential oils such as lemon, eucalyptus, citronella, and garlic are somewhat effective.¹ Additionally, prophylactic dosing of antihistamines may prevent milder reactions.

Although often supportive, treatment and management of mosquito bites depends on the extent of the reaction. For common local reactions, symptomatic management with topical anesthetics, calamine lotion, or corticosteroid creams is appropriate. If superinfection from scratching is a concern, antibiotics may be appropriate.

Management of more severe and systemic reactions such as HMB also is supportive, and the addition of oral corticosteroids to decrease inflammation is required.⁷ Severe HMB also has been treated with immunosuppressive and anticancer drugs, though the efficacy is limited. Venom immunotherapy is a preventative option for patients with mosquito-specific IgE antibodies, and hematopoietic stem cell transplant may be required in patients with HMB.^14,16

Conclusion

Mosquito allergens can cause a variety of reactions, ranging from those limited to the skin to those characterized by severe systemic effects. Although common local reactions can be symptomatically treated with topical medication, more severe reactions such as HMB require more involved clinical management. Hypersensitivity to mosquito bites is an important condition to recognize, as it is related to multiple organ impairment as well as later development of malignancy. Patients should be closely monitored during the entire clinical course and in the years following.

Jellyfish stings are one of the most common marine injuries, with an estimated 150 million stings occurring annually worldwide.¹ Most jellyfish stings result in painful localized skin reactions that are self-limited and can be treated with conservative measures including hot water immersion and topical anesthetics. Life-threatening systemic reactions (eg, anaphylaxis, Irukandji syndrome) can occur with some species.^2-4 Mainstream media reports do not reflect the true incidence and variability of jellyfish-related injuries that are commonly encountered in the clinic.³

Characteristics of Jellyfish

There are roughly 10,000 known species of jellyfish, with approximately 100 of them posing danger to humans.⁵ Jellyfish belong to the phylum Cnidaria, which is comprised of 5 classes of both free-floating and sessile animals: Staurozoa (stauromedusae), Hydrozoa (hydroids, fire corals, and Portuguese man-of-war), Scyphozoa (true jellyfish), Anthozoa (corals and sea anemones), and Cubozoa (box jellyfish and Irukandji jellyfish).^1,2,6 Jellyfish typically have several tentacles suspended from a free-floating gelatinous body or bell; these tentacles are covered with thousands of cells unique to Cnidaria called nematocytes or cnidocytes containing specialized stinging organelles known as nematocysts. When triggered by physical (eg, human or foreign-body contact) or chemical stimuli, each nematocyst ejects a hollow filament or barb externally, releasing venom into the victim.^7,8

The scyphozoan, hydrozoan, and cubozoan life cycles generally consist of a bottom-dwelling, sessile polyp form that produces multiple free-swimming ephyrae through an asexual reproductive process called strobilation. These ephyrae grow into the fully mature medusae, recognizable as jellyfish (Figure 1).⁵ Additionally, jellyfish populations experience cycles of temporal and spatial population abundance and crashes known as jellyfish blooms. In 2017, Kaffenberger et al⁹ reviewed the shifting landscape of skin diseases in North America attributable to major changes in climate and weather patterns, including the rise in jellyfish blooms and envenomation outbreaks worldwide (eg, Physalia physalis [Portuguese man-of-war][Figure 2] along the southeastern US coastline, Porpita pacifica off Japanese beaches). Some research suggests jellyfish surges relate to climate change and human interactions with jellyfish habitats by way of eutrophication and fishing (removing predators of jellyfish).^9,10

Clinical Presentation

Jellyfish injuries can vary greatly in clinical symptoms, but they do follow some basic patterns. The severity of pain and symptoms is related to the jellyfish species, the number of stinging cells (nematocysts) that are triggered, and the potency of the venom that is absorbed by the victim.^11-13 Most stings are minor, and patients experience immediate localized pain with serpiginous raised erythematous or urticarial lesions following the distribution of tentacle contact; these lesions have been described as tentaclelike and resembling a string of beads (Figure 3).¹² Pain usually lasts a couple hours, while the skin lesions can last hours to days and can even recur years later. This pattern fits that of the well-known hydrozoans P physalis and Physalia utriculus (bluebottle), which are endemic to the Atlantic and Indo-Pacific Oceans, respectively. The scyphozoan jellyfish causing similar presentations include Pelagia noctiluca (Mauve stinger), Aurelia aurita (Moon jellyfish), and Cyanea species. The cubozoan Chironex fleckeri (Australian box jellyfish or sea wasp) also causes tentaclelike stings but is widely considered the most dangerous jellyfish, as its venom is known to cause cardiac or respiratory arrest.^4,11 More than 100 fatalities have been reported following severe envenomations from C fleckeri in Australian and Indo-Pacific waters.⁶

Stings from another box jellyfish species, Carukia barnesi, cause a unique presentation known as Irukandji syndrome. Carukia barnesi is a small box jellyfish with a bell measuring roughly 2 cm in diameter. It has nematocysts on both its bell and tentacles. It inhabits deeper waters and typically stings divers but also can wash ashore and injure beach tourists. Although Irukandji syndrome usually is associated with C barnesi, which is endemic to Northern Australian beaches, other jellyfish species including P physalis rarely have been linked to this potentially fatal syndrome.^6,11 Unlike the immediate cutaneous and systemic findings described in C fleckeri encounters, symptoms of Irukandji-like stings can be delayed by up to 30 minutes. Patients may present with severe generalized pain (lower back, chest, headache), signs of excess catecholamine release (tachycardia, hypertension, anxiety, diaphoresis, agitation), or cardiopulmonary decompensation (arrhythmia, cardiac arrest, pulmonary edema).^6,11,14.15 Anaphylactic reactions also have been reported in those sensitized by prior stings.¹⁶

Management

Prevention of drowning is key in all marine injuries. Rescuers should remove the individual from the water, establish the ABCs—airway, breathing, and circulation—and seek acute medical attention. If immediate resuscitation is not required, douse the wound as soon as possible with a solution that halts further nematocyst discharge, which may contain alcohol, vinegar, or bicarbonate, depending on the prevalent species. General guidance is available to providers through evidence-based, point-of-care databases including UpToDate and DynaMed, as well as through the American Heart Association (AHA) or a country’s equivalent council on emergency care if residing outside the United States. Pressure immobilization bandages as a means of decreasing venom redistribution is no longer recommended by the AHA because animal studies have shown increased nematocyst discharge after pressure application.¹⁷ As such, touching or applying pressure to the affected area is not recommended until after a proper rinse solution has been applied. Tentacles may be removed mechanically with gloved hands or sand and seawater with minimal compression or agitation.

