Dirk M. Elston, MD

The Asteraceae (formerly Compositae) family of plants is derived from the ancient Greek word aster, meaning “star,” referring to the starlike arrangement of flower petals around a central disc known as a capitulum. What initially appears as a single flower is actually a composite of several smaller flowers, hence the former name Compositae.¹ Well-known members of the Asteraceae family include ornamental annuals (eg, sunflowers, marigolds, cosmos), herbaceous ­perennials (eg, chrysanthemums, dandelions), vegetables (eg, lettuce, chicory, artichokes), herbs (eg, chamomile, tarragon), and weeds (eg, ragweed, horseweed, capeweed)(Figure 1).²

There are more than 25,000 species of Asteraceae plants that thrive in a wide range of climates worldwide. Cases of Asteraceae-induced skin reactions have been reported in North America, Europe, Asia, and Australia.³ Members of the Asteraceae family are ubiquitous in gardens, along roadsides, and in the wilderness. Occupational exposure commonly affects gardeners, florists, farmers, and forestry workers through either direct contact with plants or via airborne pollen. Furthermore, plants of the Asteraceae family are used in various products, including pediculicides (eg, insect repellents), cosmetics (eg, eye creams, body washes), and food products (eg, cooking oils, sweetening agents, coffee substitutes, herbal teas).^4-6 These plants have substantial allergic potential, resulting in numerous cutaneous reactions.

Allergic Potential

Asteraceae plants can elicit both immediate and delayed hypersensitivity reactions (HSRs); for instance, exposure to ragweed pollen may cause an IgE-mediated type 1 HSR manifesting as allergic rhinitis or a type IV HSR manifesting as airborne allergic contact dermatitis.^7,8 The main contact allergens present in Asteraceae plants are sesquiterpene lactones, which are found in the leaves, stems, flowers, and pollen.^9-11 Sesquiterpene lactones consist of an α-methyl group attached to a lactone ring combined with a sesquiterpene.¹² Patch testing can be used to diagnose Asteraceae allergy; however, the results are not consistently reliable because there is no perfect screening allergen. Patch test preparations commonly used to detect Asteraceae allergy include Compositae mix (consisting of Anthemis nobilis extract, Chamomilla recutita extract, Achillea millefolium extract, Tanacetum vulgare extract, Arnica montana extract, and parthenolide) and sesquiterpene lactone mix (consisting of alantolactone, dehydrocostus lactone, and costunolide). In North America, the prevalence of positive patch tests to Compositae mix and sesquiterpene lactone mix is approximately 2% and 0.5%, respectively.¹³ When patch testing is performed, both Compositae mix and sesquiterpene lactone mix should be utilized to minimize the risk of missing Asteraceae allergy, as sesquiterpene lactone mix alone does not detect all Compositae-sensitized patients. Additionally, it may be necessary to test supplemental Asteraceae allergens, including preparations from specific plants to which the patient has been exposed. Exposure to Asteraceae-containing cosmetic products may lead to dermatitis, though this is highly dependent on the particular plant species involved. For instance, the prevalence of sensitization is high in arnica (tincture) and elecampane but low with more commonly used species such as German chamomile.¹⁴

Cutaneous Manifestations

Asteraceae dermatitis, which also is known as Australian bush dermatitis, weed dermatitis, and chrysanthemum dermatitis,² can manifest on any area of the body that directly contacts the plant or is exposed to the pollen. Asteraceae dermatitis historically was reported in older adults with a recent history of plant exposure.^6,15 However, recent data have shown a female preponderance and a younger mean age of onset (46–49 years).¹⁶

There are multiple distinct clinical manifestations of Asteraceae dermatitis. The most common cutaneous finding is localized vesicular or eczematous patches on the hands or wrists. Other variations include eczematous rashes on the exposed skin of the hands, arms, face, and neck; generalized eczema; and isolated facial eczema.^16,17 These variations can be attributed to contact dermatitis caused by airborne pollen, which may mimic photodermatitis. However, airborne Asteraceae dermatitis can be distinguished clinically from photodermatitis by the involvement of sun-protected areas such as the skinfolds of the eyelids, retroauricular sulci, and nasolabial folds (Figure 2).^2,9 In rare cases, systemic allergic contact dermatitis can occur if the Asteraceae allergen is ingested.^2,18

Management

While complete avoidance of Asteraceae plants is ideal, it often is unrealistic due to their abundance in nature. Therefore, minimizing exposure to the causative plants is recommended. Primary preventive measures such as wearing protective gloves and clothing and applying bentonite clay prior to exposure should be taken when working outdoors. Promptly showering after contact with plants also can reduce the risk for Asteraceae dermatitis.

Symptomatic treatment is appropriate for mild cases and includes topical corticosteroids and calcineurin inhibitors. For severe cases, systemic corticosteroids may be needed for acute flares, with azathioprine, mycophenolate, cyclosporine, or methotrexate available for recalcitrant disease. Verma et al²⁵ found that treatment with azathioprine for 6 months resulted in greater than 60% clearance in all 12 patients, with a majority achieving 80% to 100% clearance. Methotrexate has been used at doses of 15 mg once weekly.²⁶ Narrowband UVB and psoralen plus UVA have been effective in extensive cases; however, care should be exercised in patients with photosensitive dermatitis, who instead should practice strict photoprotection.^27-29 Lakshmi et al³⁰ reported the use of cyclosporine during the acute phase of Asteraceae dermatitis at a dose of 2.5 mg/kg daily for 4 to 8 weeks. There have been several case reports of dupilumab treating allergic contact dermatitis; however, there have been 3 cases of patients with atopic dermatitis developing Asteraceae dermatitis while taking dupilumab.^31,32 Recently, oral Janus kinase inhibitors have shown success in treating refractory cases of airborne Asteraceae dermatitis.^33,34 Further research is needed to determine the safety and efficacy of dupilumab and Janus kinase inhibitors for treatment of Asteraceae dermatitis.

Final Thoughts

The Asteraceae plant family is vast and diverse, with more than 200 species reported to cause allergic contact dermatitis.¹² Common modes of contact include gardening, occupational exposure, airborne pollen, and use of pediculicides and cosmetics that contain components of Asteraceae plants. Educating patients on how to minimize contact with Asteraceae plants is the most effective management strategy; topical agents and oral immunosuppressives can be used for symptomatic treatment.

The Asteraceae (formerly Compositae) family of plants is derived from the ancient Greek word aster, meaning “star,” referring to the starlike arrangement of flower petals around a central disc known as a capitulum. What initially appears as a single flower is actually a composite of several smaller flowers, hence the former name Compositae.¹ Well-known members of the Asteraceae family include ornamental annuals (eg, sunflowers, marigolds, cosmos), herbaceous ­perennials (eg, chrysanthemums, dandelions), vegetables (eg, lettuce, chicory, artichokes), herbs (eg, chamomile, tarragon), and weeds (eg, ragweed, horseweed, capeweed)(Figure 1).²

There are more than 25,000 species of Asteraceae plants that thrive in a wide range of climates worldwide. Cases of Asteraceae-induced skin reactions have been reported in North America, Europe, Asia, and Australia.³ Members of the Asteraceae family are ubiquitous in gardens, along roadsides, and in the wilderness. Occupational exposure commonly affects gardeners, florists, farmers, and forestry workers through either direct contact with plants or via airborne pollen. Furthermore, plants of the Asteraceae family are used in various products, including pediculicides (eg, insect repellents), cosmetics (eg, eye creams, body washes), and food products (eg, cooking oils, sweetening agents, coffee substitutes, herbal teas).^4-6 These plants have substantial allergic potential, resulting in numerous cutaneous reactions.

Allergic Potential

Asteraceae plants can elicit both immediate and delayed hypersensitivity reactions (HSRs); for instance, exposure to ragweed pollen may cause an IgE-mediated type 1 HSR manifesting as allergic rhinitis or a type IV HSR manifesting as airborne allergic contact dermatitis.^7,8 The main contact allergens present in Asteraceae plants are sesquiterpene lactones, which are found in the leaves, stems, flowers, and pollen.^9-11 Sesquiterpene lactones consist of an α-methyl group attached to a lactone ring combined with a sesquiterpene.¹² Patch testing can be used to diagnose Asteraceae allergy; however, the results are not consistently reliable because there is no perfect screening allergen. Patch test preparations commonly used to detect Asteraceae allergy include Compositae mix (consisting of Anthemis nobilis extract, Chamomilla recutita extract, Achillea millefolium extract, Tanacetum vulgare extract, Arnica montana extract, and parthenolide) and sesquiterpene lactone mix (consisting of alantolactone, dehydrocostus lactone, and costunolide). In North America, the prevalence of positive patch tests to Compositae mix and sesquiterpene lactone mix is approximately 2% and 0.5%, respectively.¹³ When patch testing is performed, both Compositae mix and sesquiterpene lactone mix should be utilized to minimize the risk of missing Asteraceae allergy, as sesquiterpene lactone mix alone does not detect all Compositae-sensitized patients. Additionally, it may be necessary to test supplemental Asteraceae allergens, including preparations from specific plants to which the patient has been exposed. Exposure to Asteraceae-containing cosmetic products may lead to dermatitis, though this is highly dependent on the particular plant species involved. For instance, the prevalence of sensitization is high in arnica (tincture) and elecampane but low with more commonly used species such as German chamomile.¹⁴

Cutaneous Manifestations

Asteraceae dermatitis, which also is known as Australian bush dermatitis, weed dermatitis, and chrysanthemum dermatitis,² can manifest on any area of the body that directly contacts the plant or is exposed to the pollen. Asteraceae dermatitis historically was reported in older adults with a recent history of plant exposure.^6,15 However, recent data have shown a female preponderance and a younger mean age of onset (46–49 years).¹⁶

There are multiple distinct clinical manifestations of Asteraceae dermatitis. The most common cutaneous finding is localized vesicular or eczematous patches on the hands or wrists. Other variations include eczematous rashes on the exposed skin of the hands, arms, face, and neck; generalized eczema; and isolated facial eczema.^16,17 These variations can be attributed to contact dermatitis caused by airborne pollen, which may mimic photodermatitis. However, airborne Asteraceae dermatitis can be distinguished clinically from photodermatitis by the involvement of sun-protected areas such as the skinfolds of the eyelids, retroauricular sulci, and nasolabial folds (Figure 2).^2,9 In rare cases, systemic allergic contact dermatitis can occur if the Asteraceae allergen is ingested.^2,18

Management

While complete avoidance of Asteraceae plants is ideal, it often is unrealistic due to their abundance in nature. Therefore, minimizing exposure to the causative plants is recommended. Primary preventive measures such as wearing protective gloves and clothing and applying bentonite clay prior to exposure should be taken when working outdoors. Promptly showering after contact with plants also can reduce the risk for Asteraceae dermatitis.

Symptomatic treatment is appropriate for mild cases and includes topical corticosteroids and calcineurin inhibitors. For severe cases, systemic corticosteroids may be needed for acute flares, with azathioprine, mycophenolate, cyclosporine, or methotrexate available for recalcitrant disease. Verma et al²⁵ found that treatment with azathioprine for 6 months resulted in greater than 60% clearance in all 12 patients, with a majority achieving 80% to 100% clearance. Methotrexate has been used at doses of 15 mg once weekly.²⁶ Narrowband UVB and psoralen plus UVA have been effective in extensive cases; however, care should be exercised in patients with photosensitive dermatitis, who instead should practice strict photoprotection.^27-29 Lakshmi et al³⁰ reported the use of cyclosporine during the acute phase of Asteraceae dermatitis at a dose of 2.5 mg/kg daily for 4 to 8 weeks. There have been several case reports of dupilumab treating allergic contact dermatitis; however, there have been 3 cases of patients with atopic dermatitis developing Asteraceae dermatitis while taking dupilumab.^31,32 Recently, oral Janus kinase inhibitors have shown success in treating refractory cases of airborne Asteraceae dermatitis.^33,34 Further research is needed to determine the safety and efficacy of dupilumab and Janus kinase inhibitors for treatment of Asteraceae dermatitis.

Final Thoughts

The Asteraceae plant family is vast and diverse, with more than 200 species reported to cause allergic contact dermatitis.¹² Common modes of contact include gardening, occupational exposure, airborne pollen, and use of pediculicides and cosmetics that contain components of Asteraceae plants. Educating patients on how to minimize contact with Asteraceae plants is the most effective management strategy; topical agents and oral immunosuppressives can be used for symptomatic treatment.

The Asteraceae (formerly Compositae) family of plants is derived from the ancient Greek word aster, meaning “star,” referring to the starlike arrangement of flower petals around a central disc known as a capitulum. What initially appears as a single flower is actually a composite of several smaller flowers, hence the former name Compositae.¹ Well-known members of the Asteraceae family include ornamental annuals (eg, sunflowers, marigolds, cosmos), herbaceous ­perennials (eg, chrysanthemums, dandelions), vegetables (eg, lettuce, chicory, artichokes), herbs (eg, chamomile, tarragon), and weeds (eg, ragweed, horseweed, capeweed)(Figure 1).²

There are more than 25,000 species of Asteraceae plants that thrive in a wide range of climates worldwide. Cases of Asteraceae-induced skin reactions have been reported in North America, Europe, Asia, and Australia.³ Members of the Asteraceae family are ubiquitous in gardens, along roadsides, and in the wilderness. Occupational exposure commonly affects gardeners, florists, farmers, and forestry workers through either direct contact with plants or via airborne pollen. Furthermore, plants of the Asteraceae family are used in various products, including pediculicides (eg, insect repellents), cosmetics (eg, eye creams, body washes), and food products (eg, cooking oils, sweetening agents, coffee substitutes, herbal teas).^4-6 These plants have substantial allergic potential, resulting in numerous cutaneous reactions.

Allergic Potential

Asteraceae plants can elicit both immediate and delayed hypersensitivity reactions (HSRs); for instance, exposure to ragweed pollen may cause an IgE-mediated type 1 HSR manifesting as allergic rhinitis or a type IV HSR manifesting as airborne allergic contact dermatitis.^7,8 The main contact allergens present in Asteraceae plants are sesquiterpene lactones, which are found in the leaves, stems, flowers, and pollen.^9-11 Sesquiterpene lactones consist of an α-methyl group attached to a lactone ring combined with a sesquiterpene.¹² Patch testing can be used to diagnose Asteraceae allergy; however, the results are not consistently reliable because there is no perfect screening allergen. Patch test preparations commonly used to detect Asteraceae allergy include Compositae mix (consisting of Anthemis nobilis extract, Chamomilla recutita extract, Achillea millefolium extract, Tanacetum vulgare extract, Arnica montana extract, and parthenolide) and sesquiterpene lactone mix (consisting of alantolactone, dehydrocostus lactone, and costunolide). In North America, the prevalence of positive patch tests to Compositae mix and sesquiterpene lactone mix is approximately 2% and 0.5%, respectively.¹³ When patch testing is performed, both Compositae mix and sesquiterpene lactone mix should be utilized to minimize the risk of missing Asteraceae allergy, as sesquiterpene lactone mix alone does not detect all Compositae-sensitized patients. Additionally, it may be necessary to test supplemental Asteraceae allergens, including preparations from specific plants to which the patient has been exposed. Exposure to Asteraceae-containing cosmetic products may lead to dermatitis, though this is highly dependent on the particular plant species involved. For instance, the prevalence of sensitization is high in arnica (tincture) and elecampane but low with more commonly used species such as German chamomile.¹⁴

Cutaneous Manifestations

Asteraceae dermatitis, which also is known as Australian bush dermatitis, weed dermatitis, and chrysanthemum dermatitis,² can manifest on any area of the body that directly contacts the plant or is exposed to the pollen. Asteraceae dermatitis historically was reported in older adults with a recent history of plant exposure.^6,15 However, recent data have shown a female preponderance and a younger mean age of onset (46–49 years).¹⁶

There are multiple distinct clinical manifestations of Asteraceae dermatitis. The most common cutaneous finding is localized vesicular or eczematous patches on the hands or wrists. Other variations include eczematous rashes on the exposed skin of the hands, arms, face, and neck; generalized eczema; and isolated facial eczema.^16,17 These variations can be attributed to contact dermatitis caused by airborne pollen, which may mimic photodermatitis. However, airborne Asteraceae dermatitis can be distinguished clinically from photodermatitis by the involvement of sun-protected areas such as the skinfolds of the eyelids, retroauricular sulci, and nasolabial folds (Figure 2).^2,9 In rare cases, systemic allergic contact dermatitis can occur if the Asteraceae allergen is ingested.^2,18

Management

While complete avoidance of Asteraceae plants is ideal, it often is unrealistic due to their abundance in nature. Therefore, minimizing exposure to the causative plants is recommended. Primary preventive measures such as wearing protective gloves and clothing and applying bentonite clay prior to exposure should be taken when working outdoors. Promptly showering after contact with plants also can reduce the risk for Asteraceae dermatitis.

Symptomatic treatment is appropriate for mild cases and includes topical corticosteroids and calcineurin inhibitors. For severe cases, systemic corticosteroids may be needed for acute flares, with azathioprine, mycophenolate, cyclosporine, or methotrexate available for recalcitrant disease. Verma et al²⁵ found that treatment with azathioprine for 6 months resulted in greater than 60% clearance in all 12 patients, with a majority achieving 80% to 100% clearance. Methotrexate has been used at doses of 15 mg once weekly.²⁶ Narrowband UVB and psoralen plus UVA have been effective in extensive cases; however, care should be exercised in patients with photosensitive dermatitis, who instead should practice strict photoprotection.^27-29 Lakshmi et al³⁰ reported the use of cyclosporine during the acute phase of Asteraceae dermatitis at a dose of 2.5 mg/kg daily for 4 to 8 weeks. There have been several case reports of dupilumab treating allergic contact dermatitis; however, there have been 3 cases of patients with atopic dermatitis developing Asteraceae dermatitis while taking dupilumab.^31,32 Recently, oral Janus kinase inhibitors have shown success in treating refractory cases of airborne Asteraceae dermatitis.^33,34 Further research is needed to determine the safety and efficacy of dupilumab and Janus kinase inhibitors for treatment of Asteraceae dermatitis.

Final Thoughts

The Asteraceae plant family is vast and diverse, with more than 200 species reported to cause allergic contact dermatitis.¹² Common modes of contact include gardening, occupational exposure, airborne pollen, and use of pediculicides and cosmetics that contain components of Asteraceae plants. Educating patients on how to minimize contact with Asteraceae plants is the most effective management strategy; topical agents and oral immunosuppressives can be used for symptomatic treatment.

THE DIAGNOSIS: Dengue Hemorrhagic Fever

The retiform purpura observed in our patient was suggestive of a vasculitic, thrombotic, or embolic etiology. Dengue IgM serologic testing performed based on her extensive travel history and recent return from a dengue-endemic area was positive, indicating acute infection. A clinical diagnosis of dengue hemorrhagic fever (DHF) was made based on the hemorrhagic appearance of the lesion. Histopathology revealed leukocytoclastic vasculitis (Figure). Anti–double-stranded DNA, antideoxyribonuclease, C3 and C4, CH50 (total hemolytic complement), antineutrophil cytoplasmic antibodies, HIV, and hepatitis B virus tests were normal. Direct immunofluorescence was negative.

Dengue virus is a single-stranded RNA virus transmitted by Aedes aegypti and Aedes albopictus mosquitoes and is one of the most prevalent arthropod-borne viruses affecting humans today.^1,2 Infection with the dengue virus generally is seen in travelers visiting tropical regions of Africa, Mexico, South America, South and Central Asia, Southeast Asia, and the Caribbean.¹ The Table shows the global distribution of dengue serotypes from 2000 to 2014.^3,4 There are 4 serotypes of the dengue virus: DENV-1 to DENV-4. Infection with 1 strain elicits longlasting immunity to that strain, but subsequent infection with another strain can result in severe DHF due to antibody cross-reaction.¹

Dengue virus infection ranges from mildly symptomatic to a spectrum of increasingly severe conditions that comprise dengue fever (DF) and DHF, as well as dengue shock syndrome and brain stem hemorrhage, which may be fatal.^2,5 Dengue fever manifests as severe myalgia, fever, headache (usually retro-orbital), arthralgia, erythema, and rubelliform exanthema.⁶ The frequency of skin eruptions in patients with DF varies with the virus strain and outbreaks.⁷ The lesions initially develop with the onset of fever and manifest as flushing or erythematous mottling of the face, neck, and chest areas.^1,7 The morbilliform eruption develops 2 to 6 days after the onset of the fever, beginning on the trunk and spreading to the face and extremities.^1,7 The rash may become confluent with characteristic sparing of small round areas of normal skin described as white islands in a sea of red.² Verrucous papules on the ears also have been described and may resemble those seen in Cowden syndrome. In patients with prior infection with a different strain of the virus, hemorrhagic lesions may develop, including characteristic retiform purpura, a positive tourniquet test, and the appearance of petechiae on the lower legs. Pruritus and desquamation, especially on the palms and soles, may follow the termination of the eruption.⁷

The differential diagnosis of DF includes measles, rubella, enteroviruses, and influenza. Chikungunya and West Nile viruses in Asia and Africa and the O’nyong-nyong virus in Africa are also arboviruses that cause a clinical picture similar to DF but not DHF. Other diagnostic considerations include phases of scarlet fever, typhoid, malaria, leptospirosis, hepatitis A, and trypanosomal and rickettsial diseases.⁷ The differential diagnosis of DHF includes antineutrophil cytoplasmic antibody–associated vasculitis, rheumatoid vasculitis, and bacterial septic vasculitis.

Acute clinical diagnosis of DF can be challenging because of the nonspecific symptoms that can be seen in almost every infectious disease. Clinical presentation assessment should be confirmed with laboratory testing.⁶ Dengue virus infection usually is confirmed by the identification of viral genomic RNA, antigens, or the antibodies it elicits. Enzyme-linked immunosorbent assay–based serologic tests are cost-effective and easy to perform.⁵ IgM antibodies usually show cross-reactivity with platelets, but the antibody levels are not positively correlated with the severity of DF.⁸ Primary infection with the dengue virus is characterized by the elevation of specific IgM levels that usually occurs 3 to 5 days after symptom onset and persists during the postfebrile stage (up to 30 to 60 days). In secondary infections, the IgM levels usually rise more slowly and reach a lower level than in primary infections.⁹ For both primary and secondary infections, testing IgM levels after the febrile stage may be helpful with the laboratory diagnosis.

Currently, there is no antiviral drug available for dengue. Treatment of dengue infection is symptomatic and supportive.²

Dengue hemorrhagic fever is indicated by a rising hematocrit (≥20%) and a falling platelet count (>100,000/mm³) accompanying clinical signs of hemorrhage. Treatment includes intravenous fluid replacement and careful clinical monitoring of hematocrit levels, platelet count, vitals, urine output, and other signs of shock.⁵ For patients with a history of dengue infection, travel to areas with other serotypes is not recommended.

If any travel to a high-risk area is planned, countryspecific travel recommendations and warnings should be reviewed from the Centers for Disease Control and Prevention’s website (https://wwwnc.cdc.gov/travel/notices/level1/dengue-global). Use of an Environmental Protection Agency–registered insect repellent to avoid mosquito bites and acetaminophen for managing symptoms is advised. During travel, staying in places with window and door screens and using a bed net during sleep are suggested. Long-sleeved shirts and long pants also are preferred. Travelers should see a health care provider if they have symptoms of dengue.¹⁰

African tick bite fever (ATBF) is caused by Rickettsia africae transmitted by Amblyomma ticks. Skin findings in ATBF include erythematous, firm, tender papules with central eschars consistent with the feeding patterns of ticks.¹¹ Histopathology of ATBF usually includes fibrinoid necrosis of vessels in the dermis with a perivascular inflammatory infiltrate and coagulation necrosis of the surrounding dermis consistent with eschar formation.¹² The lack of an eschar weighs against this diagnosis.

African trypanosomiasis (also known as sleeping sickness) is caused by protozoa transmitted by the tsetse fly. A chancrelike, circumscribed, rubbery, indurated red or violaceous nodule measuring 2 to 5 cm in diameter often develops as the earliest cutaneous sign of the disease.¹³ Nonspecific histopathologic findings, such as infiltration of lymphocytes and macrophages and proliferation of endothelial cells and fibroblasts, may be observed.¹⁴ Extravascular parasites have been noted in skin biopsies.¹⁵ In later stages, skin lesions called trypanids may be observed as macular, papular, annular, targetoid, purpuric, and erythematous lesions, and histopathologic findings consistent with vasculitis also may be seen.¹³

Chikungunya virus infection is an acute-onset, mosquito-borne viral disease. Skin manifestations may start with nonspecific, generalized, morbilliform, maculopapular rashes coinciding with fever, which also may be seen initially with DHF. Skin hyperpigmentation, mostly centrofacial and involving the nose (chik sign); purpuric and ecchymotic lesions over the trunk and flexors of limbs in adults, often surmounted by subepidermal bullae and lesions resembling toxic epidermal necrolysis; and nonhealing ulcers in the genital and groin areas are common skin manifestations of chikungunya infection.¹⁶ Intraepithelial splitting with acantholysis and perivascular lymphohistiocytic infiltration may be observed in the histopathology of blistering lesions, which are not consistent with DHF.¹⁷

Zika virus infection is caused by an arbovirus within the Flaviviridae family, which also includes the dengue virus. Initial mucocutaneous findings of the Zika virus include nonspecific diffuse maculopapular eruptions. The eruption generally spares the palms and soles; however, various manifestations including involvement of the palms and soles have been reported.¹⁸ The morbilliform eruption begins on the face and extends to the trunk and extremities. Mild hemorrhagic manifestations, including petechiae and bleeding gums, may be observed. Distinguishing between dengue and Zika virus infection relies on the severity of symptoms and laboratory tests, including polymerase chain reaction or IgM antibody testing.¹⁹ The other conditions listed do not produce hemorrhagic fever.

THE DIAGNOSIS: Dengue Hemorrhagic Fever

The retiform purpura observed in our patient was suggestive of a vasculitic, thrombotic, or embolic etiology. Dengue IgM serologic testing performed based on her extensive travel history and recent return from a dengue-endemic area was positive, indicating acute infection. A clinical diagnosis of dengue hemorrhagic fever (DHF) was made based on the hemorrhagic appearance of the lesion. Histopathology revealed leukocytoclastic vasculitis (Figure). Anti–double-stranded DNA, antideoxyribonuclease, C3 and C4, CH50 (total hemolytic complement), antineutrophil cytoplasmic antibodies, HIV, and hepatitis B virus tests were normal. Direct immunofluorescence was negative.

Dengue virus is a single-stranded RNA virus transmitted by Aedes aegypti and Aedes albopictus mosquitoes and is one of the most prevalent arthropod-borne viruses affecting humans today.^1,2 Infection with the dengue virus generally is seen in travelers visiting tropical regions of Africa, Mexico, South America, South and Central Asia, Southeast Asia, and the Caribbean.¹ The Table shows the global distribution of dengue serotypes from 2000 to 2014.^3,4 There are 4 serotypes of the dengue virus: DENV-1 to DENV-4. Infection with 1 strain elicits longlasting immunity to that strain, but subsequent infection with another strain can result in severe DHF due to antibody cross-reaction.¹

Dengue virus infection ranges from mildly symptomatic to a spectrum of increasingly severe conditions that comprise dengue fever (DF) and DHF, as well as dengue shock syndrome and brain stem hemorrhage, which may be fatal.^2,5 Dengue fever manifests as severe myalgia, fever, headache (usually retro-orbital), arthralgia, erythema, and rubelliform exanthema.⁶ The frequency of skin eruptions in patients with DF varies with the virus strain and outbreaks.⁷ The lesions initially develop with the onset of fever and manifest as flushing or erythematous mottling of the face, neck, and chest areas.^1,7 The morbilliform eruption develops 2 to 6 days after the onset of the fever, beginning on the trunk and spreading to the face and extremities.^1,7 The rash may become confluent with characteristic sparing of small round areas of normal skin described as white islands in a sea of red.² Verrucous papules on the ears also have been described and may resemble those seen in Cowden syndrome. In patients with prior infection with a different strain of the virus, hemorrhagic lesions may develop, including characteristic retiform purpura, a positive tourniquet test, and the appearance of petechiae on the lower legs. Pruritus and desquamation, especially on the palms and soles, may follow the termination of the eruption.⁷

The differential diagnosis of DF includes measles, rubella, enteroviruses, and influenza. Chikungunya and West Nile viruses in Asia and Africa and the O’nyong-nyong virus in Africa are also arboviruses that cause a clinical picture similar to DF but not DHF. Other diagnostic considerations include phases of scarlet fever, typhoid, malaria, leptospirosis, hepatitis A, and trypanosomal and rickettsial diseases.⁷ The differential diagnosis of DHF includes antineutrophil cytoplasmic antibody–associated vasculitis, rheumatoid vasculitis, and bacterial septic vasculitis.

Acute clinical diagnosis of DF can be challenging because of the nonspecific symptoms that can be seen in almost every infectious disease. Clinical presentation assessment should be confirmed with laboratory testing.⁶ Dengue virus infection usually is confirmed by the identification of viral genomic RNA, antigens, or the antibodies it elicits. Enzyme-linked immunosorbent assay–based serologic tests are cost-effective and easy to perform.⁵ IgM antibodies usually show cross-reactivity with platelets, but the antibody levels are not positively correlated with the severity of DF.⁸ Primary infection with the dengue virus is characterized by the elevation of specific IgM levels that usually occurs 3 to 5 days after symptom onset and persists during the postfebrile stage (up to 30 to 60 days). In secondary infections, the IgM levels usually rise more slowly and reach a lower level than in primary infections.⁹ For both primary and secondary infections, testing IgM levels after the febrile stage may be helpful with the laboratory diagnosis.

Currently, there is no antiviral drug available for dengue. Treatment of dengue infection is symptomatic and supportive.²

Dengue hemorrhagic fever is indicated by a rising hematocrit (≥20%) and a falling platelet count (>100,000/mm³) accompanying clinical signs of hemorrhage. Treatment includes intravenous fluid replacement and careful clinical monitoring of hematocrit levels, platelet count, vitals, urine output, and other signs of shock.⁵ For patients with a history of dengue infection, travel to areas with other serotypes is not recommended.

If any travel to a high-risk area is planned, countryspecific travel recommendations and warnings should be reviewed from the Centers for Disease Control and Prevention’s website (https://wwwnc.cdc.gov/travel/notices/level1/dengue-global). Use of an Environmental Protection Agency–registered insect repellent to avoid mosquito bites and acetaminophen for managing symptoms is advised. During travel, staying in places with window and door screens and using a bed net during sleep are suggested. Long-sleeved shirts and long pants also are preferred. Travelers should see a health care provider if they have symptoms of dengue.¹⁰

African tick bite fever (ATBF) is caused by Rickettsia africae transmitted by Amblyomma ticks. Skin findings in ATBF include erythematous, firm, tender papules with central eschars consistent with the feeding patterns of ticks.¹¹ Histopathology of ATBF usually includes fibrinoid necrosis of vessels in the dermis with a perivascular inflammatory infiltrate and coagulation necrosis of the surrounding dermis consistent with eschar formation.¹² The lack of an eschar weighs against this diagnosis.

African trypanosomiasis (also known as sleeping sickness) is caused by protozoa transmitted by the tsetse fly. A chancrelike, circumscribed, rubbery, indurated red or violaceous nodule measuring 2 to 5 cm in diameter often develops as the earliest cutaneous sign of the disease.¹³ Nonspecific histopathologic findings, such as infiltration of lymphocytes and macrophages and proliferation of endothelial cells and fibroblasts, may be observed.¹⁴ Extravascular parasites have been noted in skin biopsies.¹⁵ In later stages, skin lesions called trypanids may be observed as macular, papular, annular, targetoid, purpuric, and erythematous lesions, and histopathologic findings consistent with vasculitis also may be seen.¹³

Chikungunya virus infection is an acute-onset, mosquito-borne viral disease. Skin manifestations may start with nonspecific, generalized, morbilliform, maculopapular rashes coinciding with fever, which also may be seen initially with DHF. Skin hyperpigmentation, mostly centrofacial and involving the nose (chik sign); purpuric and ecchymotic lesions over the trunk and flexors of limbs in adults, often surmounted by subepidermal bullae and lesions resembling toxic epidermal necrolysis; and nonhealing ulcers in the genital and groin areas are common skin manifestations of chikungunya infection.¹⁶ Intraepithelial splitting with acantholysis and perivascular lymphohistiocytic infiltration may be observed in the histopathology of blistering lesions, which are not consistent with DHF.¹⁷

Zika virus infection is caused by an arbovirus within the Flaviviridae family, which also includes the dengue virus. Initial mucocutaneous findings of the Zika virus include nonspecific diffuse maculopapular eruptions. The eruption generally spares the palms and soles; however, various manifestations including involvement of the palms and soles have been reported.¹⁸ The morbilliform eruption begins on the face and extends to the trunk and extremities. Mild hemorrhagic manifestations, including petechiae and bleeding gums, may be observed. Distinguishing between dengue and Zika virus infection relies on the severity of symptoms and laboratory tests, including polymerase chain reaction or IgM antibody testing.¹⁹ The other conditions listed do not produce hemorrhagic fever.

THE DIAGNOSIS: Dengue Hemorrhagic Fever

The retiform purpura observed in our patient was suggestive of a vasculitic, thrombotic, or embolic etiology. Dengue IgM serologic testing performed based on her extensive travel history and recent return from a dengue-endemic area was positive, indicating acute infection. A clinical diagnosis of dengue hemorrhagic fever (DHF) was made based on the hemorrhagic appearance of the lesion. Histopathology revealed leukocytoclastic vasculitis (Figure). Anti–double-stranded DNA, antideoxyribonuclease, C3 and C4, CH50 (total hemolytic complement), antineutrophil cytoplasmic antibodies, HIV, and hepatitis B virus tests were normal. Direct immunofluorescence was negative.

Dengue virus is a single-stranded RNA virus transmitted by Aedes aegypti and Aedes albopictus mosquitoes and is one of the most prevalent arthropod-borne viruses affecting humans today.^1,2 Infection with the dengue virus generally is seen in travelers visiting tropical regions of Africa, Mexico, South America, South and Central Asia, Southeast Asia, and the Caribbean.¹ The Table shows the global distribution of dengue serotypes from 2000 to 2014.^3,4 There are 4 serotypes of the dengue virus: DENV-1 to DENV-4. Infection with 1 strain elicits longlasting immunity to that strain, but subsequent infection with another strain can result in severe DHF due to antibody cross-reaction.¹

Dengue virus infection ranges from mildly symptomatic to a spectrum of increasingly severe conditions that comprise dengue fever (DF) and DHF, as well as dengue shock syndrome and brain stem hemorrhage, which may be fatal.^2,5 Dengue fever manifests as severe myalgia, fever, headache (usually retro-orbital), arthralgia, erythema, and rubelliform exanthema.⁶ The frequency of skin eruptions in patients with DF varies with the virus strain and outbreaks.⁷ The lesions initially develop with the onset of fever and manifest as flushing or erythematous mottling of the face, neck, and chest areas.^1,7 The morbilliform eruption develops 2 to 6 days after the onset of the fever, beginning on the trunk and spreading to the face and extremities.^1,7 The rash may become confluent with characteristic sparing of small round areas of normal skin described as white islands in a sea of red.² Verrucous papules on the ears also have been described and may resemble those seen in Cowden syndrome. In patients with prior infection with a different strain of the virus, hemorrhagic lesions may develop, including characteristic retiform purpura, a positive tourniquet test, and the appearance of petechiae on the lower legs. Pruritus and desquamation, especially on the palms and soles, may follow the termination of the eruption.⁷

The differential diagnosis of DF includes measles, rubella, enteroviruses, and influenza. Chikungunya and West Nile viruses in Asia and Africa and the O’nyong-nyong virus in Africa are also arboviruses that cause a clinical picture similar to DF but not DHF. Other diagnostic considerations include phases of scarlet fever, typhoid, malaria, leptospirosis, hepatitis A, and trypanosomal and rickettsial diseases.⁷ The differential diagnosis of DHF includes antineutrophil cytoplasmic antibody–associated vasculitis, rheumatoid vasculitis, and bacterial septic vasculitis.

Acute clinical diagnosis of DF can be challenging because of the nonspecific symptoms that can be seen in almost every infectious disease. Clinical presentation assessment should be confirmed with laboratory testing.⁶ Dengue virus infection usually is confirmed by the identification of viral genomic RNA, antigens, or the antibodies it elicits. Enzyme-linked immunosorbent assay–based serologic tests are cost-effective and easy to perform.⁵ IgM antibodies usually show cross-reactivity with platelets, but the antibody levels are not positively correlated with the severity of DF.⁸ Primary infection with the dengue virus is characterized by the elevation of specific IgM levels that usually occurs 3 to 5 days after symptom onset and persists during the postfebrile stage (up to 30 to 60 days). In secondary infections, the IgM levels usually rise more slowly and reach a lower level than in primary infections.⁹ For both primary and secondary infections, testing IgM levels after the febrile stage may be helpful with the laboratory diagnosis.

Currently, there is no antiviral drug available for dengue. Treatment of dengue infection is symptomatic and supportive.²

Dengue hemorrhagic fever is indicated by a rising hematocrit (≥20%) and a falling platelet count (>100,000/mm³) accompanying clinical signs of hemorrhage. Treatment includes intravenous fluid replacement and careful clinical monitoring of hematocrit levels, platelet count, vitals, urine output, and other signs of shock.⁵ For patients with a history of dengue infection, travel to areas with other serotypes is not recommended.

If any travel to a high-risk area is planned, countryspecific travel recommendations and warnings should be reviewed from the Centers for Disease Control and Prevention’s website (https://wwwnc.cdc.gov/travel/notices/level1/dengue-global). Use of an Environmental Protection Agency–registered insect repellent to avoid mosquito bites and acetaminophen for managing symptoms is advised. During travel, staying in places with window and door screens and using a bed net during sleep are suggested. Long-sleeved shirts and long pants also are preferred. Travelers should see a health care provider if they have symptoms of dengue.¹⁰

African tick bite fever (ATBF) is caused by Rickettsia africae transmitted by Amblyomma ticks. Skin findings in ATBF include erythematous, firm, tender papules with central eschars consistent with the feeding patterns of ticks.¹¹ Histopathology of ATBF usually includes fibrinoid necrosis of vessels in the dermis with a perivascular inflammatory infiltrate and coagulation necrosis of the surrounding dermis consistent with eschar formation.¹² The lack of an eschar weighs against this diagnosis.