When acetic acid is appropriate, such as for cubozoan stings, commercially available vinegar (5% acetic acid in the United States) is preferred.^16,17 Tap water can cause discharge of nematocysts, and seawater is preferred when no other solution is available.¹⁸ Most marine venoms are heat labile. Immersion in hot water can produce pain relief, but ice can be just as efficacious and is preferred by some patients. Prior reports of patients stung by Physalia species demonstrated greater pain relief with hot water immersion compared to ice pack application.^18,19

In the setting of anaphylaxis, patients should receive epinephrine and be transported to a hospital with appropriate hemodynamic monitoring and supportive care. If the species of jellyfish has been identified, species-specific antivenin also may be available in certain regions (eg, C fleckeri antivenin manufactured in Australia), but it is unclear if it improves outcomes when compared with supportive care alone.^6,16

Conclusion

Following jellyfish stings, most skin lesions will spontaneously resolve. Patients likely will present days to weeks following the inciting event with mild cutaneous symptoms that are amenable to topical corticosteroids. Recurrent dermatitis following a jellyfish sting is uncommon and is thought to be due to an immunologic mechanism consistent with type IV hypersensitivity reactions. Patients may require multiple courses of treatment before complete resolution.²⁰

Patient education regarding marine envenomation and mechanical barriers such as wetsuits or stinger suits can reduce the risk for injury from jellyfish stings. Sting-inhibiting lotions also are commercially available, though more research is needed.²¹ Many beaches that are known to harbor the dangerous box jellyfish provide stinger nets to direct travelers to safer waters. Complete avoidance during jellyfish season is recommended in highly endemic areas.¹

Jellyfish stings are one of the most common marine injuries, with an estimated 150 million stings occurring annually worldwide.¹ Most jellyfish stings result in painful localized skin reactions that are self-limited and can be treated with conservative measures including hot water immersion and topical anesthetics. Life-threatening systemic reactions (eg, anaphylaxis, Irukandji syndrome) can occur with some species.^2-4 Mainstream media reports do not reflect the true incidence and variability of jellyfish-related injuries that are commonly encountered in the clinic.³

Characteristics of Jellyfish

There are roughly 10,000 known species of jellyfish, with approximately 100 of them posing danger to humans.⁵ Jellyfish belong to the phylum Cnidaria, which is comprised of 5 classes of both free-floating and sessile animals: Staurozoa (stauromedusae), Hydrozoa (hydroids, fire corals, and Portuguese man-of-war), Scyphozoa (true jellyfish), Anthozoa (corals and sea anemones), and Cubozoa (box jellyfish and Irukandji jellyfish).^1,2,6 Jellyfish typically have several tentacles suspended from a free-floating gelatinous body or bell; these tentacles are covered with thousands of cells unique to Cnidaria called nematocytes or cnidocytes containing specialized stinging organelles known as nematocysts. When triggered by physical (eg, human or foreign-body contact) or chemical stimuli, each nematocyst ejects a hollow filament or barb externally, releasing venom into the victim.^7,8

The scyphozoan, hydrozoan, and cubozoan life cycles generally consist of a bottom-dwelling, sessile polyp form that produces multiple free-swimming ephyrae through an asexual reproductive process called strobilation. These ephyrae grow into the fully mature medusae, recognizable as jellyfish (Figure 1).⁵ Additionally, jellyfish populations experience cycles of temporal and spatial population abundance and crashes known as jellyfish blooms. In 2017, Kaffenberger et al⁹ reviewed the shifting landscape of skin diseases in North America attributable to major changes in climate and weather patterns, including the rise in jellyfish blooms and envenomation outbreaks worldwide (eg, Physalia physalis [Portuguese man-of-war][Figure 2] along the southeastern US coastline, Porpita pacifica off Japanese beaches). Some research suggests jellyfish surges relate to climate change and human interactions with jellyfish habitats by way of eutrophication and fishing (removing predators of jellyfish).^9,10

Clinical Presentation

Jellyfish injuries can vary greatly in clinical symptoms, but they do follow some basic patterns. The severity of pain and symptoms is related to the jellyfish species, the number of stinging cells (nematocysts) that are triggered, and the potency of the venom that is absorbed by the victim.^11-13 Most stings are minor, and patients experience immediate localized pain with serpiginous raised erythematous or urticarial lesions following the distribution of tentacle contact; these lesions have been described as tentaclelike and resembling a string of beads (Figure 3).¹² Pain usually lasts a couple hours, while the skin lesions can last hours to days and can even recur years later. This pattern fits that of the well-known hydrozoans P physalis and Physalia utriculus (bluebottle), which are endemic to the Atlantic and Indo-Pacific Oceans, respectively. The scyphozoan jellyfish causing similar presentations include Pelagia noctiluca (Mauve stinger), Aurelia aurita (Moon jellyfish), and Cyanea species. The cubozoan Chironex fleckeri (Australian box jellyfish or sea wasp) also causes tentaclelike stings but is widely considered the most dangerous jellyfish, as its venom is known to cause cardiac or respiratory arrest.^4,11 More than 100 fatalities have been reported following severe envenomations from C fleckeri in Australian and Indo-Pacific waters.⁶

Stings from another box jellyfish species, Carukia barnesi, cause a unique presentation known as Irukandji syndrome. Carukia barnesi is a small box jellyfish with a bell measuring roughly 2 cm in diameter. It has nematocysts on both its bell and tentacles. It inhabits deeper waters and typically stings divers but also can wash ashore and injure beach tourists. Although Irukandji syndrome usually is associated with C barnesi, which is endemic to Northern Australian beaches, other jellyfish species including P physalis rarely have been linked to this potentially fatal syndrome.^6,11 Unlike the immediate cutaneous and systemic findings described in C fleckeri encounters, symptoms of Irukandji-like stings can be delayed by up to 30 minutes. Patients may present with severe generalized pain (lower back, chest, headache), signs of excess catecholamine release (tachycardia, hypertension, anxiety, diaphoresis, agitation), or cardiopulmonary decompensation (arrhythmia, cardiac arrest, pulmonary edema).^6,11,14.15 Anaphylactic reactions also have been reported in those sensitized by prior stings.¹⁶

Management

Prevention of drowning is key in all marine injuries. Rescuers should remove the individual from the water, establish the ABCs—airway, breathing, and circulation—and seek acute medical attention. If immediate resuscitation is not required, douse the wound as soon as possible with a solution that halts further nematocyst discharge, which may contain alcohol, vinegar, or bicarbonate, depending on the prevalent species. General guidance is available to providers through evidence-based, point-of-care databases including UpToDate and DynaMed, as well as through the American Heart Association (AHA) or a country’s equivalent council on emergency care if residing outside the United States. Pressure immobilization bandages as a means of decreasing venom redistribution is no longer recommended by the AHA because animal studies have shown increased nematocyst discharge after pressure application.¹⁷ As such, touching or applying pressure to the affected area is not recommended until after a proper rinse solution has been applied. Tentacles may be removed mechanically with gloved hands or sand and seawater with minimal compression or agitation.

When acetic acid is appropriate, such as for cubozoan stings, commercially available vinegar (5% acetic acid in the United States) is preferred.^16,17 Tap water can cause discharge of nematocysts, and seawater is preferred when no other solution is available.¹⁸ Most marine venoms are heat labile. Immersion in hot water can produce pain relief, but ice can be just as efficacious and is preferred by some patients. Prior reports of patients stung by Physalia species demonstrated greater pain relief with hot water immersion compared to ice pack application.^18,19

In the setting of anaphylaxis, patients should receive epinephrine and be transported to a hospital with appropriate hemodynamic monitoring and supportive care. If the species of jellyfish has been identified, species-specific antivenin also may be available in certain regions (eg, C fleckeri antivenin manufactured in Australia), but it is unclear if it improves outcomes when compared with supportive care alone.^6,16

Conclusion

Following jellyfish stings, most skin lesions will spontaneously resolve. Patients likely will present days to weeks following the inciting event with mild cutaneous symptoms that are amenable to topical corticosteroids. Recurrent dermatitis following a jellyfish sting is uncommon and is thought to be due to an immunologic mechanism consistent with type IV hypersensitivity reactions. Patients may require multiple courses of treatment before complete resolution.²⁰

Patient education regarding marine envenomation and mechanical barriers such as wetsuits or stinger suits can reduce the risk for injury from jellyfish stings. Sting-inhibiting lotions also are commercially available, though more research is needed.²¹ Many beaches that are known to harbor the dangerous box jellyfish provide stinger nets to direct travelers to safer waters. Complete avoidance during jellyfish season is recommended in highly endemic areas.¹

Jellyfish stings are one of the most common marine injuries, with an estimated 150 million stings occurring annually worldwide.¹ Most jellyfish stings result in painful localized skin reactions that are self-limited and can be treated with conservative measures including hot water immersion and topical anesthetics. Life-threatening systemic reactions (eg, anaphylaxis, Irukandji syndrome) can occur with some species.^2-4 Mainstream media reports do not reflect the true incidence and variability of jellyfish-related injuries that are commonly encountered in the clinic.³

Characteristics of Jellyfish

There are roughly 10,000 known species of jellyfish, with approximately 100 of them posing danger to humans.⁵ Jellyfish belong to the phylum Cnidaria, which is comprised of 5 classes of both free-floating and sessile animals: Staurozoa (stauromedusae), Hydrozoa (hydroids, fire corals, and Portuguese man-of-war), Scyphozoa (true jellyfish), Anthozoa (corals and sea anemones), and Cubozoa (box jellyfish and Irukandji jellyfish).^1,2,6 Jellyfish typically have several tentacles suspended from a free-floating gelatinous body or bell; these tentacles are covered with thousands of cells unique to Cnidaria called nematocytes or cnidocytes containing specialized stinging organelles known as nematocysts. When triggered by physical (eg, human or foreign-body contact) or chemical stimuli, each nematocyst ejects a hollow filament or barb externally, releasing venom into the victim.^7,8

The scyphozoan, hydrozoan, and cubozoan life cycles generally consist of a bottom-dwelling, sessile polyp form that produces multiple free-swimming ephyrae through an asexual reproductive process called strobilation. These ephyrae grow into the fully mature medusae, recognizable as jellyfish (Figure 1).⁵ Additionally, jellyfish populations experience cycles of temporal and spatial population abundance and crashes known as jellyfish blooms. In 2017, Kaffenberger et al⁹ reviewed the shifting landscape of skin diseases in North America attributable to major changes in climate and weather patterns, including the rise in jellyfish blooms and envenomation outbreaks worldwide (eg, Physalia physalis [Portuguese man-of-war][Figure 2] along the southeastern US coastline, Porpita pacifica off Japanese beaches). Some research suggests jellyfish surges relate to climate change and human interactions with jellyfish habitats by way of eutrophication and fishing (removing predators of jellyfish).^9,10

Clinical Presentation

Jellyfish injuries can vary greatly in clinical symptoms, but they do follow some basic patterns. The severity of pain and symptoms is related to the jellyfish species, the number of stinging cells (nematocysts) that are triggered, and the potency of the venom that is absorbed by the victim.^11-13 Most stings are minor, and patients experience immediate localized pain with serpiginous raised erythematous or urticarial lesions following the distribution of tentacle contact; these lesions have been described as tentaclelike and resembling a string of beads (Figure 3).¹² Pain usually lasts a couple hours, while the skin lesions can last hours to days and can even recur years later. This pattern fits that of the well-known hydrozoans P physalis and Physalia utriculus (bluebottle), which are endemic to the Atlantic and Indo-Pacific Oceans, respectively. The scyphozoan jellyfish causing similar presentations include Pelagia noctiluca (Mauve stinger), Aurelia aurita (Moon jellyfish), and Cyanea species. The cubozoan Chironex fleckeri (Australian box jellyfish or sea wasp) also causes tentaclelike stings but is widely considered the most dangerous jellyfish, as its venom is known to cause cardiac or respiratory arrest.^4,11 More than 100 fatalities have been reported following severe envenomations from C fleckeri in Australian and Indo-Pacific waters.⁶

Stings from another box jellyfish species, Carukia barnesi, cause a unique presentation known as Irukandji syndrome. Carukia barnesi is a small box jellyfish with a bell measuring roughly 2 cm in diameter. It has nematocysts on both its bell and tentacles. It inhabits deeper waters and typically stings divers but also can wash ashore and injure beach tourists. Although Irukandji syndrome usually is associated with C barnesi, which is endemic to Northern Australian beaches, other jellyfish species including P physalis rarely have been linked to this potentially fatal syndrome.^6,11 Unlike the immediate cutaneous and systemic findings described in C fleckeri encounters, symptoms of Irukandji-like stings can be delayed by up to 30 minutes. Patients may present with severe generalized pain (lower back, chest, headache), signs of excess catecholamine release (tachycardia, hypertension, anxiety, diaphoresis, agitation), or cardiopulmonary decompensation (arrhythmia, cardiac arrest, pulmonary edema).^6,11,14.15 Anaphylactic reactions also have been reported in those sensitized by prior stings.¹⁶

Management

Prevention of drowning is key in all marine injuries. Rescuers should remove the individual from the water, establish the ABCs—airway, breathing, and circulation—and seek acute medical attention. If immediate resuscitation is not required, douse the wound as soon as possible with a solution that halts further nematocyst discharge, which may contain alcohol, vinegar, or bicarbonate, depending on the prevalent species. General guidance is available to providers through evidence-based, point-of-care databases including UpToDate and DynaMed, as well as through the American Heart Association (AHA) or a country’s equivalent council on emergency care if residing outside the United States. Pressure immobilization bandages as a means of decreasing venom redistribution is no longer recommended by the AHA because animal studies have shown increased nematocyst discharge after pressure application.¹⁷ As such, touching or applying pressure to the affected area is not recommended until after a proper rinse solution has been applied. Tentacles may be removed mechanically with gloved hands or sand and seawater with minimal compression or agitation.