African trypanosomiasis (also known as sleeping sickness) is caused by protozoa transmitted by the tsetse fly. A chancrelike, circumscribed, rubbery, indurated red or violaceous nodule measuring 2 to 5 cm in diameter often develops as the earliest cutaneous sign of the disease.¹³ Nonspecific histopathologic findings, such as infiltration of lymphocytes and macrophages and proliferation of endothelial cells and fibroblasts, may be observed.¹⁴ Extravascular parasites have been noted in skin biopsies.¹⁵ In later stages, skin lesions called trypanids may be observed as macular, papular, annular, targetoid, purpuric, and erythematous lesions, and histopathologic findings consistent with vasculitis also may be seen.¹³

Chikungunya virus infection is an acute-onset, mosquito-borne viral disease. Skin manifestations may start with nonspecific, generalized, morbilliform, maculopapular rashes coinciding with fever, which also may be seen initially with DHF. Skin hyperpigmentation, mostly centrofacial and involving the nose (chik sign); purpuric and ecchymotic lesions over the trunk and flexors of limbs in adults, often surmounted by subepidermal bullae and lesions resembling toxic epidermal necrolysis; and nonhealing ulcers in the genital and groin areas are common skin manifestations of chikungunya infection.¹⁶ Intraepithelial splitting with acantholysis and perivascular lymphohistiocytic infiltration may be observed in the histopathology of blistering lesions, which are not consistent with DHF.¹⁷

Zika virus infection is caused by an arbovirus within the Flaviviridae family, which also includes the dengue virus. Initial mucocutaneous findings of the Zika virus include nonspecific diffuse maculopapular eruptions. The eruption generally spares the palms and soles; however, various manifestations including involvement of the palms and soles have been reported.¹⁸ The morbilliform eruption begins on the face and extends to the trunk and extremities. Mild hemorrhagic manifestations, including petechiae and bleeding gums, may be observed. Distinguishing between dengue and Zika virus infection relies on the severity of symptoms and laboratory tests, including polymerase chain reaction or IgM antibody testing.¹⁹ The other conditions listed do not produce hemorrhagic fever.

The Diagnosis: Mycobacterial Infection

An injury sustained in a wet environment that results in chronic indolent abscesses, nodules, or draining sinus tracts suggests a mycobacterial infection. In our patient, a culture revealed MycobacteriuM fortuitum, which is classified in the rapid grower nontuberculous mycobacteria (NTM) group, along with Mycobacterium chelonae and Mycobacterium abscessus.¹ The patient’s history of skin injury while cutting wet grass and the common presence of M fortuitum in the environment suggested that the organism entered the wound. The patient healed completely following surgical excision and a 2-month course of clarithromycin 1 g daily and rifampin 600 mg daily.

MycobacteriuM fortuitum was first isolated from an amphibian source in 1905 and later identified in a human with cutaneous infection in 1938. It commonly is found in soil and water.2 Skin and soft-tissue infections with M fortuitum usually are acquired from direct entry of the organism through a damaged skin barrier from trauma, medical injection, surgery, or tattoo placement.^2,3

Skin lesions caused by NTM often are nonspecific and can mimic a variety of other dermatologic conditions, making clinical diagnosis challenging. As such, cutaneous manifestations of M fortuitum infection can include recurrent cutaneous abscesses, nodular lesions, chronic discharging sinuses, cellulitis, and surgical site infections.4 Although cutaneous infection with M fortuitum classically manifests with a single subcutaneous nodule at the site of trauma or surgery,⁵ it also can manifest as multiple draining sinus tracts, as seen in our patient. Hence, the diagnosis and treatment of cutaneous NTM infection is challenging, especially when M fortuitum skin manifestations can take up to 4 to 6 weeks to develop after inoculation. Diagnosis often requires a detailed patient history, tissue cultures, and histopathology.⁵

In recent years, rapid detection with polymerase chain reaction (PCR) techniques has been employed more widely. Notably, a molecular system based on multiplex real-time PCR with high-resolution melting was shown to have a sensitivity of up to 54% for distinguishing M fortuitum from other NTM.⁶ More recently, a 2-step real-time PCR method has demonstrated diagnostic sensitivity and specificity for differentiating NTM from Mycobacterium tuberculosis infections and identifying the causative NTM agent.⁷

Compared to immunocompetent individuals, those who are immunocompromised are more susceptible to less pathogenic strains of NTM, which can cause dissemination and lead to tenosynovitis, myositis, osteomyelitis, and septic arthritis.^8-12 Nonetheless, cases of infections with NTM—including M fortuitum—are becoming harder to treat. Several single nucleotide polymorphisms and point mutations have been demonstrated in the ribosomal RNA methylase gene erm(39) related to clarithromycin resistance and in the rrl gene related to linezolid resistance.¹³ Due to increasing inducible resistance to common classes of antibiotics, such as macrolides and linezolid, treatment of M fortuitum requires multidrug regimens.^13,14 Drug susceptibility testing also may be required, as M fortuitum has shown low resistance to tigecycline, tetracycline, cefmetazole, imipenem, and aminoglycosides (eg, amikacin, tobramycin, neomycin, gentamycin). Surgery is an important adjunctive tool in treating M fortuitum infections; patients with a single lesion are more likely to undergo surgical treatment alone or in combination with antibiotic therapy.¹⁵ More recently, antimicrobial photodynamic therapy has been explored as an alternative to eliminate NTM, including M fortuitum.¹⁶

The differential diagnosis for skin lesions manifesting with draining fistulae and sinus tracts includes conditions with infectious (cellulitis and chromomycosis) and inflammatory (pyoderma gangrenosum [PG] and hidradenitis suppurativa [HS]) causes.

Cellulitis is a common infection of the skin and subcutaneous tissue that predominantly is caused by gram-positive organisms such as β-hemolytic streptococci.¹⁷ Clinical manifestations include acute skin erythema, swelling, tenderness, and warmth. The legs are the most common sites of infection, but any area of the skin can be involved.17 Cellulitis comprises 10% of all infectious disease hospitalizations and up to 11% of all dermatologic admissions.^18,19 It frequently is misdiagnosed, perhaps due to the lack of a reliable confirmatory laboratory test or imaging study, in addition to the plethora of diseases that mimic cellulitis, such as stasis dermatitis, lipodermatosclerosis, contact dermatitis, lymphedema, eosinophilic cellulitis, and papular urticaria.^20,21 The consequences of misdiagnosis include but are not limited to unnecessary hospitalizations, inappropriate antibiotic use, and delayed management of the disease; thus, there is an urgent need for a reliable standard test to confirm the diagnosis, especially among nonspecialist physicians. ²⁰ Most patients with uncomplicated cellulitis can be treated with empiric oral antibiotics that target β-hemolytic streptococci (ie, penicillin V potassium, amoxicillin).¹⁷ Methicillin-resistant Staphylococcus aureus coverage generally is unnecessary for nonpurulent cellulitis, but clinicians can consider adding amoxicillin-clavulanate, dicloxacillin, and cephalexin to the regimen. For purulent cellulitis, incision and drainage should be performed. In severe cases that manifest with sepsis, altered mental status, or hemodynamic instability, inpatient management is required.¹⁷

Chromomycosis (also known as chromoblastomycosis) is a chronic, indolent, granulomatous, suppurative mycosis of the skin and subcutaneous tissue²² that is caused by traumatic inoculation of various fungi of the order Chaetothyriales and family Herpotrichiellaceae, which are present in soil, plants, and decomposing wood. Chromomycosis is prevalent in tropical and subtropical regions.^23,24 Clinically, it manifests as oligosymptomatic or asymptomatic lesions around an infection site that can manifest as papules with centrifugal growth evolving into nodular, verrucous, plaque, tumoral, or atrophic forms.²² Diagnosis is made with direct microscopy using potassium hydroxide, which reveals muriform bodies. Fungal culture in Sabouraud agar also can be used to isolate the causative pathogen.²² Unfortunately, chromomycosis is difficult to treat, with low cure rates and high relapse rates. Antifungal agents combined with surgery, cryotherapy, or thermotherapy often are used, with cure rates ranging from 15% to 80%.^22,25

Pyoderma gangrenosum is a reactive noninfectious inflammatory dermatosis associated with inflammatory bowel disease and rheumatoid arthritis. The exact etiology is not clearly understood, but it generally is considered an autoinflammatory disorder.²⁶ The most common form—classical PG—occurs in approximately 85% of cases and manifests as a painful erythematous lesion that progresses to a blistered or necrotic ulcer. It primarily affects the lower legs but can occur in other body sites.²⁷ The diagnosis is based on clinical symptoms after excluding other similar conditions; histopathology of biopsied wound tissues often are required for confirmation. Treatment of PG starts with fast-acting immunosuppressive drugs (corticosteroids and/or cyclosporine) followed by slowacting immunosuppressive drugs (biologics).²⁶

Hidradenitis suppurativa is a chronic recurrent disease of the hair follicle unit that develops after puberty.²⁸ Clinically, HS manifests with painful nodules, abscesses, chronically draining fistulas, and scarring in areas of the body rich in apocrine glands.^29,30 Treatment of HS is challenging due to its diverse clinical manifestations and unclear etiology. Topical therapy, systemic treatments, biologic agents, surgery, and light therapy have shown variable results.^28,31

The Diagnosis: Mycobacterial Infection

An injury sustained in a wet environment that results in chronic indolent abscesses, nodules, or draining sinus tracts suggests a mycobacterial infection. In our patient, a culture revealed MycobacteriuM fortuitum, which is classified in the rapid grower nontuberculous mycobacteria (NTM) group, along with Mycobacterium chelonae and Mycobacterium abscessus.¹ The patient’s history of skin injury while cutting wet grass and the common presence of M fortuitum in the environment suggested that the organism entered the wound. The patient healed completely following surgical excision and a 2-month course of clarithromycin 1 g daily and rifampin 600 mg daily.

MycobacteriuM fortuitum was first isolated from an amphibian source in 1905 and later identified in a human with cutaneous infection in 1938. It commonly is found in soil and water.2 Skin and soft-tissue infections with M fortuitum usually are acquired from direct entry of the organism through a damaged skin barrier from trauma, medical injection, surgery, or tattoo placement.^2,3

Skin lesions caused by NTM often are nonspecific and can mimic a variety of other dermatologic conditions, making clinical diagnosis challenging. As such, cutaneous manifestations of M fortuitum infection can include recurrent cutaneous abscesses, nodular lesions, chronic discharging sinuses, cellulitis, and surgical site infections.4 Although cutaneous infection with M fortuitum classically manifests with a single subcutaneous nodule at the site of trauma or surgery,⁵ it also can manifest as multiple draining sinus tracts, as seen in our patient. Hence, the diagnosis and treatment of cutaneous NTM infection is challenging, especially when M fortuitum skin manifestations can take up to 4 to 6 weeks to develop after inoculation. Diagnosis often requires a detailed patient history, tissue cultures, and histopathology.⁵

In recent years, rapid detection with polymerase chain reaction (PCR) techniques has been employed more widely. Notably, a molecular system based on multiplex real-time PCR with high-resolution melting was shown to have a sensitivity of up to 54% for distinguishing M fortuitum from other NTM.⁶ More recently, a 2-step real-time PCR method has demonstrated diagnostic sensitivity and specificity for differentiating NTM from Mycobacterium tuberculosis infections and identifying the causative NTM agent.⁷

Compared to immunocompetent individuals, those who are immunocompromised are more susceptible to less pathogenic strains of NTM, which can cause dissemination and lead to tenosynovitis, myositis, osteomyelitis, and septic arthritis.^8-12 Nonetheless, cases of infections with NTM—including M fortuitum—are becoming harder to treat. Several single nucleotide polymorphisms and point mutations have been demonstrated in the ribosomal RNA methylase gene erm(39) related to clarithromycin resistance and in the rrl gene related to linezolid resistance.¹³ Due to increasing inducible resistance to common classes of antibiotics, such as macrolides and linezolid, treatment of M fortuitum requires multidrug regimens.^13,14 Drug susceptibility testing also may be required, as M fortuitum has shown low resistance to tigecycline, tetracycline, cefmetazole, imipenem, and aminoglycosides (eg, amikacin, tobramycin, neomycin, gentamycin). Surgery is an important adjunctive tool in treating M fortuitum infections; patients with a single lesion are more likely to undergo surgical treatment alone or in combination with antibiotic therapy.¹⁵ More recently, antimicrobial photodynamic therapy has been explored as an alternative to eliminate NTM, including M fortuitum.¹⁶

The differential diagnosis for skin lesions manifesting with draining fistulae and sinus tracts includes conditions with infectious (cellulitis and chromomycosis) and inflammatory (pyoderma gangrenosum [PG] and hidradenitis suppurativa [HS]) causes.

Cellulitis is a common infection of the skin and subcutaneous tissue that predominantly is caused by gram-positive organisms such as β-hemolytic streptococci.¹⁷ Clinical manifestations include acute skin erythema, swelling, tenderness, and warmth. The legs are the most common sites of infection, but any area of the skin can be involved.17 Cellulitis comprises 10% of all infectious disease hospitalizations and up to 11% of all dermatologic admissions.^18,19 It frequently is misdiagnosed, perhaps due to the lack of a reliable confirmatory laboratory test or imaging study, in addition to the plethora of diseases that mimic cellulitis, such as stasis dermatitis, lipodermatosclerosis, contact dermatitis, lymphedema, eosinophilic cellulitis, and papular urticaria.^20,21 The consequences of misdiagnosis include but are not limited to unnecessary hospitalizations, inappropriate antibiotic use, and delayed management of the disease; thus, there is an urgent need for a reliable standard test to confirm the diagnosis, especially among nonspecialist physicians. ²⁰ Most patients with uncomplicated cellulitis can be treated with empiric oral antibiotics that target β-hemolytic streptococci (ie, penicillin V potassium, amoxicillin).¹⁷ Methicillin-resistant Staphylococcus aureus coverage generally is unnecessary for nonpurulent cellulitis, but clinicians can consider adding amoxicillin-clavulanate, dicloxacillin, and cephalexin to the regimen. For purulent cellulitis, incision and drainage should be performed. In severe cases that manifest with sepsis, altered mental status, or hemodynamic instability, inpatient management is required.¹⁷

Chromomycosis (also known as chromoblastomycosis) is a chronic, indolent, granulomatous, suppurative mycosis of the skin and subcutaneous tissue²² that is caused by traumatic inoculation of various fungi of the order Chaetothyriales and family Herpotrichiellaceae, which are present in soil, plants, and decomposing wood. Chromomycosis is prevalent in tropical and subtropical regions.^23,24 Clinically, it manifests as oligosymptomatic or asymptomatic lesions around an infection site that can manifest as papules with centrifugal growth evolving into nodular, verrucous, plaque, tumoral, or atrophic forms.²² Diagnosis is made with direct microscopy using potassium hydroxide, which reveals muriform bodies. Fungal culture in Sabouraud agar also can be used to isolate the causative pathogen.²² Unfortunately, chromomycosis is difficult to treat, with low cure rates and high relapse rates. Antifungal agents combined with surgery, cryotherapy, or thermotherapy often are used, with cure rates ranging from 15% to 80%.^22,25

Pyoderma gangrenosum is a reactive noninfectious inflammatory dermatosis associated with inflammatory bowel disease and rheumatoid arthritis. The exact etiology is not clearly understood, but it generally is considered an autoinflammatory disorder.²⁶ The most common form—classical PG—occurs in approximately 85% of cases and manifests as a painful erythematous lesion that progresses to a blistered or necrotic ulcer. It primarily affects the lower legs but can occur in other body sites.²⁷ The diagnosis is based on clinical symptoms after excluding other similar conditions; histopathology of biopsied wound tissues often are required for confirmation. Treatment of PG starts with fast-acting immunosuppressive drugs (corticosteroids and/or cyclosporine) followed by slowacting immunosuppressive drugs (biologics).²⁶

Hidradenitis suppurativa is a chronic recurrent disease of the hair follicle unit that develops after puberty.²⁸ Clinically, HS manifests with painful nodules, abscesses, chronically draining fistulas, and scarring in areas of the body rich in apocrine glands.^29,30 Treatment of HS is challenging due to its diverse clinical manifestations and unclear etiology. Topical therapy, systemic treatments, biologic agents, surgery, and light therapy have shown variable results.^28,31

The Diagnosis: Mycobacterial Infection

An injury sustained in a wet environment that results in chronic indolent abscesses, nodules, or draining sinus tracts suggests a mycobacterial infection. In our patient, a culture revealed MycobacteriuM fortuitum, which is classified in the rapid grower nontuberculous mycobacteria (NTM) group, along with Mycobacterium chelonae and Mycobacterium abscessus.¹ The patient’s history of skin injury while cutting wet grass and the common presence of M fortuitum in the environment suggested that the organism entered the wound. The patient healed completely following surgical excision and a 2-month course of clarithromycin 1 g daily and rifampin 600 mg daily.

MycobacteriuM fortuitum was first isolated from an amphibian source in 1905 and later identified in a human with cutaneous infection in 1938. It commonly is found in soil and water.2 Skin and soft-tissue infections with M fortuitum usually are acquired from direct entry of the organism through a damaged skin barrier from trauma, medical injection, surgery, or tattoo placement.^2,3

Skin lesions caused by NTM often are nonspecific and can mimic a variety of other dermatologic conditions, making clinical diagnosis challenging. As such, cutaneous manifestations of M fortuitum infection can include recurrent cutaneous abscesses, nodular lesions, chronic discharging sinuses, cellulitis, and surgical site infections.4 Although cutaneous infection with M fortuitum classically manifests with a single subcutaneous nodule at the site of trauma or surgery,⁵ it also can manifest as multiple draining sinus tracts, as seen in our patient. Hence, the diagnosis and treatment of cutaneous NTM infection is challenging, especially when M fortuitum skin manifestations can take up to 4 to 6 weeks to develop after inoculation. Diagnosis often requires a detailed patient history, tissue cultures, and histopathology.⁵

In recent years, rapid detection with polymerase chain reaction (PCR) techniques has been employed more widely. Notably, a molecular system based on multiplex real-time PCR with high-resolution melting was shown to have a sensitivity of up to 54% for distinguishing M fortuitum from other NTM.⁶ More recently, a 2-step real-time PCR method has demonstrated diagnostic sensitivity and specificity for differentiating NTM from Mycobacterium tuberculosis infections and identifying the causative NTM agent.⁷

Compared to immunocompetent individuals, those who are immunocompromised are more susceptible to less pathogenic strains of NTM, which can cause dissemination and lead to tenosynovitis, myositis, osteomyelitis, and septic arthritis.^8-12 Nonetheless, cases of infections with NTM—including M fortuitum—are becoming harder to treat. Several single nucleotide polymorphisms and point mutations have been demonstrated in the ribosomal RNA methylase gene erm(39) related to clarithromycin resistance and in the rrl gene related to linezolid resistance.¹³ Due to increasing inducible resistance to common classes of antibiotics, such as macrolides and linezolid, treatment of M fortuitum requires multidrug regimens.^13,14 Drug susceptibility testing also may be required, as M fortuitum has shown low resistance to tigecycline, tetracycline, cefmetazole, imipenem, and aminoglycosides (eg, amikacin, tobramycin, neomycin, gentamycin). Surgery is an important adjunctive tool in treating M fortuitum infections; patients with a single lesion are more likely to undergo surgical treatment alone or in combination with antibiotic therapy.¹⁵ More recently, antimicrobial photodynamic therapy has been explored as an alternative to eliminate NTM, including M fortuitum.¹⁶

The differential diagnosis for skin lesions manifesting with draining fistulae and sinus tracts includes conditions with infectious (cellulitis and chromomycosis) and inflammatory (pyoderma gangrenosum [PG] and hidradenitis suppurativa [HS]) causes.