When acetic acid is appropriate, such as for cubozoan stings, commercially available vinegar (5% acetic acid in the United States) is preferred.^16,17 Tap water can cause discharge of nematocysts, and seawater is preferred when no other solution is available.¹⁸ Most marine venoms are heat labile. Immersion in hot water can produce pain relief, but ice can be just as efficacious and is preferred by some patients. Prior reports of patients stung by Physalia species demonstrated greater pain relief with hot water immersion compared to ice pack application.^18,19

In the setting of anaphylaxis, patients should receive epinephrine and be transported to a hospital with appropriate hemodynamic monitoring and supportive care. If the species of jellyfish has been identified, species-specific antivenin also may be available in certain regions (eg, C fleckeri antivenin manufactured in Australia), but it is unclear if it improves outcomes when compared with supportive care alone.^6,16

Conclusion

Following jellyfish stings, most skin lesions will spontaneously resolve. Patients likely will present days to weeks following the inciting event with mild cutaneous symptoms that are amenable to topical corticosteroids. Recurrent dermatitis following a jellyfish sting is uncommon and is thought to be due to an immunologic mechanism consistent with type IV hypersensitivity reactions. Patients may require multiple courses of treatment before complete resolution.²⁰

Patient education regarding marine envenomation and mechanical barriers such as wetsuits or stinger suits can reduce the risk for injury from jellyfish stings. Sting-inhibiting lotions also are commercially available, though more research is needed.²¹ Many beaches that are known to harbor the dangerous box jellyfish provide stinger nets to direct travelers to safer waters. Complete avoidance during jellyfish season is recommended in highly endemic areas.¹

Causes of Lepidopterism

Caterpillars are wormlike organisms that serve as the larval stage of moths and butterflies, which belong to the order Lepidoptera. There are almost 165,000 discovered species, with 13,000 found in the United States.^1,2 Roughly 150 species are known to have the potential to cause an adverse reaction in humans, with 50 of these in the United States.¹Lepidopterism describes systemic and cutaneous reactions to moths, butterflies, and caterpillars; erucism describes strictly cutaneous reactions.¹

Although the rate of lepidopterism is thought to be underreported because it often is self-limited and of a mild nature, a review found caterpillars to be the cause of roughly 2.2% of reported bites and stings annually.² Cases increase in number with seasonal increases in caterpillars, which vary by region and species. For example, the Megalopyge opercularis (southern flannel moth) caterpillar was noted to have 2 peaks in a Texas-based study: 12% of reported stings occurred in July; 59% from October through November.³ In general, the likelihood of exposure increases during warmer months, and exposure is more common in people who work outdoors in a rural area or in a suburban area where there are many caterpillar-infested trees.⁴

Most cases of lepidopterism are caused by caterpillars, not by adult butterflies and moths, because the former have many tubular, or porous, hairlike structures called setae that are embedded in the integument. Setae were once thought to be connected to poison-secreting glandular cells, but current belief is that venomous caterpillars lack specialized gland cells and instead produce venom through secretory epithelial cells located above the integument.¹ Venom accumulates in the hemolymph and is stored in the setae or other types of bristles, such as scoli (wartlike bumps that bear setae) or spines.⁵ With a large amount of chitin, bristles have a tendency to fracture and release venom upon contact.¹ It is thought that some species of caterpillars formulate venom by ingesting toxins or toxin precursors from plants; for example, the tiger moth (family Arctiidae) is known to produce venom containing biogenic amines, pyrrolizidine, alkaloids, and cardiac glycosides obtained through food sources.⁵

Even if a caterpillar does not produce venom, its setae might embed into skin or mucous membranes and cause an adverse irritant reaction.¹ Setae also might dislodge and be transported in the air to embed in objects—some remaining stable in the environment for longer than a year.² In contrast to setae, spines are permanently fixed into the integument; for that reason, only direct contact with the caterpillar can result in an adverse reaction. Although it is mostly caterpillars that contain setae and spines, certain species of moths also might contain these structures or might acquire them as they emerge from the cocoon, which often contains incorporated setae.²

Reactions in Humans

Lepidopterism encompasses 3 principal reactions in humans: sting reaction, hypersensitivity reaction, and lonomism (a hemorrhagic diathesis produced by Lonomia caterpillars). The type and severity of the reaction depends on (1) the species of caterpillar or moth and (2) the individual patient.² There are approximately 12 families of caterpillars, mainly of the moth variety, that can cause an adverse reaction in humans.¹ Tables 1 and 2 list examples of species that cause each type of reaction.⁶

Chemicals and toxins contained in the poison of setae and spines vary by species of caterpillar. Numerous kinds have been isolated from different venoms,^1,2 including several peptides, histamine, histamine-releasing substances, acetylcholine, phospholipase A, hyaluronidase, formic acid, proteins with trypsinlike activity, serine proteases such as kallikrein, and other enzymes with vasodegenerative and fibrinolytic properties

Stings: An Immediate Adverse Reaction—Depending on the venom, a sting might result in mild to severe burning pain, accompanied by welts, vesicles, and red papules or plaques.² Figure 1 demonstrates a particularly mild sting from a caterpillar of the family Automeris, examples of which are seen in Figures 2 and 3 and eFigure 1. Components of the venom determine the mechanism of the sting and the pain that accompanies it. For example, a recent study demonstrated that the venom of the Latoia consocia caterpillar induces pain through the ion-channel receptor known as transient receptor potential vanilloid 1, which integrates and sends painful stimuli from the peripheral nervous system to the central nervous system.⁷ It is thought that a variety of ion channels are targets of the venom of caterpillars.

One of the most characteristic sting patterns is that of the caterpillar of family Megalopygidae (flannel moth)(eFigures 2 and 3). The stings of these caterpillars create a unique tram-track pattern of hemorrhagic macules or papules (Figure 4).⁴ A study found that 90% of reported M opercularis envenomations consist primarily of cutaneous symptoms, with 84% of those symptoms being irritation or pain; 45% a puncture or wound; 29% erythema; and 15% edema.³ Systemic findings can include headache, fever, adenopathy, nausea, vomiting, abdominal pain, and chest pain.⁴ Symptoms normally are self-limited, though they can last minutes or hours.

Hypersensitivity Reaction—Studies demonstrate that the symptoms of this reaction are a mixture of type I hypersensitivity, type IV hypersensitivity, and a foreign-body response.² The specific hypersensitivity reaction depends on the venom and the exposed individual—most commonly including a combination of pruritic papules, urticarial wheals, flares, and dermatitis.² A reaction that is a result of direct contact with the caterpillar or moth will appear on exposed areas; however, because setae embed in linens and clothing, they might cause a reaction anywhere on the body. Although usually self-limited, a hypersensitivity reaction might develop within minutes and can last for days or weeks.

Stings and hypersensitivity reactions to caterpillars and moths tend to lead to a nonspecific histologic presentation characterized by epidermal edema and a superficial perivascular lymphocytic infiltrate, often with eosinophils.⁶ After approximately 1 week, a foreign-body response to setae can lead to tuberculoid granulomas accompanied by neutrophils in the dermis and occasionally in subcutaneous tissues (Figures 5 and 6).⁸ If setae have not yet been removed, they also might be visible in skin scrapings.

Additional complications can accompany the hypersensitivity reaction to setae or spines. Type I hypersensitivity reactions can lead to severe reactions on second contact due to previously sensitized IgE antibodies. Although the first reaction appears mild, second contact might result in angioedema, wheezing, dyspnea, or anaphylaxis, or a combination of these findings.⁹ In addition, some patients who come in contact with Dendrolimus caterpillars might develop a condition known as dendrolimiasis, characterized by dermatitis in addition to arthritis or chondritis.⁶ The arthritis is normally monoarticular and can result in complete destruction of the joint. Pararamose, a condition with a similar presentation, is caused by the Brazilian moth Premolis semirufa.⁶

Contact of setae or spines with mucous membranes or inhalation of setae also might result in edema, dysphagia, dyspnea, drooling, rhinitis, or conjunctivitis, or a combination of these findings.⁶ In addition, setae can embed in the eye and cause an inflammatory reaction—ophthalmia nodosa—most commonly caused by caterpillars of the pine processionary moth (Thaumetopoea pityocampa) and characterized by immediate chemosis, which can progress to liquefactive necrosis and hypopyon, later developing into a granulomatous foreign-body response.^2,10 The process is thought to be the result of a combination of the thaumetopoein toxin in the setae and an IgE-mediated response to other proteins.¹⁰

Due to their harpoon shape and forward-only motion, setae might migrate deeper, potentially even to the optic nerve.¹¹ Because migration might take years and the barbed shape of setae does not always allow removal, some patients require lifetime monitoring with slit-lamp examination.Chronic problems, such as cataracts and persistent posterior uveitis, have been reported.^10,11

Lonomism—One of the most serious (though rarest) reactions to caterpillars is lonomism, a condition caused by the caterpillars of Lonomia achelous and Lonomia obliqua moths. These caterpillars have a unique combination of toxins filling their branched spines, which ultimately leads to the same outcome: a hemorrhagic diathesis.

The toxin of L achelous comprises several proteases that degrade fibrin, fibrinogen, and factor XIII while activating prothrombin. In contrast, L obliqua poison causes a hemorrhagic diathesis by promoting a consumptive coagulopathy through enzymes that activate factor X and prothrombin.

With initial contact with either of these Lonomia caterpillars, the patient experiences severe pain accompanied by systemic symptoms, including headache, nausea, and vomiting. Shortly afterward, symptoms of a hemorrhagic diathesis manifest, including bleeding gums, hematuria, bleeding from prior wounds, and epistaxis.⁵ Serious complications of the hemorrhagic diathesis, such as hemorrhage of major organs, leads to death in 4% of patients.⁵ A reported case of a patient whose Lonomia caterpillar sting went unrecognized until a week after the accident ended with progression to stage V chronic renal disease.¹²

Recent research has focused on the specific mechanism of injury caused by Lonomia species. A study found that the venom of L obliqua causes cytoskeleton rearrangement and migration in vascular smooth muscle cells (VSMCs) by inducing formation of reactive oxygen species through activation of nicotinamide adenine dinucleotide phosphate oxidase.¹³ Thus, the venom directly contributes to the proinflammatory phenotype of endothelial cells seen following envenomation. The same study also demonstrated that elevated reactive oxygen species trigger extracellular signal-regulated kinase pathway activation in VSMCs, leading to cell proliferation, re-stenosis, and ischemia.¹³ This finding was confirmed by another study,¹⁴ which demonstrated an increase in Rac1, a signaling protein involved in the extracellular signal-regulated kinase pathway, in VSMCs upon exposure to L obliqua venom. These studies propose potential new targets for treatment to prevent vascular damage.

Reactions to Adult Organisms—Although it is more common for the caterpillar form of these organisms to cause an adverse reaction, the adult moth also might be capable of causing a similar reaction by retaining setae from the cocoon or by their own spines. The most notable example of this is female moths of the genus Hylesia, which possess spines attached to glands on the abdomen. The poison in these spines—a mixture of proteases and chitinase—causes a dermatitis known as Caripito itch—the name derived from a river port in Venezuela where this moth caused a memorable epidemic of moth-induced dermatitis.^7,15 Caripito itch is known for intense pruritus that most commonly lasts days or weeks, possibly longer than 1 year.

Diagnostic Difficulties

The challenge of diagnosing a caterpillar- or moth-induced reaction in humans arises from (1) the lack of clinical history (the caterpillar might not be seen at all by the patient or the examiner) and (2) the similarity of these reactions to those with more common triggers.

When setae remain embedded in the skin or mucous membranes, skin scrapings allow accelerated diagnosis. On a skin scraping prepared with 20% potassium hydroxide, setae appear as tapered and barbed hairlike structures, which allows them to be distinguished from other similar-appearing but differently shaped structures, such as glass fibers.

When setae do not remain embedded in the skin or when the cause of the reaction is due to spines, the physician is left with a nonspecific histologic picture and a large differential diagnosis to be narrowed down based on the history and occasionally the pattern of the skin lesion.

A challenge in sting diagnosis is differentiating a caterpillar or moth sting from that of another organism. In certain cases, such as those of the family Megalopygidae, specific patterns of stings might assist in making the diagnosis. Hypersensitivity reactions are associated with a wider differential diagnosis, including irritant or allergic dermatitis from other causes, scabies, eczema, lichen planus, lichen simplex chronicus, seborrheic dermatitis, and tinea corporis, to name a few.⁶ Skin scrapings can be examined for other features, such as burrows in the case of scabies, to further narrow the differential.

Stings and hypersensitivity reactions lacking a proper history and associated with more severe systemic symptoms have caused misdiagnosis or led to a workup for the wrong condition; for example, the picture of abdominal pain, nausea, vomiting, tachycardia, leukocytosis, hypokalemia, and metabolic acidosis can simulate appendicitis.¹⁶ Upon discovery of a puss caterpillar sting in a patient, her symptoms resolved after treatment with ondansetron, morphine, and intravenous fluids.¹⁶

In lonomism, the diagnosis must be established by laboratory measurement of the fibrinogen level, clotting factors, prothrombin time, and activated partial thromboplastin time.⁴ The differential diagnosis associated with lonomism includes disseminated intravascular coagulation (DIC), snakebite, and a hereditary bleeding disorder.⁴ The combination of laboratory tests and an extensive medical history allows a diagnosis. Absence of a personal or family history of bleeding excludes a diagnosis of hereditary bleeding disorder, whereas the absence of known causes of DIC or thrombocytopenia allows DIC to be excluded from the differential.