Cellulitis is a common infection of the skin and subcutaneous tissue that predominantly is caused by gram-positive organisms such as β-hemolytic streptococci.¹⁷ Clinical manifestations include acute skin erythema, swelling, tenderness, and warmth. The legs are the most common sites of infection, but any area of the skin can be involved.17 Cellulitis comprises 10% of all infectious disease hospitalizations and up to 11% of all dermatologic admissions.^18,19 It frequently is misdiagnosed, perhaps due to the lack of a reliable confirmatory laboratory test or imaging study, in addition to the plethora of diseases that mimic cellulitis, such as stasis dermatitis, lipodermatosclerosis, contact dermatitis, lymphedema, eosinophilic cellulitis, and papular urticaria.^20,21 The consequences of misdiagnosis include but are not limited to unnecessary hospitalizations, inappropriate antibiotic use, and delayed management of the disease; thus, there is an urgent need for a reliable standard test to confirm the diagnosis, especially among nonspecialist physicians. ²⁰ Most patients with uncomplicated cellulitis can be treated with empiric oral antibiotics that target β-hemolytic streptococci (ie, penicillin V potassium, amoxicillin).¹⁷ Methicillin-resistant Staphylococcus aureus coverage generally is unnecessary for nonpurulent cellulitis, but clinicians can consider adding amoxicillin-clavulanate, dicloxacillin, and cephalexin to the regimen. For purulent cellulitis, incision and drainage should be performed. In severe cases that manifest with sepsis, altered mental status, or hemodynamic instability, inpatient management is required.¹⁷

Chromomycosis (also known as chromoblastomycosis) is a chronic, indolent, granulomatous, suppurative mycosis of the skin and subcutaneous tissue²² that is caused by traumatic inoculation of various fungi of the order Chaetothyriales and family Herpotrichiellaceae, which are present in soil, plants, and decomposing wood. Chromomycosis is prevalent in tropical and subtropical regions.^23,24 Clinically, it manifests as oligosymptomatic or asymptomatic lesions around an infection site that can manifest as papules with centrifugal growth evolving into nodular, verrucous, plaque, tumoral, or atrophic forms.²² Diagnosis is made with direct microscopy using potassium hydroxide, which reveals muriform bodies. Fungal culture in Sabouraud agar also can be used to isolate the causative pathogen.²² Unfortunately, chromomycosis is difficult to treat, with low cure rates and high relapse rates. Antifungal agents combined with surgery, cryotherapy, or thermotherapy often are used, with cure rates ranging from 15% to 80%.^22,25

Pyoderma gangrenosum is a reactive noninfectious inflammatory dermatosis associated with inflammatory bowel disease and rheumatoid arthritis. The exact etiology is not clearly understood, but it generally is considered an autoinflammatory disorder.²⁶ The most common form—classical PG—occurs in approximately 85% of cases and manifests as a painful erythematous lesion that progresses to a blistered or necrotic ulcer. It primarily affects the lower legs but can occur in other body sites.²⁷ The diagnosis is based on clinical symptoms after excluding other similar conditions; histopathology of biopsied wound tissues often are required for confirmation. Treatment of PG starts with fast-acting immunosuppressive drugs (corticosteroids and/or cyclosporine) followed by slowacting immunosuppressive drugs (biologics).²⁶

Hidradenitis suppurativa is a chronic recurrent disease of the hair follicle unit that develops after puberty.²⁸ Clinically, HS manifests with painful nodules, abscesses, chronically draining fistulas, and scarring in areas of the body rich in apocrine glands.^29,30 Treatment of HS is challenging due to its diverse clinical manifestations and unclear etiology. Topical therapy, systemic treatments, biologic agents, surgery, and light therapy have shown variable results.^28,31

The clinical manifestations of snakebites vary based on the species of snake, bite location, and amount and strength of the venom injected. Locally acting toxins in snake venom predominantly consist of enzymes, such as phospholipase A₂, that cause local tissue destruction and can result in pain, swelling, blistering, ecchymosis, and tissue necrosis at the site of the bite within hours to days after the bite.¹ Systemically acting toxins can target a wide variety of tissues and cause severe systemic complications including paralysis, rhabdomyolysis secondary to muscle damage, coagulopathy, sepsis, and cardiorespiratory failure.²

Although pain and swelling following snakebites typically resolve by 1 month after envenomation, copperhead snakes—a type of pit viper—may cause residual symptoms of pain and swelling lasting for a year or more.³ Additional cutaneous manifestations of copperhead snakebites include wound infections at the bite site, such as cellulitis and necrotizing fasciitis. More devastating complications that have been described following snake envenomation include tissue injury of an entire extremity and development of compartment syndrome, which requires urgent fasciotomy to prevent potential loss of the affected limb.⁴

Physicians should be aware of the potential complications of snakebites to properly manage and counsel their patients. We describe a 42-year-old woman with tender, erythematous, subcutaneous nodules persisting for 4 months following a copperhead snakebite. A biopsy confirmed the diagnosis of snakebite-associated erythema nodosum (EN).

Case Report

A 42-year-old woman presented to our clinic with progressive tender, pruritic, deep-seated, erythematous nodules in multiple locations on the legs after sustaining a bite by a copperhead snake on the left foot 4 months prior. The lesions tended to fluctuate in intensity. In the days following the bite, she initially developed painful red bumps on the left foot just proximal to the bite site with associated pain and swelling extending up to just below the left knee. She reported no other notable symptoms such as fever, arthralgia, fatigue, or gastrointestinal tract symptoms. Physical examination revealed bilateral pitting edema, which was worse in the left leg, along with multiple deep, palpable, tender subcutaneous nodules with erythematous surface change (Figure 1).

Workup performed by an outside provider over the previous month included 2 venous duplex ultrasounds of the left leg, which showed no signs of deep vein thrombosis. Additionally, the patient underwent lateral and anteroposterior radiographs of the left foot, tibia, and fibula, which showed no evidence of fracture.

Given the morphology and distribution of the lesions (Figure 2), EN was strongly favored as the cause of the symptoms, and a biopsy confirmed the diagnosis. All immunohistochemical stains including auramine-­rhodamine for acid-fast bacilli, Grocott-Gomori methenamine silver for fungal organisms, and Brown and Brenn were negative. Given the waxing and waning course of the lesions, which suggested an active neutrophilic rather than purely chronic granulomatous phase of EN, the patient was treated with colchicine 0.6 mg twice daily for 1 month.

Causes of EN and Clinical Manifestations

Erythema nodosum is a common form of septal panniculitis that can be precipitated by inflammatory conditions, infection, or medications (commonly oral contraceptive pills) but often is idiopathic.⁵ The acute phase is neutrophilic, with evolution over time to a granulomatous phase. Common etiologies include sarcoidosis; inflammatory bowel disease; and bacterial or fungal infections such as Streptococcus (especially common in children), histoplasmosis, and coccidioidomycosis. The patient was otherwise healthy and was not taking any medications that are known triggers of EN. A PubMed search of articles indexed for MEDLINE in the English-language literature using the terms copperhead snake bite, erythema nodosum snake, and copperhead snake erythema nodosum revealed no reports of EN following a bite from a copperhead snake; however, in one case, an adder bite led to erysipelas, likely due to disturbed blood and lymphatic flow, which then triggered EN.⁶ Additionally, EN has been reported as a delayed reaction to jellyfish stings.⁷

Clinical features of EN include the development of tender, erythematous, subcutaneous nodules and plaques most frequently over the pretibial region. Lesions typically evolve from raised, deep-seated nodules into flat indurated plaques over a span of weeks. Occasionally, there is a slight prodromal phase marked by nonspecific symptoms such as fever and arthralgia lasting for 3 to 6 days. Erythema nodosum typically results in spontaneous resolution after 4 to 8 weeks, and management involves treatment of any underlying condition with symptomatic care. Interestingly, our patient experienced persistent symptoms over the course of 4 months, with development of new nodular lesions throughout this time period. The most frequently used drugs for the management of symptomatic EN include nonsteroidal anti-inflammatory drugs, colchicine, and potassium iodide.⁸ A characteristic histologic finding of the granulomatous phase is the Miescher radial granuloma, which is a septal collection of histiocytes surrounding a cleft.⁹

Snakebite Reactions

Snakebites can result in a wide range of local and systemic manifestations, as snake venom may contain 20 or more toxins.¹⁰ Local complications of pit viper bites include pain, swelling, and fang marks; when examining fang marks, the presence of 2 distinct puncture wounds often indicates envenomation with a poisonous snake, whereas nonvenomous snakebites often result in smaller puncture wounds arranged in an arc. Following bites, pain can develop immediately and spread proximally up the affected limb, which occurred in our patient in the days following the bite. Intense local reactions can occur, as bites often result in intense edema of the affected limb spreading to the trunk in the days to weeks after the bite, occasionally accompanied by regional lymphadenopathy. Some bites can result in local necrosis and secondary bacterial infection caused by organisms in the oral cavity of the culprit snake.

Although they were not present in our patient, snakebites can result in a wide range of systemic toxicities ranging from clotting defects and hemolysis to neurotoxicity, myotoxicity, and nephrotoxicity.¹⁰ In severe cases, snake venom can result in disseminated intravascular coagulation, sepsis, and cardiorespiratory collapse.

The eastern copperhead (Agkistrodon contortrix) is a species of venomous snake that is endemic to eastern North America. Copperheads are members of the subfamily Crotalinae in the family Viperidae.¹¹ Reported reactions to copperhead bites include cellulitis, necrotizing fasciitis, compartment syndrome, and tissue necrosis of an entire affected extremity.^12,13 Our patient displayed no systemic symptoms to suggest envenomation.

Management of Snakebites

Treatment of snakebites varies based on the constellation and severity of symptoms as well as how recently the envenomation occurred. In urgent cases, antivenom may be administered to prevent further toxicity. In cases of progressive compartment syndrome, emergent surgical procedures such as fasciotomy or amputation are required to prevent further complications. When a superimposed bacterial infection is suspected, broad-spectrum antibiotics are required. Because our patient presented 4 months following the initial bite with isolated cutaneous manifestations, she was treated symptomatically with colchicine for EN.^1,2

Final Thoughts

Our patient presented with EN following a bite from a copperhead snake. Physicians should be aware of possible etiologies of EN to evaluate patients who present with new-onset tender subcutaneous nodules. Additionally, physicians should be aware of venomous snakes endemic to their region and also understand the various complications that can result following a snakebite, with the potential for lingering cutaneous manifestations weeks to months following the initial bite.

The clinical manifestations of snakebites vary based on the species of snake, bite location, and amount and strength of the venom injected. Locally acting toxins in snake venom predominantly consist of enzymes, such as phospholipase A₂, that cause local tissue destruction and can result in pain, swelling, blistering, ecchymosis, and tissue necrosis at the site of the bite within hours to days after the bite.¹ Systemically acting toxins can target a wide variety of tissues and cause severe systemic complications including paralysis, rhabdomyolysis secondary to muscle damage, coagulopathy, sepsis, and cardiorespiratory failure.²

Although pain and swelling following snakebites typically resolve by 1 month after envenomation, copperhead snakes—a type of pit viper—may cause residual symptoms of pain and swelling lasting for a year or more.³ Additional cutaneous manifestations of copperhead snakebites include wound infections at the bite site, such as cellulitis and necrotizing fasciitis. More devastating complications that have been described following snake envenomation include tissue injury of an entire extremity and development of compartment syndrome, which requires urgent fasciotomy to prevent potential loss of the affected limb.⁴

Physicians should be aware of the potential complications of snakebites to properly manage and counsel their patients. We describe a 42-year-old woman with tender, erythematous, subcutaneous nodules persisting for 4 months following a copperhead snakebite. A biopsy confirmed the diagnosis of snakebite-associated erythema nodosum (EN).

Case Report

A 42-year-old woman presented to our clinic with progressive tender, pruritic, deep-seated, erythematous nodules in multiple locations on the legs after sustaining a bite by a copperhead snake on the left foot 4 months prior. The lesions tended to fluctuate in intensity. In the days following the bite, she initially developed painful red bumps on the left foot just proximal to the bite site with associated pain and swelling extending up to just below the left knee. She reported no other notable symptoms such as fever, arthralgia, fatigue, or gastrointestinal tract symptoms. Physical examination revealed bilateral pitting edema, which was worse in the left leg, along with multiple deep, palpable, tender subcutaneous nodules with erythematous surface change (Figure 1).

Workup performed by an outside provider over the previous month included 2 venous duplex ultrasounds of the left leg, which showed no signs of deep vein thrombosis. Additionally, the patient underwent lateral and anteroposterior radiographs of the left foot, tibia, and fibula, which showed no evidence of fracture.

Given the morphology and distribution of the lesions (Figure 2), EN was strongly favored as the cause of the symptoms, and a biopsy confirmed the diagnosis. All immunohistochemical stains including auramine-­rhodamine for acid-fast bacilli, Grocott-Gomori methenamine silver for fungal organisms, and Brown and Brenn were negative. Given the waxing and waning course of the lesions, which suggested an active neutrophilic rather than purely chronic granulomatous phase of EN, the patient was treated with colchicine 0.6 mg twice daily for 1 month.

Causes of EN and Clinical Manifestations

Erythema nodosum is a common form of septal panniculitis that can be precipitated by inflammatory conditions, infection, or medications (commonly oral contraceptive pills) but often is idiopathic.⁵ The acute phase is neutrophilic, with evolution over time to a granulomatous phase. Common etiologies include sarcoidosis; inflammatory bowel disease; and bacterial or fungal infections such as Streptococcus (especially common in children), histoplasmosis, and coccidioidomycosis. The patient was otherwise healthy and was not taking any medications that are known triggers of EN. A PubMed search of articles indexed for MEDLINE in the English-language literature using the terms copperhead snake bite, erythema nodosum snake, and copperhead snake erythema nodosum revealed no reports of EN following a bite from a copperhead snake; however, in one case, an adder bite led to erysipelas, likely due to disturbed blood and lymphatic flow, which then triggered EN.⁶ Additionally, EN has been reported as a delayed reaction to jellyfish stings.⁷

Clinical features of EN include the development of tender, erythematous, subcutaneous nodules and plaques most frequently over the pretibial region. Lesions typically evolve from raised, deep-seated nodules into flat indurated plaques over a span of weeks. Occasionally, there is a slight prodromal phase marked by nonspecific symptoms such as fever and arthralgia lasting for 3 to 6 days. Erythema nodosum typically results in spontaneous resolution after 4 to 8 weeks, and management involves treatment of any underlying condition with symptomatic care. Interestingly, our patient experienced persistent symptoms over the course of 4 months, with development of new nodular lesions throughout this time period. The most frequently used drugs for the management of symptomatic EN include nonsteroidal anti-inflammatory drugs, colchicine, and potassium iodide.⁸ A characteristic histologic finding of the granulomatous phase is the Miescher radial granuloma, which is a septal collection of histiocytes surrounding a cleft.⁹

Snakebite Reactions

Snakebites can result in a wide range of local and systemic manifestations, as snake venom may contain 20 or more toxins.¹⁰ Local complications of pit viper bites include pain, swelling, and fang marks; when examining fang marks, the presence of 2 distinct puncture wounds often indicates envenomation with a poisonous snake, whereas nonvenomous snakebites often result in smaller puncture wounds arranged in an arc. Following bites, pain can develop immediately and spread proximally up the affected limb, which occurred in our patient in the days following the bite. Intense local reactions can occur, as bites often result in intense edema of the affected limb spreading to the trunk in the days to weeks after the bite, occasionally accompanied by regional lymphadenopathy. Some bites can result in local necrosis and secondary bacterial infection caused by organisms in the oral cavity of the culprit snake.

Although they were not present in our patient, snakebites can result in a wide range of systemic toxicities ranging from clotting defects and hemolysis to neurotoxicity, myotoxicity, and nephrotoxicity.¹⁰ In severe cases, snake venom can result in disseminated intravascular coagulation, sepsis, and cardiorespiratory collapse.

The eastern copperhead (Agkistrodon contortrix) is a species of venomous snake that is endemic to eastern North America. Copperheads are members of the subfamily Crotalinae in the family Viperidae.¹¹ Reported reactions to copperhead bites include cellulitis, necrotizing fasciitis, compartment syndrome, and tissue necrosis of an entire affected extremity.^12,13 Our patient displayed no systemic symptoms to suggest envenomation.

Management of Snakebites

Treatment of snakebites varies based on the constellation and severity of symptoms as well as how recently the envenomation occurred. In urgent cases, antivenom may be administered to prevent further toxicity. In cases of progressive compartment syndrome, emergent surgical procedures such as fasciotomy or amputation are required to prevent further complications. When a superimposed bacterial infection is suspected, broad-spectrum antibiotics are required. Because our patient presented 4 months following the initial bite with isolated cutaneous manifestations, she was treated symptomatically with colchicine for EN.^1,2

Final Thoughts

Our patient presented with EN following a bite from a copperhead snake. Physicians should be aware of possible etiologies of EN to evaluate patients who present with new-onset tender subcutaneous nodules. Additionally, physicians should be aware of venomous snakes endemic to their region and also understand the various complications that can result following a snakebite, with the potential for lingering cutaneous manifestations weeks to months following the initial bite.

The clinical manifestations of snakebites vary based on the species of snake, bite location, and amount and strength of the venom injected. Locally acting toxins in snake venom predominantly consist of enzymes, such as phospholipase A₂, that cause local tissue destruction and can result in pain, swelling, blistering, ecchymosis, and tissue necrosis at the site of the bite within hours to days after the bite.¹ Systemically acting toxins can target a wide variety of tissues and cause severe systemic complications including paralysis, rhabdomyolysis secondary to muscle damage, coagulopathy, sepsis, and cardiorespiratory failure.²

Although pain and swelling following snakebites typically resolve by 1 month after envenomation, copperhead snakes—a type of pit viper—may cause residual symptoms of pain and swelling lasting for a year or more.³ Additional cutaneous manifestations of copperhead snakebites include wound infections at the bite site, such as cellulitis and necrotizing fasciitis. More devastating complications that have been described following snake envenomation include tissue injury of an entire extremity and development of compartment syndrome, which requires urgent fasciotomy to prevent potential loss of the affected limb.⁴

Physicians should be aware of the potential complications of snakebites to properly manage and counsel their patients. We describe a 42-year-old woman with tender, erythematous, subcutaneous nodules persisting for 4 months following a copperhead snakebite. A biopsy confirmed the diagnosis of snakebite-associated erythema nodosum (EN).

Case Report

A 42-year-old woman presented to our clinic with progressive tender, pruritic, deep-seated, erythematous nodules in multiple locations on the legs after sustaining a bite by a copperhead snake on the left foot 4 months prior. The lesions tended to fluctuate in intensity. In the days following the bite, she initially developed painful red bumps on the left foot just proximal to the bite site with associated pain and swelling extending up to just below the left knee. She reported no other notable symptoms such as fever, arthralgia, fatigue, or gastrointestinal tract symptoms. Physical examination revealed bilateral pitting edema, which was worse in the left leg, along with multiple deep, palpable, tender subcutaneous nodules with erythematous surface change (Figure 1).

Workup performed by an outside provider over the previous month included 2 venous duplex ultrasounds of the left leg, which showed no signs of deep vein thrombosis. Additionally, the patient underwent lateral and anteroposterior radiographs of the left foot, tibia, and fibula, which showed no evidence of fracture.

Given the morphology and distribution of the lesions (Figure 2), EN was strongly favored as the cause of the symptoms, and a biopsy confirmed the diagnosis. All immunohistochemical stains including auramine-­rhodamine for acid-fast bacilli, Grocott-Gomori methenamine silver for fungal organisms, and Brown and Brenn were negative. Given the waxing and waning course of the lesions, which suggested an active neutrophilic rather than purely chronic granulomatous phase of EN, the patient was treated with colchicine 0.6 mg twice daily for 1 month.