Treatment Options and Prevention

Treatment—The first step is to remove any embedded setae from the skin or mucous membranes. The stepwise recommendation is to remove any constricted clothing, detach setae with adhesive tape, wash with soap and water, and dry without touching the skin.¹ Any remaining setae can be removed with additional tape or forceps; setae tend to be fragile and are difficult to remove in their entirety.

Other than removal of the setae, skin reactions are treated symptomatically. Ice packs and isopropyl alcohol have been utilized to cool burning or stinging areas. Pain, pruritus, and inflammation have been alleviated with antihistamines and topical corticosteroids.¹ When pain is severe, oral codeine or local injection of anesthetic can be used. For severe and persistent skin lesions, a course of an oral glucocorticoid can be administered. Intramuscular triamcinolone acetonide has been shown to treat pain, dermatitis, and subcutaneous nodules otherwise refractory to treatment.⁸

Antivenin specific for L obliqua exists to treat lonomism and is therefore effective only when lonomism is caused by that species. Lonomism caused by L achelous is treated with cryoprecipitate, purified fibrinogen, and antifibrinolytic drugs, such as aprotinin.⁶ Whole blood and fresh-frozen plasma have been noted to make hemorrhage worse when utilized to treat lonomism. Because the mechanism of action of the venom of Lonomia species is based, in part, on inducing a proinflammatory profile in endothelial cells, studies have demonstrated that inhibition of kallikrein might prevent vascular injury and thus prevent serious adverse effects, such as renal failure.¹⁷

Prevention—People should wear proper protective clothing when outdoors in potentially infested areas. Measures should be taken to ensure that linens and clothing are not left outside in areas where setae might be carried on the wind. Infestation control is necessary if the population of caterpillars reaches a high enough level.

Conclusion

Several species of caterpillars and moths cause adverse reactions in humans: stings, hypersensitivity reactions, and lonomism. Although most reactions are self-limited, some might have more serious effects, including organ failure and death. Mechanisms of injury vary by species of caterpillar, moth, and butterfly; current research is focused on further defining venom components and signaling pathways to isolate potential targets to aid in the diagnosis and treatment of lepidopterism.

Causes of Lepidopterism

Caterpillars are wormlike organisms that serve as the larval stage of moths and butterflies, which belong to the order Lepidoptera. There are almost 165,000 discovered species, with 13,000 found in the United States.^1,2 Roughly 150 species are known to have the potential to cause an adverse reaction in humans, with 50 of these in the United States.¹Lepidopterism describes systemic and cutaneous reactions to moths, butterflies, and caterpillars; erucism describes strictly cutaneous reactions.¹

Although the rate of lepidopterism is thought to be underreported because it often is self-limited and of a mild nature, a review found caterpillars to be the cause of roughly 2.2% of reported bites and stings annually.² Cases increase in number with seasonal increases in caterpillars, which vary by region and species. For example, the Megalopyge opercularis (southern flannel moth) caterpillar was noted to have 2 peaks in a Texas-based study: 12% of reported stings occurred in July; 59% from October through November.³ In general, the likelihood of exposure increases during warmer months, and exposure is more common in people who work outdoors in a rural area or in a suburban area where there are many caterpillar-infested trees.⁴

Most cases of lepidopterism are caused by caterpillars, not by adult butterflies and moths, because the former have many tubular, or porous, hairlike structures called setae that are embedded in the integument. Setae were once thought to be connected to poison-secreting glandular cells, but current belief is that venomous caterpillars lack specialized gland cells and instead produce venom through secretory epithelial cells located above the integument.¹ Venom accumulates in the hemolymph and is stored in the setae or other types of bristles, such as scoli (wartlike bumps that bear setae) or spines.⁵ With a large amount of chitin, bristles have a tendency to fracture and release venom upon contact.¹ It is thought that some species of caterpillars formulate venom by ingesting toxins or toxin precursors from plants; for example, the tiger moth (family Arctiidae) is known to produce venom containing biogenic amines, pyrrolizidine, alkaloids, and cardiac glycosides obtained through food sources.⁵

Even if a caterpillar does not produce venom, its setae might embed into skin or mucous membranes and cause an adverse irritant reaction.¹ Setae also might dislodge and be transported in the air to embed in objects—some remaining stable in the environment for longer than a year.² In contrast to setae, spines are permanently fixed into the integument; for that reason, only direct contact with the caterpillar can result in an adverse reaction. Although it is mostly caterpillars that contain setae and spines, certain species of moths also might contain these structures or might acquire them as they emerge from the cocoon, which often contains incorporated setae.²

Reactions in Humans

Lepidopterism encompasses 3 principal reactions in humans: sting reaction, hypersensitivity reaction, and lonomism (a hemorrhagic diathesis produced by Lonomia caterpillars). The type and severity of the reaction depends on (1) the species of caterpillar or moth and (2) the individual patient.² There are approximately 12 families of caterpillars, mainly of the moth variety, that can cause an adverse reaction in humans.¹ Tables 1 and 2 list examples of species that cause each type of reaction.⁶

Chemicals and toxins contained in the poison of setae and spines vary by species of caterpillar. Numerous kinds have been isolated from different venoms,^1,2 including several peptides, histamine, histamine-releasing substances, acetylcholine, phospholipase A, hyaluronidase, formic acid, proteins with trypsinlike activity, serine proteases such as kallikrein, and other enzymes with vasodegenerative and fibrinolytic properties

Stings: An Immediate Adverse Reaction—Depending on the venom, a sting might result in mild to severe burning pain, accompanied by welts, vesicles, and red papules or plaques.² Figure 1 demonstrates a particularly mild sting from a caterpillar of the family Automeris, examples of which are seen in Figures 2 and 3 and eFigure 1. Components of the venom determine the mechanism of the sting and the pain that accompanies it. For example, a recent study demonstrated that the venom of the Latoia consocia caterpillar induces pain through the ion-channel receptor known as transient receptor potential vanilloid 1, which integrates and sends painful stimuli from the peripheral nervous system to the central nervous system.⁷ It is thought that a variety of ion channels are targets of the venom of caterpillars.

One of the most characteristic sting patterns is that of the caterpillar of family Megalopygidae (flannel moth)(eFigures 2 and 3). The stings of these caterpillars create a unique tram-track pattern of hemorrhagic macules or papules (Figure 4).⁴ A study found that 90% of reported M opercularis envenomations consist primarily of cutaneous symptoms, with 84% of those symptoms being irritation or pain; 45% a puncture or wound; 29% erythema; and 15% edema.³ Systemic findings can include headache, fever, adenopathy, nausea, vomiting, abdominal pain, and chest pain.⁴ Symptoms normally are self-limited, though they can last minutes or hours.

Hypersensitivity Reaction—Studies demonstrate that the symptoms of this reaction are a mixture of type I hypersensitivity, type IV hypersensitivity, and a foreign-body response.² The specific hypersensitivity reaction depends on the venom and the exposed individual—most commonly including a combination of pruritic papules, urticarial wheals, flares, and dermatitis.² A reaction that is a result of direct contact with the caterpillar or moth will appear on exposed areas; however, because setae embed in linens and clothing, they might cause a reaction anywhere on the body. Although usually self-limited, a hypersensitivity reaction might develop within minutes and can last for days or weeks.

Stings and hypersensitivity reactions to caterpillars and moths tend to lead to a nonspecific histologic presentation characterized by epidermal edema and a superficial perivascular lymphocytic infiltrate, often with eosinophils.⁶ After approximately 1 week, a foreign-body response to setae can lead to tuberculoid granulomas accompanied by neutrophils in the dermis and occasionally in subcutaneous tissues (Figures 5 and 6).⁸ If setae have not yet been removed, they also might be visible in skin scrapings.

Additional complications can accompany the hypersensitivity reaction to setae or spines. Type I hypersensitivity reactions can lead to severe reactions on second contact due to previously sensitized IgE antibodies. Although the first reaction appears mild, second contact might result in angioedema, wheezing, dyspnea, or anaphylaxis, or a combination of these findings.⁹ In addition, some patients who come in contact with Dendrolimus caterpillars might develop a condition known as dendrolimiasis, characterized by dermatitis in addition to arthritis or chondritis.⁶ The arthritis is normally monoarticular and can result in complete destruction of the joint. Pararamose, a condition with a similar presentation, is caused by the Brazilian moth Premolis semirufa.⁶

Contact of setae or spines with mucous membranes or inhalation of setae also might result in edema, dysphagia, dyspnea, drooling, rhinitis, or conjunctivitis, or a combination of these findings.⁶ In addition, setae can embed in the eye and cause an inflammatory reaction—ophthalmia nodosa—most commonly caused by caterpillars of the pine processionary moth (Thaumetopoea pityocampa) and characterized by immediate chemosis, which can progress to liquefactive necrosis and hypopyon, later developing into a granulomatous foreign-body response.^2,10 The process is thought to be the result of a combination of the thaumetopoein toxin in the setae and an IgE-mediated response to other proteins.¹⁰

Due to their harpoon shape and forward-only motion, setae might migrate deeper, potentially even to the optic nerve.¹¹ Because migration might take years and the barbed shape of setae does not always allow removal, some patients require lifetime monitoring with slit-lamp examination.Chronic problems, such as cataracts and persistent posterior uveitis, have been reported.^10,11

Lonomism—One of the most serious (though rarest) reactions to caterpillars is lonomism, a condition caused by the caterpillars of Lonomia achelous and Lonomia obliqua moths. These caterpillars have a unique combination of toxins filling their branched spines, which ultimately leads to the same outcome: a hemorrhagic diathesis.

The toxin of L achelous comprises several proteases that degrade fibrin, fibrinogen, and factor XIII while activating prothrombin. In contrast, L obliqua poison causes a hemorrhagic diathesis by promoting a consumptive coagulopathy through enzymes that activate factor X and prothrombin.

With initial contact with either of these Lonomia caterpillars, the patient experiences severe pain accompanied by systemic symptoms, including headache, nausea, and vomiting. Shortly afterward, symptoms of a hemorrhagic diathesis manifest, including bleeding gums, hematuria, bleeding from prior wounds, and epistaxis.⁵ Serious complications of the hemorrhagic diathesis, such as hemorrhage of major organs, leads to death in 4% of patients.⁵ A reported case of a patient whose Lonomia caterpillar sting went unrecognized until a week after the accident ended with progression to stage V chronic renal disease.¹²

Recent research has focused on the specific mechanism of injury caused by Lonomia species. A study found that the venom of L obliqua causes cytoskeleton rearrangement and migration in vascular smooth muscle cells (VSMCs) by inducing formation of reactive oxygen species through activation of nicotinamide adenine dinucleotide phosphate oxidase.¹³ Thus, the venom directly contributes to the proinflammatory phenotype of endothelial cells seen following envenomation. The same study also demonstrated that elevated reactive oxygen species trigger extracellular signal-regulated kinase pathway activation in VSMCs, leading to cell proliferation, re-stenosis, and ischemia.¹³ This finding was confirmed by another study,¹⁴ which demonstrated an increase in Rac1, a signaling protein involved in the extracellular signal-regulated kinase pathway, in VSMCs upon exposure to L obliqua venom. These studies propose potential new targets for treatment to prevent vascular damage.

Reactions to Adult Organisms—Although it is more common for the caterpillar form of these organisms to cause an adverse reaction, the adult moth also might be capable of causing a similar reaction by retaining setae from the cocoon or by their own spines. The most notable example of this is female moths of the genus Hylesia, which possess spines attached to glands on the abdomen. The poison in these spines—a mixture of proteases and chitinase—causes a dermatitis known as Caripito itch—the name derived from a river port in Venezuela where this moth caused a memorable epidemic of moth-induced dermatitis.^7,15 Caripito itch is known for intense pruritus that most commonly lasts days or weeks, possibly longer than 1 year.

Diagnostic Difficulties

The challenge of diagnosing a caterpillar- or moth-induced reaction in humans arises from (1) the lack of clinical history (the caterpillar might not be seen at all by the patient or the examiner) and (2) the similarity of these reactions to those with more common triggers.

When setae remain embedded in the skin or mucous membranes, skin scrapings allow accelerated diagnosis. On a skin scraping prepared with 20% potassium hydroxide, setae appear as tapered and barbed hairlike structures, which allows them to be distinguished from other similar-appearing but differently shaped structures, such as glass fibers.

When setae do not remain embedded in the skin or when the cause of the reaction is due to spines, the physician is left with a nonspecific histologic picture and a large differential diagnosis to be narrowed down based on the history and occasionally the pattern of the skin lesion.

A challenge in sting diagnosis is differentiating a caterpillar or moth sting from that of another organism. In certain cases, such as those of the family Megalopygidae, specific patterns of stings might assist in making the diagnosis. Hypersensitivity reactions are associated with a wider differential diagnosis, including irritant or allergic dermatitis from other causes, scabies, eczema, lichen planus, lichen simplex chronicus, seborrheic dermatitis, and tinea corporis, to name a few.⁶ Skin scrapings can be examined for other features, such as burrows in the case of scabies, to further narrow the differential.

Stings and hypersensitivity reactions lacking a proper history and associated with more severe systemic symptoms have caused misdiagnosis or led to a workup for the wrong condition; for example, the picture of abdominal pain, nausea, vomiting, tachycardia, leukocytosis, hypokalemia, and metabolic acidosis can simulate appendicitis.¹⁶ Upon discovery of a puss caterpillar sting in a patient, her symptoms resolved after treatment with ondansetron, morphine, and intravenous fluids.¹⁶

In lonomism, the diagnosis must be established by laboratory measurement of the fibrinogen level, clotting factors, prothrombin time, and activated partial thromboplastin time.⁴ The differential diagnosis associated with lonomism includes disseminated intravascular coagulation (DIC), snakebite, and a hereditary bleeding disorder.⁴ The combination of laboratory tests and an extensive medical history allows a diagnosis. Absence of a personal or family history of bleeding excludes a diagnosis of hereditary bleeding disorder, whereas the absence of known causes of DIC or thrombocytopenia allows DIC to be excluded from the differential.