Causes of EN and Clinical Manifestations

Erythema nodosum is a common form of septal panniculitis that can be precipitated by inflammatory conditions, infection, or medications (commonly oral contraceptive pills) but often is idiopathic.⁵ The acute phase is neutrophilic, with evolution over time to a granulomatous phase. Common etiologies include sarcoidosis; inflammatory bowel disease; and bacterial or fungal infections such as Streptococcus (especially common in children), histoplasmosis, and coccidioidomycosis. The patient was otherwise healthy and was not taking any medications that are known triggers of EN. A PubMed search of articles indexed for MEDLINE in the English-language literature using the terms copperhead snake bite, erythema nodosum snake, and copperhead snake erythema nodosum revealed no reports of EN following a bite from a copperhead snake; however, in one case, an adder bite led to erysipelas, likely due to disturbed blood and lymphatic flow, which then triggered EN.⁶ Additionally, EN has been reported as a delayed reaction to jellyfish stings.⁷

Clinical features of EN include the development of tender, erythematous, subcutaneous nodules and plaques most frequently over the pretibial region. Lesions typically evolve from raised, deep-seated nodules into flat indurated plaques over a span of weeks. Occasionally, there is a slight prodromal phase marked by nonspecific symptoms such as fever and arthralgia lasting for 3 to 6 days. Erythema nodosum typically results in spontaneous resolution after 4 to 8 weeks, and management involves treatment of any underlying condition with symptomatic care. Interestingly, our patient experienced persistent symptoms over the course of 4 months, with development of new nodular lesions throughout this time period. The most frequently used drugs for the management of symptomatic EN include nonsteroidal anti-inflammatory drugs, colchicine, and potassium iodide.⁸ A characteristic histologic finding of the granulomatous phase is the Miescher radial granuloma, which is a septal collection of histiocytes surrounding a cleft.⁹

Snakebite Reactions

Snakebites can result in a wide range of local and systemic manifestations, as snake venom may contain 20 or more toxins.¹⁰ Local complications of pit viper bites include pain, swelling, and fang marks; when examining fang marks, the presence of 2 distinct puncture wounds often indicates envenomation with a poisonous snake, whereas nonvenomous snakebites often result in smaller puncture wounds arranged in an arc. Following bites, pain can develop immediately and spread proximally up the affected limb, which occurred in our patient in the days following the bite. Intense local reactions can occur, as bites often result in intense edema of the affected limb spreading to the trunk in the days to weeks after the bite, occasionally accompanied by regional lymphadenopathy. Some bites can result in local necrosis and secondary bacterial infection caused by organisms in the oral cavity of the culprit snake.

Although they were not present in our patient, snakebites can result in a wide range of systemic toxicities ranging from clotting defects and hemolysis to neurotoxicity, myotoxicity, and nephrotoxicity.¹⁰ In severe cases, snake venom can result in disseminated intravascular coagulation, sepsis, and cardiorespiratory collapse.

The eastern copperhead (Agkistrodon contortrix) is a species of venomous snake that is endemic to eastern North America. Copperheads are members of the subfamily Crotalinae in the family Viperidae.¹¹ Reported reactions to copperhead bites include cellulitis, necrotizing fasciitis, compartment syndrome, and tissue necrosis of an entire affected extremity.^12,13 Our patient displayed no systemic symptoms to suggest envenomation.

Management of Snakebites

Treatment of snakebites varies based on the constellation and severity of symptoms as well as how recently the envenomation occurred. In urgent cases, antivenom may be administered to prevent further toxicity. In cases of progressive compartment syndrome, emergent surgical procedures such as fasciotomy or amputation are required to prevent further complications. When a superimposed bacterial infection is suspected, broad-spectrum antibiotics are required. Because our patient presented 4 months following the initial bite with isolated cutaneous manifestations, she was treated symptomatically with colchicine for EN.^1,2

Final Thoughts

Our patient presented with EN following a bite from a copperhead snake. Physicians should be aware of possible etiologies of EN to evaluate patients who present with new-onset tender subcutaneous nodules. Additionally, physicians should be aware of venomous snakes endemic to their region and also understand the various complications that can result following a snakebite, with the potential for lingering cutaneous manifestations weeks to months following the initial bite.

Recognizing cutaneous drug eruptions is important for treatment and prevention of recurrence. Fixed drug eruptions (FDEs) typically are harmless but can have major negative cosmetic consequences for patients. In its more severe forms, patients are at risk for widespread epithelial necrosis with accompanying complications. We report 1 patient with generalized FDE and 2 with generalized bullous FDE. We also discuss the recognition and treatment of the condition. Two patients previously had been diagnosed with systemic lupus erythematosus (SLE).

Case Series

Patient 1—A 60-year-old woman presented to dermatology with a rash on the trunk and groin folds of 4 days’ duration. She had a history of SLE and cutaneous lupus treated with hydroxychloroquine 200 mg twice daily and topical corticosteroids. She had started sulfamethoxazole-trimethoprim for a urinary tract infection with a rash appearing 1 day later. She reported burning skin pain with progression to blisters that “sloughed” off. She denied any known history of allergy to sulfa drugs. Prior to evaluation by dermatology, she visited an urgent care facility and was prescribed hydroxyzine and intramuscular corticosteroids. At presentation to dermatology 3 days after taking sulfamethoxazole-trimethoprim, she had annular flaccid bullae and superficial erosions with dusky borders on the right posterior thigh, right side of the chest, left inframammary fold, and right inguinal fold (Figure 1). She had no ocular, oral, or vaginal erosions. A diagnosis of generalized bullous FDE was favored over erythema multiforme or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Shave biopsies from lesions on the right posterior thigh and right inguinal fold demonstrated interface dermatitis with epidermal necrosis, pigment incontinence, and numerous eosinophils. Direct immunofluorescence of the perilesional skin was negative for immunoprotein deposition. These findings were consistent with the clinical impression of generalized bullous FDE. Prior to receiving the histopathology report, the patient was initiated on a regimen of cyclosporine 5 mg/kg/d in the setting of normal renal function and followed until the eruption resolved completely. Cyclosporine was tapered at 2 weeks and discontinued at 3 weeks.

Patient 2—A 32-year-old woman presented for follow-up management of discoid lupus erythematosus. She had a history of systemic and cutaneous lupus, juvenile rheumatoid arthritis, and mixed connective tissue disease managed with prednisone, hydroxychloroquine, azathioprine, and belimumab. Physical examination revealed scarring alopecia with dyspigmentation and active inflammation consistent with uncontrolled cutaneous lupus. However, she also had oval-shaped hyperpigmented patches over the left breast, clavicle, and anterior chest consistent with a generalized FDE (Figure 2). The patient did not recall a history of similar lesions and could not identify a possible trigger. She was counseled on possible culprits and advised to avoid unnecessary medications. She had an unremarkable clinical course; therefore, no further intervention was necessary.

 

Patient 3—A 33-year-old man presented to the emergency department with a painful rash on the chest and back of 2 days’ duration that began 1 hour after taking naproxen (dosage unknown) for back pain. He had no notable medical history. The patient stated that the rash had slowly worsened and started to develop blisters. He visited an urgent care facility 1 day prior to the current presentation and was started on a 5-day course of prednisone 40 mg daily; the first 2 doses did not help. He denied any mucosal involvement apart from a tender lesion on the penis. He reported a history of an allergic reaction to penicillin. Physical examination revealed extensive dusky violaceous annular plaques with erythematous borders across the anterior and posterior trunk (Figure 3). Multiple flaccid bullae developed within these plaques, involving 15% of the body surface area. He was diagnosed with generalized bullous FDE based on the clinical history and histopathology. He was admitted to the burn intensive care unit and treated with cyclosporine 3 mg/kg/d with subsequent resolution of the eruption.

Comment

Presentation of FDEs—A fixed drug eruption manifests with 1 or more well-demarcated, red or violaceous, annular patches that resolve with postinflammatory hyperpigmentation; it occasionally may manifest with bullae. Initial eruptions may occur up to 2 weeks following medication exposure, but recurrent eruptions usually happen within minutes to hours later. They often are in the same location as prior lesions. A fixed drug eruption can be solitary, scattered, or generalized; a generalized FDE typically demonstrates multiple bilateral lesions that may itch, burn, or cause no symptoms. Patients can experience an FDE at any age, though the median age is reported as 35 to 60 years of age.¹ A fixed drug eruption usually occurs after ingestion of oral medications, though there have been a few reports with iodinated contrast.² Well-known culprits include antibiotics (eg, sulfamethoxazole-trimethoprim, tetracyclines, penicillins/cephalosporins, quinolones, dapsone), nonsteroidal anti-inflammatory drugs, acetaminophen (eg, paracetamol), barbiturates, antimalarials, and anticonvulsants. It also can occur with vaccines or with certain foods (fixed food eruption).^3,4 Clinicians may try an oral drug challenge to identify the cause of an FDE, but in patients with a history of a generalized FDE, the risk for developing an increasingly severe reaction with repeated exposure to the medication is too high.⁵

Histopathology—Patch testing at the site of prior eruption with suspected drug culprits may be useful.⁶ Histopathology of FDE typically demonstrates vacuolar changes at the dermoepidermal junction with a lichenoid lymphocytic infiltrate. Early lesions often show a predominance of eosinophils. Subepidermal clefting is a feature of the bullous variant. In an active lesion, there are large numbers of CD8+ T lymphocytes expressing natural killer cell–associated molecules.⁷ The pathologic mechanism is not well understood, though it has been hypothesized that memory CD8+ cells are maintained in specific regions of the epidermis by IL-15 produced in the microenvironment and are activated upon rechallenge.⁷Considerations in Generalized Bullous FDE—Generalized FDE is defined in the literature as an FDE with involvement of 3 of 6 body areas: head, neck, trunk, upper limbs, lower limbs, and genital area. It may cover more or less than 10% of the body surface area.^8-10 Although an isolated FDE frequently is asymptomatic and may not be cause for alarm, recurring drug eruptions increase the risk for development of generalized bullous FDE. Generalized bullous FDE is a rare subset. It is frequently misdiagnosed, and data on its incidence are uncertain.¹¹ Of note, several pathologies causing bullous lesions may be in the differential diagnosis, including bullous pemphigoid; pemphigus vulgaris; bullous SLE; or bullae from cutaneous lupus, staphylococcal scalded skin syndrome, erythema multiforme, or SJS/TEN.¹² When matched for body surface area involvement with SJS/TEN, generalized bullous FDE shares nearly identical mortality rates¹⁰; therefore, these patients should be treated with the same level of urgency and admitted to a critical care or burn unit, as they are at serious risk for infection and other complications.¹³

Clinical history and presentation along with histopathologic findings help to narrow down the differential diagnosis. Clinically, generalized bullous FDE does not affect the surrounding skin and manifests sooner after drug exposure (1–24 hours) with less mucosal involvement than SJS/TEN.⁹ Additionally, SJS/TEN patients frequently have generalized malaise and/or fever, while generalized bullous FDE patients do not. Finally, patients with generalized bullous FDE may report a history of a cutaneous eruption similar in morphology or in the same location.

Histopathologically, generalized bullous FDE may be similar to FDE with the addition of a subepidermal blister. Generalized bullous FDE patients have greater eosinophil infiltration and dermal melanophages than patients with SJS/TEN.⁹ Cellular infiltrates in generalized bullous FDE include more dermal CD41 cells, such as Foxp31 regulatory T cells; fewer intraepidermal CD561 cells; and fewer intraepidermal cells with granulysin.⁹ Occasionally, generalized bullous FDE causes full-thickness necrosis. In those cases, generalized bullous FDE cannot reliably be distinguished from other conditions with epidermal necrolysis on histopathology.¹³

FDE Diagnostics—A cytotoxin produced by cytotoxic T lymphocytes, granulysin can be measured to aid in diagnosis of FDE, though this test may not be widely available. High levels of granulysin in the blister fluid and serum can be used to distinguish SJS/TEN, erythema multiforme, and localized and generalized bullous FDE from other non–cytotoxic T lymphocyte–mediated bullous skin disorders, such as bullous pemphigoid, pemphigus, and bullous SLE.¹⁴ Blister granulysin levels are notably lower in generalized bullous FDE than in SJS/TEN.^9,14 Chen et al¹⁴ also found that granulysin levels can be used to gauge disease progression given that the levels sharply decrease after patients have reached maximal skin detachment.

Management—Avoidance of the inciting drug often is sufficient for patients with an FDE, as demonstrated in patient 2 in our case series. Clinicians also should counsel patients on avoidance of potential cross-reacting drugs. Symptomatic treatment for itch or pain is appropriate and may include antihistamines or topical steroids. Nonsteroidal anti-inflammatory drugs may exacerbate or be causative of FDE. For generalized bullous FDE, cyclosporine is favored in the literature^15,16 and was used to successfully treat both patients 1 and 3 in our case series. A short course of systemic corticosteroids or intravenous immunoglobulin also may be considered. Mild cases of generalized bullous FDE may be treated with close outpatient follow-up (patient 1), while severe cases require inpatient or even critical care monitoring with aggressive medical management to prevent the progression of skin desquamation (patient 3). Patients with severe oral lesions may require inpatient support for fluid maintenance.

Lupus History—Two patients in our case series had a history of lupus. Lupus itself can cause primary bullous lesions. Similar to FDE, bullous SLE can involve sun-exposed and nonexposed areas of the skin as well as the mucous membranes with a predilection for the lower vermilion lip.¹⁷ In bullous SLE, tense subepidermal blisters with a neutrophil-rich infiltrate form due to circulating antibodies to type VII collagen. These blisters have an erythematous or urticated base, most commonly on the face, upper trunk, and proximal extremities.¹⁸ In both SLE with skin manifestations and lupus limited to the skin, bullae may form due to extensive vacuolar degeneration. Similar to TEN, they can form rapidly in a widespread distribution.¹⁷ However, there is limited mucosal involvement, no clear drug association, and a better prognosis. Bullae caused by lupus will frequently demonstrate deposition of immunoproteins IgG, IgM, IgA, and complement component 3 at the basement membrane zone in perilesional skin on direct immunofluorescence. However, negative direct immunofluorescence does not rule out lupus.¹² At the same time, patients with lupus frequently have comorbidities requiring multiple medications; the need for these medications may predispose patients to higher rates of cutaneous drug eruptions.¹⁹ To our knowledge, there is no known association between FDE and lupus.

Conclusion

Patients with acute eruptions following the initiation of a new prescription or over-the-counter medication require urgent evaluation. Generalized bullous FDE requires timely diagnosis and intervention. Patients with lupus have an increased risk for cutaneous drug eruptions due to polypharmacy. Further investigation is necessary to determine if there is a pathophysiologic mechanism responsible for the development of FDE in lupus patients.

Recognizing cutaneous drug eruptions is important for treatment and prevention of recurrence. Fixed drug eruptions (FDEs) typically are harmless but can have major negative cosmetic consequences for patients. In its more severe forms, patients are at risk for widespread epithelial necrosis with accompanying complications. We report 1 patient with generalized FDE and 2 with generalized bullous FDE. We also discuss the recognition and treatment of the condition. Two patients previously had been diagnosed with systemic lupus erythematosus (SLE).

Case Series

Patient 1—A 60-year-old woman presented to dermatology with a rash on the trunk and groin folds of 4 days’ duration. She had a history of SLE and cutaneous lupus treated with hydroxychloroquine 200 mg twice daily and topical corticosteroids. She had started sulfamethoxazole-trimethoprim for a urinary tract infection with a rash appearing 1 day later. She reported burning skin pain with progression to blisters that “sloughed” off. She denied any known history of allergy to sulfa drugs. Prior to evaluation by dermatology, she visited an urgent care facility and was prescribed hydroxyzine and intramuscular corticosteroids. At presentation to dermatology 3 days after taking sulfamethoxazole-trimethoprim, she had annular flaccid bullae and superficial erosions with dusky borders on the right posterior thigh, right side of the chest, left inframammary fold, and right inguinal fold (Figure 1). She had no ocular, oral, or vaginal erosions. A diagnosis of generalized bullous FDE was favored over erythema multiforme or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Shave biopsies from lesions on the right posterior thigh and right inguinal fold demonstrated interface dermatitis with epidermal necrosis, pigment incontinence, and numerous eosinophils. Direct immunofluorescence of the perilesional skin was negative for immunoprotein deposition. These findings were consistent with the clinical impression of generalized bullous FDE. Prior to receiving the histopathology report, the patient was initiated on a regimen of cyclosporine 5 mg/kg/d in the setting of normal renal function and followed until the eruption resolved completely. Cyclosporine was tapered at 2 weeks and discontinued at 3 weeks.

Patient 2—A 32-year-old woman presented for follow-up management of discoid lupus erythematosus. She had a history of systemic and cutaneous lupus, juvenile rheumatoid arthritis, and mixed connective tissue disease managed with prednisone, hydroxychloroquine, azathioprine, and belimumab. Physical examination revealed scarring alopecia with dyspigmentation and active inflammation consistent with uncontrolled cutaneous lupus. However, she also had oval-shaped hyperpigmented patches over the left breast, clavicle, and anterior chest consistent with a generalized FDE (Figure 2). The patient did not recall a history of similar lesions and could not identify a possible trigger. She was counseled on possible culprits and advised to avoid unnecessary medications. She had an unremarkable clinical course; therefore, no further intervention was necessary.

 

Patient 3—A 33-year-old man presented to the emergency department with a painful rash on the chest and back of 2 days’ duration that began 1 hour after taking naproxen (dosage unknown) for back pain. He had no notable medical history. The patient stated that the rash had slowly worsened and started to develop blisters. He visited an urgent care facility 1 day prior to the current presentation and was started on a 5-day course of prednisone 40 mg daily; the first 2 doses did not help. He denied any mucosal involvement apart from a tender lesion on the penis. He reported a history of an allergic reaction to penicillin. Physical examination revealed extensive dusky violaceous annular plaques with erythematous borders across the anterior and posterior trunk (Figure 3). Multiple flaccid bullae developed within these plaques, involving 15% of the body surface area. He was diagnosed with generalized bullous FDE based on the clinical history and histopathology. He was admitted to the burn intensive care unit and treated with cyclosporine 3 mg/kg/d with subsequent resolution of the eruption.

Comment

Presentation of FDEs—A fixed drug eruption manifests with 1 or more well-demarcated, red or violaceous, annular patches that resolve with postinflammatory hyperpigmentation; it occasionally may manifest with bullae. Initial eruptions may occur up to 2 weeks following medication exposure, but recurrent eruptions usually happen within minutes to hours later. They often are in the same location as prior lesions. A fixed drug eruption can be solitary, scattered, or generalized; a generalized FDE typically demonstrates multiple bilateral lesions that may itch, burn, or cause no symptoms. Patients can experience an FDE at any age, though the median age is reported as 35 to 60 years of age.¹ A fixed drug eruption usually occurs after ingestion of oral medications, though there have been a few reports with iodinated contrast.² Well-known culprits include antibiotics (eg, sulfamethoxazole-trimethoprim, tetracyclines, penicillins/cephalosporins, quinolones, dapsone), nonsteroidal anti-inflammatory drugs, acetaminophen (eg, paracetamol), barbiturates, antimalarials, and anticonvulsants. It also can occur with vaccines or with certain foods (fixed food eruption).^3,4 Clinicians may try an oral drug challenge to identify the cause of an FDE, but in patients with a history of a generalized FDE, the risk for developing an increasingly severe reaction with repeated exposure to the medication is too high.⁵

Histopathology—Patch testing at the site of prior eruption with suspected drug culprits may be useful.⁶ Histopathology of FDE typically demonstrates vacuolar changes at the dermoepidermal junction with a lichenoid lymphocytic infiltrate. Early lesions often show a predominance of eosinophils. Subepidermal clefting is a feature of the bullous variant. In an active lesion, there are large numbers of CD8+ T lymphocytes expressing natural killer cell–associated molecules.⁷ The pathologic mechanism is not well understood, though it has been hypothesized that memory CD8+ cells are maintained in specific regions of the epidermis by IL-15 produced in the microenvironment and are activated upon rechallenge.⁷Considerations in Generalized Bullous FDE—Generalized FDE is defined in the literature as an FDE with involvement of 3 of 6 body areas: head, neck, trunk, upper limbs, lower limbs, and genital area. It may cover more or less than 10% of the body surface area.^8-10 Although an isolated FDE frequently is asymptomatic and may not be cause for alarm, recurring drug eruptions increase the risk for development of generalized bullous FDE. Generalized bullous FDE is a rare subset. It is frequently misdiagnosed, and data on its incidence are uncertain.¹¹ Of note, several pathologies causing bullous lesions may be in the differential diagnosis, including bullous pemphigoid; pemphigus vulgaris; bullous SLE; or bullae from cutaneous lupus, staphylococcal scalded skin syndrome, erythema multiforme, or SJS/TEN.¹² When matched for body surface area involvement with SJS/TEN, generalized bullous FDE shares nearly identical mortality rates¹⁰; therefore, these patients should be treated with the same level of urgency and admitted to a critical care or burn unit, as they are at serious risk for infection and other complications.¹³

Clinical history and presentation along with histopathologic findings help to narrow down the differential diagnosis. Clinically, generalized bullous FDE does not affect the surrounding skin and manifests sooner after drug exposure (1–24 hours) with less mucosal involvement than SJS/TEN.⁹ Additionally, SJS/TEN patients frequently have generalized malaise and/or fever, while generalized bullous FDE patients do not. Finally, patients with generalized bullous FDE may report a history of a cutaneous eruption similar in morphology or in the same location.