Treatment Options and Prevention

Treatment—The first step is to remove any embedded setae from the skin or mucous membranes. The stepwise recommendation is to remove any constricted clothing, detach setae with adhesive tape, wash with soap and water, and dry without touching the skin.¹ Any remaining setae can be removed with additional tape or forceps; setae tend to be fragile and are difficult to remove in their entirety.

Other than removal of the setae, skin reactions are treated symptomatically. Ice packs and isopropyl alcohol have been utilized to cool burning or stinging areas. Pain, pruritus, and inflammation have been alleviated with antihistamines and topical corticosteroids.¹ When pain is severe, oral codeine or local injection of anesthetic can be used. For severe and persistent skin lesions, a course of an oral glucocorticoid can be administered. Intramuscular triamcinolone acetonide has been shown to treat pain, dermatitis, and subcutaneous nodules otherwise refractory to treatment.⁸

Antivenin specific for L obliqua exists to treat lonomism and is therefore effective only when lonomism is caused by that species. Lonomism caused by L achelous is treated with cryoprecipitate, purified fibrinogen, and antifibrinolytic drugs, such as aprotinin.⁶ Whole blood and fresh-frozen plasma have been noted to make hemorrhage worse when utilized to treat lonomism. Because the mechanism of action of the venom of Lonomia species is based, in part, on inducing a proinflammatory profile in endothelial cells, studies have demonstrated that inhibition of kallikrein might prevent vascular injury and thus prevent serious adverse effects, such as renal failure.¹⁷

Prevention—People should wear proper protective clothing when outdoors in potentially infested areas. Measures should be taken to ensure that linens and clothing are not left outside in areas where setae might be carried on the wind. Infestation control is necessary if the population of caterpillars reaches a high enough level.

Conclusion

Several species of caterpillars and moths cause adverse reactions in humans: stings, hypersensitivity reactions, and lonomism. Although most reactions are self-limited, some might have more serious effects, including organ failure and death. Mechanisms of injury vary by species of caterpillar, moth, and butterfly; current research is focused on further defining venom components and signaling pathways to isolate potential targets to aid in the diagnosis and treatment of lepidopterism.

Causes of Lepidopterism

Caterpillars are wormlike organisms that serve as the larval stage of moths and butterflies, which belong to the order Lepidoptera. There are almost 165,000 discovered species, with 13,000 found in the United States.^1,2 Roughly 150 species are known to have the potential to cause an adverse reaction in humans, with 50 of these in the United States.¹Lepidopterism describes systemic and cutaneous reactions to moths, butterflies, and caterpillars; erucism describes strictly cutaneous reactions.¹

Although the rate of lepidopterism is thought to be underreported because it often is self-limited and of a mild nature, a review found caterpillars to be the cause of roughly 2.2% of reported bites and stings annually.² Cases increase in number with seasonal increases in caterpillars, which vary by region and species. For example, the Megalopyge opercularis (southern flannel moth) caterpillar was noted to have 2 peaks in a Texas-based study: 12% of reported stings occurred in July; 59% from October through November.³ In general, the likelihood of exposure increases during warmer months, and exposure is more common in people who work outdoors in a rural area or in a suburban area where there are many caterpillar-infested trees.⁴

Most cases of lepidopterism are caused by caterpillars, not by adult butterflies and moths, because the former have many tubular, or porous, hairlike structures called setae that are embedded in the integument. Setae were once thought to be connected to poison-secreting glandular cells, but current belief is that venomous caterpillars lack specialized gland cells and instead produce venom through secretory epithelial cells located above the integument.¹ Venom accumulates in the hemolymph and is stored in the setae or other types of bristles, such as scoli (wartlike bumps that bear setae) or spines.⁵ With a large amount of chitin, bristles have a tendency to fracture and release venom upon contact.¹ It is thought that some species of caterpillars formulate venom by ingesting toxins or toxin precursors from plants; for example, the tiger moth (family Arctiidae) is known to produce venom containing biogenic amines, pyrrolizidine, alkaloids, and cardiac glycosides obtained through food sources.⁵

Even if a caterpillar does not produce venom, its setae might embed into skin or mucous membranes and cause an adverse irritant reaction.¹ Setae also might dislodge and be transported in the air to embed in objects—some remaining stable in the environment for longer than a year.² In contrast to setae, spines are permanently fixed into the integument; for that reason, only direct contact with the caterpillar can result in an adverse reaction. Although it is mostly caterpillars that contain setae and spines, certain species of moths also might contain these structures or might acquire them as they emerge from the cocoon, which often contains incorporated setae.²

Reactions in Humans

Lepidopterism encompasses 3 principal reactions in humans: sting reaction, hypersensitivity reaction, and lonomism (a hemorrhagic diathesis produced by Lonomia caterpillars). The type and severity of the reaction depends on (1) the species of caterpillar or moth and (2) the individual patient.² There are approximately 12 families of caterpillars, mainly of the moth variety, that can cause an adverse reaction in humans.¹ Tables 1 and 2 list examples of species that cause each type of reaction.⁶

Chemicals and toxins contained in the poison of setae and spines vary by species of caterpillar. Numerous kinds have been isolated from different venoms,^1,2 including several peptides, histamine, histamine-releasing substances, acetylcholine, phospholipase A, hyaluronidase, formic acid, proteins with trypsinlike activity, serine proteases such as kallikrein, and other enzymes with vasodegenerative and fibrinolytic properties

Stings: An Immediate Adverse Reaction—Depending on the venom, a sting might result in mild to severe burning pain, accompanied by welts, vesicles, and red papules or plaques.² Figure 1 demonstrates a particularly mild sting from a caterpillar of the family Automeris, examples of which are seen in Figures 2 and 3 and eFigure 1. Components of the venom determine the mechanism of the sting and the pain that accompanies it. For example, a recent study demonstrated that the venom of the Latoia consocia caterpillar induces pain through the ion-channel receptor known as transient receptor potential vanilloid 1, which integrates and sends painful stimuli from the peripheral nervous system to the central nervous system.⁷ It is thought that a variety of ion channels are targets of the venom of caterpillars.

One of the most characteristic sting patterns is that of the caterpillar of family Megalopygidae (flannel moth)(eFigures 2 and 3). The stings of these caterpillars create a unique tram-track pattern of hemorrhagic macules or papules (Figure 4).⁴ A study found that 90% of reported M opercularis envenomations consist primarily of cutaneous symptoms, with 84% of those symptoms being irritation or pain; 45% a puncture or wound; 29% erythema; and 15% edema.³ Systemic findings can include headache, fever, adenopathy, nausea, vomiting, abdominal pain, and chest pain.⁴ Symptoms normally are self-limited, though they can last minutes or hours.