Histopathologically, generalized bullous FDE may be similar to FDE with the addition of a subepidermal blister. Generalized bullous FDE patients have greater eosinophil infiltration and dermal melanophages than patients with SJS/TEN.⁹ Cellular infiltrates in generalized bullous FDE include more dermal CD41 cells, such as Foxp31 regulatory T cells; fewer intraepidermal CD561 cells; and fewer intraepidermal cells with granulysin.⁹ Occasionally, generalized bullous FDE causes full-thickness necrosis. In those cases, generalized bullous FDE cannot reliably be distinguished from other conditions with epidermal necrolysis on histopathology.¹³

FDE Diagnostics—A cytotoxin produced by cytotoxic T lymphocytes, granulysin can be measured to aid in diagnosis of FDE, though this test may not be widely available. High levels of granulysin in the blister fluid and serum can be used to distinguish SJS/TEN, erythema multiforme, and localized and generalized bullous FDE from other non–cytotoxic T lymphocyte–mediated bullous skin disorders, such as bullous pemphigoid, pemphigus, and bullous SLE.¹⁴ Blister granulysin levels are notably lower in generalized bullous FDE than in SJS/TEN.^9,14 Chen et al¹⁴ also found that granulysin levels can be used to gauge disease progression given that the levels sharply decrease after patients have reached maximal skin detachment.

Management—Avoidance of the inciting drug often is sufficient for patients with an FDE, as demonstrated in patient 2 in our case series. Clinicians also should counsel patients on avoidance of potential cross-reacting drugs. Symptomatic treatment for itch or pain is appropriate and may include antihistamines or topical steroids. Nonsteroidal anti-inflammatory drugs may exacerbate or be causative of FDE. For generalized bullous FDE, cyclosporine is favored in the literature^15,16 and was used to successfully treat both patients 1 and 3 in our case series. A short course of systemic corticosteroids or intravenous immunoglobulin also may be considered. Mild cases of generalized bullous FDE may be treated with close outpatient follow-up (patient 1), while severe cases require inpatient or even critical care monitoring with aggressive medical management to prevent the progression of skin desquamation (patient 3). Patients with severe oral lesions may require inpatient support for fluid maintenance.

Lupus History—Two patients in our case series had a history of lupus. Lupus itself can cause primary bullous lesions. Similar to FDE, bullous SLE can involve sun-exposed and nonexposed areas of the skin as well as the mucous membranes with a predilection for the lower vermilion lip.¹⁷ In bullous SLE, tense subepidermal blisters with a neutrophil-rich infiltrate form due to circulating antibodies to type VII collagen. These blisters have an erythematous or urticated base, most commonly on the face, upper trunk, and proximal extremities.¹⁸ In both SLE with skin manifestations and lupus limited to the skin, bullae may form due to extensive vacuolar degeneration. Similar to TEN, they can form rapidly in a widespread distribution.¹⁷ However, there is limited mucosal involvement, no clear drug association, and a better prognosis. Bullae caused by lupus will frequently demonstrate deposition of immunoproteins IgG, IgM, IgA, and complement component 3 at the basement membrane zone in perilesional skin on direct immunofluorescence. However, negative direct immunofluorescence does not rule out lupus.¹² At the same time, patients with lupus frequently have comorbidities requiring multiple medications; the need for these medications may predispose patients to higher rates of cutaneous drug eruptions.¹⁹ To our knowledge, there is no known association between FDE and lupus.

Conclusion

Patients with acute eruptions following the initiation of a new prescription or over-the-counter medication require urgent evaluation. Generalized bullous FDE requires timely diagnosis and intervention. Patients with lupus have an increased risk for cutaneous drug eruptions due to polypharmacy. Further investigation is necessary to determine if there is a pathophysiologic mechanism responsible for the development of FDE in lupus patients.

Recognizing cutaneous drug eruptions is important for treatment and prevention of recurrence. Fixed drug eruptions (FDEs) typically are harmless but can have major negative cosmetic consequences for patients. In its more severe forms, patients are at risk for widespread epithelial necrosis with accompanying complications. We report 1 patient with generalized FDE and 2 with generalized bullous FDE. We also discuss the recognition and treatment of the condition. Two patients previously had been diagnosed with systemic lupus erythematosus (SLE).

Case Series

Patient 1—A 60-year-old woman presented to dermatology with a rash on the trunk and groin folds of 4 days’ duration. She had a history of SLE and cutaneous lupus treated with hydroxychloroquine 200 mg twice daily and topical corticosteroids. She had started sulfamethoxazole-trimethoprim for a urinary tract infection with a rash appearing 1 day later. She reported burning skin pain with progression to blisters that “sloughed” off. She denied any known history of allergy to sulfa drugs. Prior to evaluation by dermatology, she visited an urgent care facility and was prescribed hydroxyzine and intramuscular corticosteroids. At presentation to dermatology 3 days after taking sulfamethoxazole-trimethoprim, she had annular flaccid bullae and superficial erosions with dusky borders on the right posterior thigh, right side of the chest, left inframammary fold, and right inguinal fold (Figure 1). She had no ocular, oral, or vaginal erosions. A diagnosis of generalized bullous FDE was favored over erythema multiforme or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Shave biopsies from lesions on the right posterior thigh and right inguinal fold demonstrated interface dermatitis with epidermal necrosis, pigment incontinence, and numerous eosinophils. Direct immunofluorescence of the perilesional skin was negative for immunoprotein deposition. These findings were consistent with the clinical impression of generalized bullous FDE. Prior to receiving the histopathology report, the patient was initiated on a regimen of cyclosporine 5 mg/kg/d in the setting of normal renal function and followed until the eruption resolved completely. Cyclosporine was tapered at 2 weeks and discontinued at 3 weeks.

Patient 2—A 32-year-old woman presented for follow-up management of discoid lupus erythematosus. She had a history of systemic and cutaneous lupus, juvenile rheumatoid arthritis, and mixed connective tissue disease managed with prednisone, hydroxychloroquine, azathioprine, and belimumab. Physical examination revealed scarring alopecia with dyspigmentation and active inflammation consistent with uncontrolled cutaneous lupus. However, she also had oval-shaped hyperpigmented patches over the left breast, clavicle, and anterior chest consistent with a generalized FDE (Figure 2). The patient did not recall a history of similar lesions and could not identify a possible trigger. She was counseled on possible culprits and advised to avoid unnecessary medications. She had an unremarkable clinical course; therefore, no further intervention was necessary.

 

Patient 3—A 33-year-old man presented to the emergency department with a painful rash on the chest and back of 2 days’ duration that began 1 hour after taking naproxen (dosage unknown) for back pain. He had no notable medical history. The patient stated that the rash had slowly worsened and started to develop blisters. He visited an urgent care facility 1 day prior to the current presentation and was started on a 5-day course of prednisone 40 mg daily; the first 2 doses did not help. He denied any mucosal involvement apart from a tender lesion on the penis. He reported a history of an allergic reaction to penicillin. Physical examination revealed extensive dusky violaceous annular plaques with erythematous borders across the anterior and posterior trunk (Figure 3). Multiple flaccid bullae developed within these plaques, involving 15% of the body surface area. He was diagnosed with generalized bullous FDE based on the clinical history and histopathology. He was admitted to the burn intensive care unit and treated with cyclosporine 3 mg/kg/d with subsequent resolution of the eruption.

Comment

Presentation of FDEs—A fixed drug eruption manifests with 1 or more well-demarcated, red or violaceous, annular patches that resolve with postinflammatory hyperpigmentation; it occasionally may manifest with bullae. Initial eruptions may occur up to 2 weeks following medication exposure, but recurrent eruptions usually happen within minutes to hours later. They often are in the same location as prior lesions. A fixed drug eruption can be solitary, scattered, or generalized; a generalized FDE typically demonstrates multiple bilateral lesions that may itch, burn, or cause no symptoms. Patients can experience an FDE at any age, though the median age is reported as 35 to 60 years of age.¹ A fixed drug eruption usually occurs after ingestion of oral medications, though there have been a few reports with iodinated contrast.² Well-known culprits include antibiotics (eg, sulfamethoxazole-trimethoprim, tetracyclines, penicillins/cephalosporins, quinolones, dapsone), nonsteroidal anti-inflammatory drugs, acetaminophen (eg, paracetamol), barbiturates, antimalarials, and anticonvulsants. It also can occur with vaccines or with certain foods (fixed food eruption).^3,4 Clinicians may try an oral drug challenge to identify the cause of an FDE, but in patients with a history of a generalized FDE, the risk for developing an increasingly severe reaction with repeated exposure to the medication is too high.⁵

Histopathology—Patch testing at the site of prior eruption with suspected drug culprits may be useful.⁶ Histopathology of FDE typically demonstrates vacuolar changes at the dermoepidermal junction with a lichenoid lymphocytic infiltrate. Early lesions often show a predominance of eosinophils. Subepidermal clefting is a feature of the bullous variant. In an active lesion, there are large numbers of CD8+ T lymphocytes expressing natural killer cell–associated molecules.⁷ The pathologic mechanism is not well understood, though it has been hypothesized that memory CD8+ cells are maintained in specific regions of the epidermis by IL-15 produced in the microenvironment and are activated upon rechallenge.⁷Considerations in Generalized Bullous FDE—Generalized FDE is defined in the literature as an FDE with involvement of 3 of 6 body areas: head, neck, trunk, upper limbs, lower limbs, and genital area. It may cover more or less than 10% of the body surface area.^8-10 Although an isolated FDE frequently is asymptomatic and may not be cause for alarm, recurring drug eruptions increase the risk for development of generalized bullous FDE. Generalized bullous FDE is a rare subset. It is frequently misdiagnosed, and data on its incidence are uncertain.¹¹ Of note, several pathologies causing bullous lesions may be in the differential diagnosis, including bullous pemphigoid; pemphigus vulgaris; bullous SLE; or bullae from cutaneous lupus, staphylococcal scalded skin syndrome, erythema multiforme, or SJS/TEN.¹² When matched for body surface area involvement with SJS/TEN, generalized bullous FDE shares nearly identical mortality rates¹⁰; therefore, these patients should be treated with the same level of urgency and admitted to a critical care or burn unit, as they are at serious risk for infection and other complications.¹³

Clinical history and presentation along with histopathologic findings help to narrow down the differential diagnosis. Clinically, generalized bullous FDE does not affect the surrounding skin and manifests sooner after drug exposure (1–24 hours) with less mucosal involvement than SJS/TEN.⁹ Additionally, SJS/TEN patients frequently have generalized malaise and/or fever, while generalized bullous FDE patients do not. Finally, patients with generalized bullous FDE may report a history of a cutaneous eruption similar in morphology or in the same location.

Histopathologically, generalized bullous FDE may be similar to FDE with the addition of a subepidermal blister. Generalized bullous FDE patients have greater eosinophil infiltration and dermal melanophages than patients with SJS/TEN.⁹ Cellular infiltrates in generalized bullous FDE include more dermal CD41 cells, such as Foxp31 regulatory T cells; fewer intraepidermal CD561 cells; and fewer intraepidermal cells with granulysin.⁹ Occasionally, generalized bullous FDE causes full-thickness necrosis. In those cases, generalized bullous FDE cannot reliably be distinguished from other conditions with epidermal necrolysis on histopathology.¹³

FDE Diagnostics—A cytotoxin produced by cytotoxic T lymphocytes, granulysin can be measured to aid in diagnosis of FDE, though this test may not be widely available. High levels of granulysin in the blister fluid and serum can be used to distinguish SJS/TEN, erythema multiforme, and localized and generalized bullous FDE from other non–cytotoxic T lymphocyte–mediated bullous skin disorders, such as bullous pemphigoid, pemphigus, and bullous SLE.¹⁴ Blister granulysin levels are notably lower in generalized bullous FDE than in SJS/TEN.^9,14 Chen et al¹⁴ also found that granulysin levels can be used to gauge disease progression given that the levels sharply decrease after patients have reached maximal skin detachment.

Management—Avoidance of the inciting drug often is sufficient for patients with an FDE, as demonstrated in patient 2 in our case series. Clinicians also should counsel patients on avoidance of potential cross-reacting drugs. Symptomatic treatment for itch or pain is appropriate and may include antihistamines or topical steroids. Nonsteroidal anti-inflammatory drugs may exacerbate or be causative of FDE. For generalized bullous FDE, cyclosporine is favored in the literature^15,16 and was used to successfully treat both patients 1 and 3 in our case series. A short course of systemic corticosteroids or intravenous immunoglobulin also may be considered. Mild cases of generalized bullous FDE may be treated with close outpatient follow-up (patient 1), while severe cases require inpatient or even critical care monitoring with aggressive medical management to prevent the progression of skin desquamation (patient 3). Patients with severe oral lesions may require inpatient support for fluid maintenance.

Lupus History—Two patients in our case series had a history of lupus. Lupus itself can cause primary bullous lesions. Similar to FDE, bullous SLE can involve sun-exposed and nonexposed areas of the skin as well as the mucous membranes with a predilection for the lower vermilion lip.¹⁷ In bullous SLE, tense subepidermal blisters with a neutrophil-rich infiltrate form due to circulating antibodies to type VII collagen. These blisters have an erythematous or urticated base, most commonly on the face, upper trunk, and proximal extremities.¹⁸ In both SLE with skin manifestations and lupus limited to the skin, bullae may form due to extensive vacuolar degeneration. Similar to TEN, they can form rapidly in a widespread distribution.¹⁷ However, there is limited mucosal involvement, no clear drug association, and a better prognosis. Bullae caused by lupus will frequently demonstrate deposition of immunoproteins IgG, IgM, IgA, and complement component 3 at the basement membrane zone in perilesional skin on direct immunofluorescence. However, negative direct immunofluorescence does not rule out lupus.¹² At the same time, patients with lupus frequently have comorbidities requiring multiple medications; the need for these medications may predispose patients to higher rates of cutaneous drug eruptions.¹⁹ To our knowledge, there is no known association between FDE and lupus.

Conclusion

Patients with acute eruptions following the initiation of a new prescription or over-the-counter medication require urgent evaluation. Generalized bullous FDE requires timely diagnosis and intervention. Patients with lupus have an increased risk for cutaneous drug eruptions due to polypharmacy. Further investigation is necessary to determine if there is a pathophysiologic mechanism responsible for the development of FDE in lupus patients.

The Diagnosis: Erythema Ab Igne

Based on the patient's long-standing history of back pain treated with heating pads as well as the normal laboratory findings and skin examination, a diagnosis of erythema ab igne (EAI) was made.

Erythema ab igne presents as reticulated brownish erythema or hyperpigmentation on sites exposed to prolonged use of heat sources such as heating pads, laptops, and space heaters. Erythema ab igne most commonly affects the lower back, thighs, or legs^1-6; however, EAI can appear on atypical sites such as the forehead and eyebrows due to newer technology (eg, virtual reality headsets).⁷ The level of heat required for EAI to occur is below the threshold for thermal burns (<45 °C [113 °F]).1 Erythema ab igne can occur at any age, and woman are more commonly affected than men.⁸ The pathophysiology currently is unknown; however, recurrent and prolonged heat exposure may damage superficial vessels. As a result, hemosiderin accumulates in the skin, and hyperpigmentation subsequently occurs.⁹

The diagnosis of EAI is clinical, and early stages of the rash present as blanching reticulated erythema in areas associated with heat exposure. If the offending source of heat is not removed, EAI can progress to nonblanching, fixed, hyperpigmented plaques with skin atrophy, bullae, or hyperkeratosis. Patients often are asymptomatic; however, mild burning may occur.² Histopathology reveals cellular atypia, epidermal atrophy, dilation of dermal blood vessels, a minute inflammatory infiltrate, and keratinocyte apoptosis.¹⁰ Skin biopsy may be necessary in cases of suspected malignancy due to chronic heat exposure. Lesions that ulcerate or evolve should raise suspicion for malignancy.¹¹ Squamous cell carcinoma is the most common malignancy associated with EAI; other malignancies that may manifest include basal cell carcinoma, Merkel cell carcinoma, or cutaneous marginal zone lymphoma.^2,12-14

Erythema ab igne often is mistaken for livedo reticularis, which appears more erythematous without hyperpigmentation or epidermal changes and may be associated with a pathologic state.¹⁵ The differential diagnosis in our patient, who was in her 40s with a history of fatigue and joint pain, included livedo reticularis associated with lupus; however, the history of heating pad use, normal laboratory findings, and presence of epidermal changes suggested EAI. Lupus typically affects the hand and knee joints.¹⁶ Additionally, livedo reticularis more commonly appears on the legs.¹⁵

Other differentials for EAI include livedo racemosa, cutaneous T-cell lymphoma, and cutis marmorata. Livedo racemosa presents with broken rings of erythema in young to middle-aged women and primarily affects the trunk and proximal limbs. It is associated with an underlying condition such as polyarteritis nodosa and less commonly with lupus erythematosus with antiphospholipid or Sneddon syndrome.^15,17 Cutaneous T-cell lymphoma typically manifests with poikilodermatous patches larger than the palm, especially in covered areas of skin.¹⁸ Cutis marmorata is transient and temperature dependent.⁹

The key intervention for EAI is removal of the offending heat source.² Patients should be counseled that the erythema and hyperpigmentation may take months to years to resolve. Topical hydroquinone or tretinoin may be used in cases of persistent hyperpigmentation.¹⁹ Patients who continue to use heating pads for long-standing pain should be advised to limit their use to short intervals without occlusion. If malignancy is a concern, a biopsy should be performed.²⁰

The Diagnosis: Erythema Ab Igne

Based on the patient's long-standing history of back pain treated with heating pads as well as the normal laboratory findings and skin examination, a diagnosis of erythema ab igne (EAI) was made.

Erythema ab igne presents as reticulated brownish erythema or hyperpigmentation on sites exposed to prolonged use of heat sources such as heating pads, laptops, and space heaters. Erythema ab igne most commonly affects the lower back, thighs, or legs^1-6; however, EAI can appear on atypical sites such as the forehead and eyebrows due to newer technology (eg, virtual reality headsets).⁷ The level of heat required for EAI to occur is below the threshold for thermal burns (<45 °C [113 °F]).1 Erythema ab igne can occur at any age, and woman are more commonly affected than men.⁸ The pathophysiology currently is unknown; however, recurrent and prolonged heat exposure may damage superficial vessels. As a result, hemosiderin accumulates in the skin, and hyperpigmentation subsequently occurs.⁹

The diagnosis of EAI is clinical, and early stages of the rash present as blanching reticulated erythema in areas associated with heat exposure. If the offending source of heat is not removed, EAI can progress to nonblanching, fixed, hyperpigmented plaques with skin atrophy, bullae, or hyperkeratosis. Patients often are asymptomatic; however, mild burning may occur.² Histopathology reveals cellular atypia, epidermal atrophy, dilation of dermal blood vessels, a minute inflammatory infiltrate, and keratinocyte apoptosis.¹⁰ Skin biopsy may be necessary in cases of suspected malignancy due to chronic heat exposure. Lesions that ulcerate or evolve should raise suspicion for malignancy.¹¹ Squamous cell carcinoma is the most common malignancy associated with EAI; other malignancies that may manifest include basal cell carcinoma, Merkel cell carcinoma, or cutaneous marginal zone lymphoma.^2,12-14

Erythema ab igne often is mistaken for livedo reticularis, which appears more erythematous without hyperpigmentation or epidermal changes and may be associated with a pathologic state.¹⁵ The differential diagnosis in our patient, who was in her 40s with a history of fatigue and joint pain, included livedo reticularis associated with lupus; however, the history of heating pad use, normal laboratory findings, and presence of epidermal changes suggested EAI. Lupus typically affects the hand and knee joints.¹⁶ Additionally, livedo reticularis more commonly appears on the legs.¹⁵

Other differentials for EAI include livedo racemosa, cutaneous T-cell lymphoma, and cutis marmorata. Livedo racemosa presents with broken rings of erythema in young to middle-aged women and primarily affects the trunk and proximal limbs. It is associated with an underlying condition such as polyarteritis nodosa and less commonly with lupus erythematosus with antiphospholipid or Sneddon syndrome.^15,17 Cutaneous T-cell lymphoma typically manifests with poikilodermatous patches larger than the palm, especially in covered areas of skin.¹⁸ Cutis marmorata is transient and temperature dependent.⁹

The key intervention for EAI is removal of the offending heat source.² Patients should be counseled that the erythema and hyperpigmentation may take months to years to resolve. Topical hydroquinone or tretinoin may be used in cases of persistent hyperpigmentation.¹⁹ Patients who continue to use heating pads for long-standing pain should be advised to limit their use to short intervals without occlusion. If malignancy is a concern, a biopsy should be performed.²⁰

The Diagnosis: Erythema Ab Igne

Based on the patient's long-standing history of back pain treated with heating pads as well as the normal laboratory findings and skin examination, a diagnosis of erythema ab igne (EAI) was made.

Erythema ab igne presents as reticulated brownish erythema or hyperpigmentation on sites exposed to prolonged use of heat sources such as heating pads, laptops, and space heaters. Erythema ab igne most commonly affects the lower back, thighs, or legs^1-6; however, EAI can appear on atypical sites such as the forehead and eyebrows due to newer technology (eg, virtual reality headsets).⁷ The level of heat required for EAI to occur is below the threshold for thermal burns (<45 °C [113 °F]).1 Erythema ab igne can occur at any age, and woman are more commonly affected than men.⁸ The pathophysiology currently is unknown; however, recurrent and prolonged heat exposure may damage superficial vessels. As a result, hemosiderin accumulates in the skin, and hyperpigmentation subsequently occurs.⁹

The diagnosis of EAI is clinical, and early stages of the rash present as blanching reticulated erythema in areas associated with heat exposure. If the offending source of heat is not removed, EAI can progress to nonblanching, fixed, hyperpigmented plaques with skin atrophy, bullae, or hyperkeratosis. Patients often are asymptomatic; however, mild burning may occur.² Histopathology reveals cellular atypia, epidermal atrophy, dilation of dermal blood vessels, a minute inflammatory infiltrate, and keratinocyte apoptosis.¹⁰ Skin biopsy may be necessary in cases of suspected malignancy due to chronic heat exposure. Lesions that ulcerate or evolve should raise suspicion for malignancy.¹¹ Squamous cell carcinoma is the most common malignancy associated with EAI; other malignancies that may manifest include basal cell carcinoma, Merkel cell carcinoma, or cutaneous marginal zone lymphoma.^2,12-14

Erythema ab igne often is mistaken for livedo reticularis, which appears more erythematous without hyperpigmentation or epidermal changes and may be associated with a pathologic state.¹⁵ The differential diagnosis in our patient, who was in her 40s with a history of fatigue and joint pain, included livedo reticularis associated with lupus; however, the history of heating pad use, normal laboratory findings, and presence of epidermal changes suggested EAI. Lupus typically affects the hand and knee joints.¹⁶ Additionally, livedo reticularis more commonly appears on the legs.¹⁵

Other differentials for EAI include livedo racemosa, cutaneous T-cell lymphoma, and cutis marmorata. Livedo racemosa presents with broken rings of erythema in young to middle-aged women and primarily affects the trunk and proximal limbs. It is associated with an underlying condition such as polyarteritis nodosa and less commonly with lupus erythematosus with antiphospholipid or Sneddon syndrome.^15,17 Cutaneous T-cell lymphoma typically manifests with poikilodermatous patches larger than the palm, especially in covered areas of skin.¹⁸ Cutis marmorata is transient and temperature dependent.⁹

The key intervention for EAI is removal of the offending heat source.² Patients should be counseled that the erythema and hyperpigmentation may take months to years to resolve. Topical hydroquinone or tretinoin may be used in cases of persistent hyperpigmentation.¹⁹ Patients who continue to use heating pads for long-standing pain should be advised to limit their use to short intervals without occlusion. If malignancy is a concern, a biopsy should be performed.²⁰

Sea urchins—members of the phylum Echinodermata and the class Echinoidea—are spiny marine invertebrates. Their consumption of fleshy algae makes them essential players in maintaining reef ecosystems.^1,2 Echinoids, a class that includes heart urchins and sand dollars, are ubiquitous in benthic marine environments, both free floating and rock boring, and inhabit a wide range of latitudes spanning from polar oceans to warm seas.³ Despite their immobility and nonaggression, sea urchin puncture wounds are common among divers, snorkelers, swimmers, surfers, and fishers who accidentally come into contact with their sharp spines. Although the epidemiology of sea urchin exposure and injury is difficult to assess, the American Association of Poison Control Centers’ most recent annual report in 2022 documents approximately 1426 annual aquatic bites and/or envenomations.⁴

Sea Urchin Morphology and Toxicity

Echinoderms (a term of Greek origin meaning spiny skin) share a radially symmetric calcium carbonate skeleton (termed stereom) that is supported by collagenous ligaments.¹ Sea urchins possess spines composed of calcite crystals, which radiate from their body and play a role in locomotion and defense against predators—namely sea otters, starfish/sea stars, wolf eels, and triggerfish, among others (Figure).⁵ These brittle spines can easily penetrate human skin and subsequently break off the sea urchin body. Most species of sea urchins possess solid spines, but a small percentage (80 of approximately 700 extant species) have hollow spines containing various toxic substances.⁶ Penetration and systemic absorption of the toxins within these spines can generate severe systemic responses.

The venomous flower urchin (Toxopneustes pileolus), found in the Indian and Pacific oceans, is one of the more common species known to produce a systemic reaction involving neuromuscular blockage.^7-9 The most common species harvested off the Pacific coast of the United States—Strongylocentrotus purpuratus (purple sea urchin) and Strongylocentrotus franciscanus (red sea urchins)—are not inherently venomous.⁸

Presentation and Diagnosis of Sea Urchin Injuries

Sea urchin injuries have a wide range of manifestations depending on the number of spines involved, the presence of venom, the depth and location of spine penetration, the duration of spine retention in the skin, and the time before treatment initiation. The most common site of sea urchin injury unsurprisingly is the lower extremities and feet, often in the context of divers and swimmers walking across the sea floor. The hands are another frequently injured site, along with the legs, arms, back, scalp, and even oral mucosa.¹¹

Although clinical history and presentation frequently reveal the mechanism of aquatic injury, patients often are unsure of the agent to which they were exposed and may be unaware of retained foreign bodies. Dermoscopy can distinguish the distinct lines radiating from the core of sea urchin spines from other foreign bodies lodged within the skin.⁶ It also can be used to locate spines for removal or for their analysis following punch biopsy.^6,12 The radiopaque nature of sea urchin spines makes radiography and magnetic resonance imaging useful tools in assessment of periarticular soft-tissue damage and spine removal.^8,11,13 Ultrasonography can reveal spines that no longer appear on radiography due to absorption by human tissue.¹⁴

Immediate Dermatologic Effects

Sea urchin injuries can be broadly categorized into immediate and delayed reactions. Immediate manifestations of contact with sea urchin spines include localized pain, bleeding, erythema, myalgia, and edema at the site of injury that can last from a few hours to 1 week without proper wound care and spine removal.⁵ Systemic symptoms ranging from dizziness, lightheadedness, paresthesia, aphonia, paralysis, coma, and death generally are only seen following injuries from venomous species, attachment of pedicellariae, injuries involving neurovascular structures, or penetration by more than 15 spines.^7,11

Initial treatment includes soaking the wound in hot water (113 °F [45 °C]) for 30 to 90 minutes and subsequently removing spines and pedicellariae to prevent development of delayed reactions.^5,15,16 The compounds in the sea urchin epithelium are heat labile and will be inactivated upon soaking in hot water.¹⁶ Extraction of spines can be difficult, as they are brittle and easily break in the skin. Successful removal has been reported using forceps and a hypodermic needle as well as excision; both approaches may require local anesthesia.^8,17 Another technique involves freezing the localized area with liquid nitrogen to allow easier removal upon skin blistering.¹⁸ Punch biopsy also has been utilized as an effective means of ensuring all spiny fragments are removed.^9,19,20 These spines often cause black or purple tattoolike staining at the puncture site, which can persist for a few days after spine extraction.⁸ Ablation using the erbium-doped:YAG laser may be helpful for removal of associated pigment.^21,22

Delayed Dermatologic Effects

Delayed reactions to sea urchin injuries often are attributable to prolonged retention of spines in the skin. Granulomatous reactions typically manifest 2 weeks after injury as firm nonsuppurative nodules with central umbilication and a hyperkeratotic surface.⁷ These nodules may or may not be painful. Histopathology most often reveals foreign body and sarcoidal-type granulomatous reactions. However, tuberculoid, necrobiotic, and suppurative granulomas also may develop.¹³ Other microscopic features include inflammatory reactions, suppurative dermatitis, focal necrosis, and microabscesses.²³ Wounds with progression to granulomatous disease often require surgical debridement.

Other more serious sequalae can result from involvement of joint capsules, especially in the hands and feet. Sea urchin injury involving joint spaces should be treated aggressively, as progression to inflammatory or infectious synovitis and tenosynovitis can cause irreversible loss of joint function. Inflammatory synovitis occurs 1 to 2 months on average after injury following a period of minimal symptoms and begins as a gradual increase in joint swelling and decrease in range of motion.⁸ Infectious tenosynovitis manifests quite similarly. Although suppurative etiologies generally progress with a more acute onset, certain infectious organisms (eg, Mycobacterium) take on an indolent course and should not be overlooked as a cause of delayed symptoms.⁸ The Kavanel cardinal signs are a sensitive tool used in the diagnosis of infectious flexor sheath tenosynovitis.^8,24 If suspicion for joint infection is high, emergency referral should be made for debridement and culture-guided antibiotic therapy. Left untreated, infectious tenosynovitis can result in tendon necrosis or rupture, digit necrosis, and systemic infection.²⁴ Patients with joint involvement should be referred to specialty care (eg, hand surgeon), as they often require synovectomy and surgical removal of foreign material.⁸

From 1 month to 1 year after injury, prolonged granulomatous synovitis of the hand may eventually lead to joint destruction known as “sea urchin arthritis.” These patients present with decreased range of motion and numerous nodules on the hand with a hyperkeratotic surface. Radiography reveals joint space narrowing, osteolysis, subchondral sclerosis, and periosteal reaction. Synovectomy and debridement are necessary to prevent irreversible joint damage or the need for arthrodesis and bone grafting.²⁴

Other Treatment Considerations

Other important considerations in the care of sea urchin spine injuries include assessment of tetanus immunization status and administration of necessary prophylaxis as soon as possible, even in delayed presentations (Table).^16,25 Cultures should be taken only if infection is suspected. Prophylactic antibiotics are not recommended unless the patient is immunocompromised or otherwise has impaired wound healing. If a patient presents with systemic symptoms, they should be referred to an emergency care facility for further management.

Final Thoughts

Sea urchin injuries can lead to serious complications if not diagnosed quickly and treated properly. Retention of sea urchin spines in the deep tissues and joint spaces may lead to granulomas, inflammatory and infectious tenosynovitis (including mycobacterial infection), and sea urchin arthritis requiring surgical debridement and possible irreversible joint damage, up to a year after initial injury. Patients should be educated on the possibility of developing these delayed reactions and instructed to seek immediate care. Joint deformities, range-of-motion deficits, and involvement of neurovascular structures should be considered emergent and referred for proper management. Shoes and diving gear offer some protection but are easily penetrable by sharp sea urchin spines. Preventive focus should be aimed at educating patients and providers on the importance of prompt spine removal upon injury. Although dermatologic and systemic manifestations vary widely, a thorough history, physical examination, and appropriate use of imaging modalities can facilitate accurate diagnosis and guide treatment.

Sea urchins—members of the phylum Echinodermata and the class Echinoidea—are spiny marine invertebrates. Their consumption of fleshy algae makes them essential players in maintaining reef ecosystems.^1,2 Echinoids, a class that includes heart urchins and sand dollars, are ubiquitous in benthic marine environments, both free floating and rock boring, and inhabit a wide range of latitudes spanning from polar oceans to warm seas.³ Despite their immobility and nonaggression, sea urchin puncture wounds are common among divers, snorkelers, swimmers, surfers, and fishers who accidentally come into contact with their sharp spines. Although the epidemiology of sea urchin exposure and injury is difficult to assess, the American Association of Poison Control Centers’ most recent annual report in 2022 documents approximately 1426 annual aquatic bites and/or envenomations.⁴

Sea Urchin Morphology and Toxicity

Echinoderms (a term of Greek origin meaning spiny skin) share a radially symmetric calcium carbonate skeleton (termed stereom) that is supported by collagenous ligaments.¹ Sea urchins possess spines composed of calcite crystals, which radiate from their body and play a role in locomotion and defense against predators—namely sea otters, starfish/sea stars, wolf eels, and triggerfish, among others (Figure).⁵ These brittle spines can easily penetrate human skin and subsequently break off the sea urchin body. Most species of sea urchins possess solid spines, but a small percentage (80 of approximately 700 extant species) have hollow spines containing various toxic substances.⁶ Penetration and systemic absorption of the toxins within these spines can generate severe systemic responses.

The venomous flower urchin (Toxopneustes pileolus), found in the Indian and Pacific oceans, is one of the more common species known to produce a systemic reaction involving neuromuscular blockage.^7-9 The most common species harvested off the Pacific coast of the United States—Strongylocentrotus purpuratus (purple sea urchin) and Strongylocentrotus franciscanus (red sea urchins)—are not inherently venomous.⁸

Presentation and Diagnosis of Sea Urchin Injuries

Sea urchin injuries have a wide range of manifestations depending on the number of spines involved, the presence of venom, the depth and location of spine penetration, the duration of spine retention in the skin, and the time before treatment initiation. The most common site of sea urchin injury unsurprisingly is the lower extremities and feet, often in the context of divers and swimmers walking across the sea floor. The hands are another frequently injured site, along with the legs, arms, back, scalp, and even oral mucosa.¹¹

Although clinical history and presentation frequently reveal the mechanism of aquatic injury, patients often are unsure of the agent to which they were exposed and may be unaware of retained foreign bodies. Dermoscopy can distinguish the distinct lines radiating from the core of sea urchin spines from other foreign bodies lodged within the skin.⁶ It also can be used to locate spines for removal or for their analysis following punch biopsy.^6,12 The radiopaque nature of sea urchin spines makes radiography and magnetic resonance imaging useful tools in assessment of periarticular soft-tissue damage and spine removal.^8,11,13 Ultrasonography can reveal spines that no longer appear on radiography due to absorption by human tissue.¹⁴

Immediate Dermatologic Effects

Sea urchin injuries can be broadly categorized into immediate and delayed reactions. Immediate manifestations of contact with sea urchin spines include localized pain, bleeding, erythema, myalgia, and edema at the site of injury that can last from a few hours to 1 week without proper wound care and spine removal.⁵ Systemic symptoms ranging from dizziness, lightheadedness, paresthesia, aphonia, paralysis, coma, and death generally are only seen following injuries from venomous species, attachment of pedicellariae, injuries involving neurovascular structures, or penetration by more than 15 spines.^7,11

Initial treatment includes soaking the wound in hot water (113 °F [45 °C]) for 30 to 90 minutes and subsequently removing spines and pedicellariae to prevent development of delayed reactions.^5,15,16 The compounds in the sea urchin epithelium are heat labile and will be inactivated upon soaking in hot water.¹⁶ Extraction of spines can be difficult, as they are brittle and easily break in the skin. Successful removal has been reported using forceps and a hypodermic needle as well as excision; both approaches may require local anesthesia.^8,17 Another technique involves freezing the localized area with liquid nitrogen to allow easier removal upon skin blistering.¹⁸ Punch biopsy also has been utilized as an effective means of ensuring all spiny fragments are removed.^9,19,20 These spines often cause black or purple tattoolike staining at the puncture site, which can persist for a few days after spine extraction.⁸ Ablation using the erbium-doped:YAG laser may be helpful for removal of associated pigment.^21,22

Delayed Dermatologic Effects

Delayed reactions to sea urchin injuries often are attributable to prolonged retention of spines in the skin. Granulomatous reactions typically manifest 2 weeks after injury as firm nonsuppurative nodules with central umbilication and a hyperkeratotic surface.⁷ These nodules may or may not be painful. Histopathology most often reveals foreign body and sarcoidal-type granulomatous reactions. However, tuberculoid, necrobiotic, and suppurative granulomas also may develop.¹³ Other microscopic features include inflammatory reactions, suppurative dermatitis, focal necrosis, and microabscesses.²³ Wounds with progression to granulomatous disease often require surgical debridement.

Other more serious sequalae can result from involvement of joint capsules, especially in the hands and feet. Sea urchin injury involving joint spaces should be treated aggressively, as progression to inflammatory or infectious synovitis and tenosynovitis can cause irreversible loss of joint function. Inflammatory synovitis occurs 1 to 2 months on average after injury following a period of minimal symptoms and begins as a gradual increase in joint swelling and decrease in range of motion.⁸ Infectious tenosynovitis manifests quite similarly. Although suppurative etiologies generally progress with a more acute onset, certain infectious organisms (eg, Mycobacterium) take on an indolent course and should not be overlooked as a cause of delayed symptoms.⁸ The Kavanel cardinal signs are a sensitive tool used in the diagnosis of infectious flexor sheath tenosynovitis.^8,24 If suspicion for joint infection is high, emergency referral should be made for debridement and culture-guided antibiotic therapy. Left untreated, infectious tenosynovitis can result in tendon necrosis or rupture, digit necrosis, and systemic infection.²⁴ Patients with joint involvement should be referred to specialty care (eg, hand surgeon), as they often require synovectomy and surgical removal of foreign material.⁸

From 1 month to 1 year after injury, prolonged granulomatous synovitis of the hand may eventually lead to joint destruction known as “sea urchin arthritis.” These patients present with decreased range of motion and numerous nodules on the hand with a hyperkeratotic surface. Radiography reveals joint space narrowing, osteolysis, subchondral sclerosis, and periosteal reaction. Synovectomy and debridement are necessary to prevent irreversible joint damage or the need for arthrodesis and bone grafting.²⁴

Other Treatment Considerations

Other important considerations in the care of sea urchin spine injuries include assessment of tetanus immunization status and administration of necessary prophylaxis as soon as possible, even in delayed presentations (Table).^16,25 Cultures should be taken only if infection is suspected. Prophylactic antibiotics are not recommended unless the patient is immunocompromised or otherwise has impaired wound healing. If a patient presents with systemic symptoms, they should be referred to an emergency care facility for further management.

Final Thoughts

Sea urchin injuries can lead to serious complications if not diagnosed quickly and treated properly. Retention of sea urchin spines in the deep tissues and joint spaces may lead to granulomas, inflammatory and infectious tenosynovitis (including mycobacterial infection), and sea urchin arthritis requiring surgical debridement and possible irreversible joint damage, up to a year after initial injury. Patients should be educated on the possibility of developing these delayed reactions and instructed to seek immediate care. Joint deformities, range-of-motion deficits, and involvement of neurovascular structures should be considered emergent and referred for proper management. Shoes and diving gear offer some protection but are easily penetrable by sharp sea urchin spines. Preventive focus should be aimed at educating patients and providers on the importance of prompt spine removal upon injury. Although dermatologic and systemic manifestations vary widely, a thorough history, physical examination, and appropriate use of imaging modalities can facilitate accurate diagnosis and guide treatment.

Sea urchins—members of the phylum Echinodermata and the class Echinoidea—are spiny marine invertebrates. Their consumption of fleshy algae makes them essential players in maintaining reef ecosystems.^1,2 Echinoids, a class that includes heart urchins and sand dollars, are ubiquitous in benthic marine environments, both free floating and rock boring, and inhabit a wide range of latitudes spanning from polar oceans to warm seas.³ Despite their immobility and nonaggression, sea urchin puncture wounds are common among divers, snorkelers, swimmers, surfers, and fishers who accidentally come into contact with their sharp spines. Although the epidemiology of sea urchin exposure and injury is difficult to assess, the American Association of Poison Control Centers’ most recent annual report in 2022 documents approximately 1426 annual aquatic bites and/or envenomations.⁴

Sea Urchin Morphology and Toxicity

Echinoderms (a term of Greek origin meaning spiny skin) share a radially symmetric calcium carbonate skeleton (termed stereom) that is supported by collagenous ligaments.¹ Sea urchins possess spines composed of calcite crystals, which radiate from their body and play a role in locomotion and defense against predators—namely sea otters, starfish/sea stars, wolf eels, and triggerfish, among others (Figure).⁵ These brittle spines can easily penetrate human skin and subsequently break off the sea urchin body. Most species of sea urchins possess solid spines, but a small percentage (80 of approximately 700 extant species) have hollow spines containing various toxic substances.⁶ Penetration and systemic absorption of the toxins within these spines can generate severe systemic responses.

The venomous flower urchin (Toxopneustes pileolus), found in the Indian and Pacific oceans, is one of the more common species known to produce a systemic reaction involving neuromuscular blockage.^7-9 The most common species harvested off the Pacific coast of the United States—Strongylocentrotus purpuratus (purple sea urchin) and Strongylocentrotus franciscanus (red sea urchins)—are not inherently venomous.⁸

Presentation and Diagnosis of Sea Urchin Injuries

Sea urchin injuries have a wide range of manifestations depending on the number of spines involved, the presence of venom, the depth and location of spine penetration, the duration of spine retention in the skin, and the time before treatment initiation. The most common site of sea urchin injury unsurprisingly is the lower extremities and feet, often in the context of divers and swimmers walking across the sea floor. The hands are another frequently injured site, along with the legs, arms, back, scalp, and even oral mucosa.¹¹

Although clinical history and presentation frequently reveal the mechanism of aquatic injury, patients often are unsure of the agent to which they were exposed and may be unaware of retained foreign bodies. Dermoscopy can distinguish the distinct lines radiating from the core of sea urchin spines from other foreign bodies lodged within the skin.⁶ It also can be used to locate spines for removal or for their analysis following punch biopsy.^6,12 The radiopaque nature of sea urchin spines makes radiography and magnetic resonance imaging useful tools in assessment of periarticular soft-tissue damage and spine removal.^8,11,13 Ultrasonography can reveal spines that no longer appear on radiography due to absorption by human tissue.¹⁴

Immediate Dermatologic Effects

Sea urchin injuries can be broadly categorized into immediate and delayed reactions. Immediate manifestations of contact with sea urchin spines include localized pain, bleeding, erythema, myalgia, and edema at the site of injury that can last from a few hours to 1 week without proper wound care and spine removal.⁵ Systemic symptoms ranging from dizziness, lightheadedness, paresthesia, aphonia, paralysis, coma, and death generally are only seen following injuries from venomous species, attachment of pedicellariae, injuries involving neurovascular structures, or penetration by more than 15 spines.^7,11

Initial treatment includes soaking the wound in hot water (113 °F [45 °C]) for 30 to 90 minutes and subsequently removing spines and pedicellariae to prevent development of delayed reactions.^5,15,16 The compounds in the sea urchin epithelium are heat labile and will be inactivated upon soaking in hot water.¹⁶ Extraction of spines can be difficult, as they are brittle and easily break in the skin. Successful removal has been reported using forceps and a hypodermic needle as well as excision; both approaches may require local anesthesia.^8,17 Another technique involves freezing the localized area with liquid nitrogen to allow easier removal upon skin blistering.¹⁸ Punch biopsy also has been utilized as an effective means of ensuring all spiny fragments are removed.^9,19,20 These spines often cause black or purple tattoolike staining at the puncture site, which can persist for a few days after spine extraction.⁸ Ablation using the erbium-doped:YAG laser may be helpful for removal of associated pigment.^21,22

Delayed Dermatologic Effects

Delayed reactions to sea urchin injuries often are attributable to prolonged retention of spines in the skin. Granulomatous reactions typically manifest 2 weeks after injury as firm nonsuppurative nodules with central umbilication and a hyperkeratotic surface.⁷ These nodules may or may not be painful. Histopathology most often reveals foreign body and sarcoidal-type granulomatous reactions. However, tuberculoid, necrobiotic, and suppurative granulomas also may develop.¹³ Other microscopic features include inflammatory reactions, suppurative dermatitis, focal necrosis, and microabscesses.²³ Wounds with progression to granulomatous disease often require surgical debridement.

Other more serious sequalae can result from involvement of joint capsules, especially in the hands and feet. Sea urchin injury involving joint spaces should be treated aggressively, as progression to inflammatory or infectious synovitis and tenosynovitis can cause irreversible loss of joint function. Inflammatory synovitis occurs 1 to 2 months on average after injury following a period of minimal symptoms and begins as a gradual increase in joint swelling and decrease in range of motion.⁸ Infectious tenosynovitis manifests quite similarly. Although suppurative etiologies generally progress with a more acute onset, certain infectious organisms (eg, Mycobacterium) take on an indolent course and should not be overlooked as a cause of delayed symptoms.⁸ The Kavanel cardinal signs are a sensitive tool used in the diagnosis of infectious flexor sheath tenosynovitis.^8,24 If suspicion for joint infection is high, emergency referral should be made for debridement and culture-guided antibiotic therapy. Left untreated, infectious tenosynovitis can result in tendon necrosis or rupture, digit necrosis, and systemic infection.²⁴ Patients with joint involvement should be referred to specialty care (eg, hand surgeon), as they often require synovectomy and surgical removal of foreign material.⁸

From 1 month to 1 year after injury, prolonged granulomatous synovitis of the hand may eventually lead to joint destruction known as “sea urchin arthritis.” These patients present with decreased range of motion and numerous nodules on the hand with a hyperkeratotic surface. Radiography reveals joint space narrowing, osteolysis, subchondral sclerosis, and periosteal reaction. Synovectomy and debridement are necessary to prevent irreversible joint damage or the need for arthrodesis and bone grafting.²⁴

Other Treatment Considerations

Other important considerations in the care of sea urchin spine injuries include assessment of tetanus immunization status and administration of necessary prophylaxis as soon as possible, even in delayed presentations (Table).^16,25 Cultures should be taken only if infection is suspected. Prophylactic antibiotics are not recommended unless the patient is immunocompromised or otherwise has impaired wound healing. If a patient presents with systemic symptoms, they should be referred to an emergency care facility for further management.

Final Thoughts

Sea urchin injuries can lead to serious complications if not diagnosed quickly and treated properly. Retention of sea urchin spines in the deep tissues and joint spaces may lead to granulomas, inflammatory and infectious tenosynovitis (including mycobacterial infection), and sea urchin arthritis requiring surgical debridement and possible irreversible joint damage, up to a year after initial injury. Patients should be educated on the possibility of developing these delayed reactions and instructed to seek immediate care. Joint deformities, range-of-motion deficits, and involvement of neurovascular structures should be considered emergent and referred for proper management. Shoes and diving gear offer some protection but are easily penetrable by sharp sea urchin spines. Preventive focus should be aimed at educating patients and providers on the importance of prompt spine removal upon injury. Although dermatologic and systemic manifestations vary widely, a thorough history, physical examination, and appropriate use of imaging modalities can facilitate accurate diagnosis and guide treatment.

Approximately 108 million individuals have been forcibly displaced across the globe as of 2022, 35 million of whom are formally designated as refugees.^1,2 The United States has coordinated resettlement of more refugee populations than any other country; the most common countries of origin are the Democratic Republic of the Congo, Syria, Afghanistan, and Myanmar.³ In 2021, policy to increase the number of refugees resettled in the United States by more than 700% (from 15,000 up to 125,000) was established; since enactment, the United States has seen more than double the refugee arrivals in 2023 than the prior year, making medical care for this population increasingly relevant for the dermatologist.⁴

Understanding how to care for this population begins with an accurate understanding of the term refugee. The United Nations defines a refugee as a person who is unwilling or unable to return to their country of nationality because of persecution or well-founded fear of persecution due to race, religion, nationality, membership in a particular social group, or political opinion. This term grants a protected status under international law and encompasses access to travel assistance, housing, cultural orientation, and medical evaluation upon resettlement.^5,6

The burden of treatable dermatologic conditions in refugee populations ranges from 19% to 96% in the literature^7,8 and varies from inflammatory disorders to infectious and parasitic diseases.⁹ In one study of 6899 displaced individuals in Greece, the prevalence of dermatologic conditions was higher than traumatic injury, cardiac disease, psychological conditions, and dental disease.¹⁰

When outlining differential diagnoses for parasitic infestations of the skin that affect refugee populations, helpful considerations include the individual’s country of origin, route traveled, and method of travel.¹¹ Parasitic infestations specifically are more common in refugee populations when there are barriers to basic hygiene, crowded living or travel conditions, or lack of access to health care, which they may experience at any point in their home country, during travel, or in resettlement housing.⁸

Even with limited examination and diagnostic resources, the skin is the most accessible first indication of patients’ overall well-being and often provides simple diagnostic clues—in combination with contextualization of the patient’s unique circumstances—necessary for successful diagnosis and treatment of scabies and pediculosis.¹² The dermatologist working with refugee populations may be the first set of eyes available and trained to discern skin infestations and therefore has the potential to improve overall outcomes.

Some parasitic infestations in refugee populations may fall under the category of neglected tropical diseases, including scabies, ascariasis, trypanosomiasis, leishmaniasis, and schistosomiasis; they affect an estimated 1 billion individuals across the globe but historically have been underrepresented in the literature and in health policy due in part to limited access to care.¹³ This review will focus on infestations by the scabies mite (Sarcoptes scabiei var hominis) and the human louse, as these frequently are encountered, easily diagnosed, and treatable by trained clinicians, even in resource-limited settings.

Scabies

Scabies is a parasitic skin infestation caused by the 8-legged mite Sarcoptes scabiei var hominis. The female mite begins the infestation process via penetration of the epidermis, particularly the stratum corneum, and commences laying eggs (Figure 1). The subsequent larvae emerge 48 to 72 hours later and remain burrowed in the epidermis. The larvae mature over the next 10 to 14 days and continue the reproductive cycle.^14,15 Symptoms of infestation occurs due to a hypersensitivity reaction to the mite and its by-products.¹⁶ Transmission of the mite primarily occurs via direct (skin-to-skin) contact with infected individuals or environmental surfaces for 24 to36 hours in specific conditions, though the latter source has been debated in the literature.

The method of transmission is particularly important when considering care for refugee populations. Scabies is found most often in those living in or traveling from tropical regions including East Asia, Southeast Asia, Oceania, and Latin America.¹⁷ In displaced or refugee populations, a lack of access to basic hygiene, extended travel in close quarters, and suboptimal health care access all may lead to an increased incidence of untreated scabies infestations.¹⁸ Scabies is more prevalent in children, with increased potential for secondary bacterial infections with Streptococcus and Staphylococcus species due to excoriation in unsanitary conditions. Secondary infection with Streptococcus pyogenes can lead to acute poststreptococcal glomerulonephritis, which accounts for a large burden of chronic kidney disease in affected populations.¹⁹ However, scabies may be found in any population, regardless of hygiene or health care access. Treating health care providers should keep a broad differential.

Presentation—The latency of scabies symptoms is 2 to 6 weeks in a primary outbreak and may be as short as 1 to 3 days with re-infestation, following the course of delayed-type hypersensitivity.²⁰ The initial hallmark symptom is pruritus with increased severity in the evening. Visible lesions, excoriations, and burrows associated with scattered vesicles or pustules may be seen over the web spaces of the hands and feet, volar surfaces of the wrists, axillae, waist, genitalia, inner thighs, or buttocks.¹⁹ Chronic infestation often manifests with genital nodules. In populations with limited access to health care, there are reports of a sensitization phenomenon in which the individual may become less symptomatic after 4 to 6 weeks and yet be a potential carrier of the mite.²¹

Those with compromised immune function, such as individuals living with HIV or severe malnutrition, may present with crusted scabies, a variant that manifests as widespread hyperkeratotic scaling with more pronounced involvement of the head, neck, and acral areas. In contrast to classic scabies, crusted scabies is associated with minimal pruritus.²²

Diagnosis—The diagnosis of scabies is largely clinical with confirmation through skin scrapings. The International Alliance for Control of Scabies has established diagnostic criteria that include a combination of clinical findings, history, and visualization of mites.²³ A dermatologist working with refugee populations may employ any combination of history (eg, nocturnal itch, exposure to an affected individual) or clinical findings along with a high degree of suspicion in those with elevated risk. Visualization of mites is helpful to confirm the diagnosis and may be completed with the application of mineral oil at the terminal end of a burrow, skin scraping with a surgical blade or needle, and examination under light microscopy.

Treatment—First-line treatment for scabies consists of application of permethrin cream 5% on the skin of the neck to the soles of the feet, which is to be left on for 8 to 14 hours followed by rinsing. Re-application is recommended in 1 to 2 weeks. Oral ivermectin is a reasonable alternative to permethrin cream due to its low cost and easy administration in large affected groups. It is not labeled for use in pregnant women or children weighing less than 15 kg but has no selective fetal toxicity. Treatment of scabies with ivermectin has the benefit of treating many other parasitic infections. Both medications are on the World Health Organization Model List of Essential Medications and are widely available for treating providers, even in resource-limited settings.²⁴

Much of the world still uses benzyl benzoate or precipitated sulfur ointment to treat scabies, and some botanicals used in folk medicine have genuine antiscabetic properties. Pruritus may persist for 1 to 4 weeks following treatment and does not indicate treatment failure. Topical camphor and menthol preparations, low-potency topical corticosteroids, or emollients all may be employed for relief.²⁵Sarna is a Spanish term for scabies and has become the proprietary name for topical antipruritic agents. Additional methods of treatment and prevention include washing clothes and linens in hot water and drying on high heat. If machine washing is not available, clothing and linens may be sealed in a plastic bag for 72 hours.

Pediculosis

Pediculosis is an infestation caused by the ectoparasite Pediculus humanus, an obligate, sesame seed–sized louse that feeds exclusively on the blood of its host (Figure 2).²⁶ Of the lice species, 2 require humans as hosts; one is P humanus and the other is Pthirus pubis (pubic lice). Pediculus humanus may be further classified into morphologies based largely on the affected area: body (P humanus corporis) or head (P humanus capitis), both of which will be discussed.²⁷

Lice primarily attach to clothing and hair shafts, then transfer to the skin for blood feeds. Females lay eggs that hatch 6 to 10 days later, subsequently maturing into adults. The lifespan of these parasites with regular access to a host is 1 to 3 months for head lice and 18 days for body lice vs only 3 to 5 days without a host.²⁸ Transmission of P humanus capitis primarily occurs via direct contact with affected individuals, either head-to-head contact or sharing of items such as brushes and headscarves; P humanus corporis also may be transmitted via direct contact with affected individuals or clothing.

Pediculosis is an important infestation to consider when providing care for refugee populations. Risk factors include lack of access to basic hygiene, including regular bathing or laundering of clothing, and crowded conditions that make direct person-to-person contact with affected individuals more likely.²⁹ Body lice are associated more often with domestic turbulence and displaced populations³⁰ in comparison to head lice, which have broad demographic variables, most often affecting females and children.²⁸ Fatty acids in adult male sebum make the scalp less hospitable to lice.

Presentation—The most common clinical manifestation of pediculosis is pruritus. Cutaneous findings can include papules, wheals, or hemorrhagic puncta secondary to the louse bite. Due to the Tyndall effect of deep hemosiderin pigment, blue-grey macules termed maculae ceruleae (Figure 3) also may be present in chronic infestations of pediculosis pubis, in contrast to pediculosis capitis or corporis.³¹ Body louse infestation is associated with a general pruritus concentrated on the neck, shoulders, and waist—areas where clothing makes the most direct contact. Lesions may be visible and include eczematous patches with excoriation and possible secondary bacterial infection. Chronic infestation may exhibit lichenification or hyperpigmentation in associated areas. Head lice most often manifest with localized scalp pruritus and associated excoriation and cervical or occipital lymphadenopathy.³²

Diagnosis—The diagnosis of pediculosis is clinical, with confirmation requiring direct examination of the insect or nits (the egg case of the parasite)(Figure 4). Body lice and associated nits can be visualized on clothing seams near areas of highest body temperature, particularly the waistband. Head lice may be visualized crawling on hair shafts or on a louse comb. Nits are firmly attached to hair shafts and are visible to the naked eye, whereas pseudonits slide freely along the hair shaft and are not a manifestation of louse infestation (Figure 5).³¹

Treatment—Treatment varies by affected area. Pediculosis corporis may be treated with permethrin cream 5% applied to the entire body and left on for 8 to 10 hours, but this may not be necessary if facilities are available to wash and dry clothing.³³ The use of oral ivermectin and permethrin-impregnated underwear both have been proposed.^34,35 Treatment of pediculosis capitis may be accomplished with a variety of topical pediculicides including permethrin, pyrethrum with piperonyl butoxide, dimethicone, malathion, benzyl alcohol, spinosad, and topical ivermectin.²² Topical corticosteroids or emollients may be employed for residual pruritus.

Equally important is environmental elimination of infestation. Clothing should be discarded if possible or washed and dried using high heat. If neither approach is possible or appropriate, clothing may be sealed in a plastic bag for 2 weeks or treated with a pediculicide. Nit combing is an important adjunct in the treatment of pediculosis capitis.³⁶ It is important to encourage return to work and/or school immediately after treatment. “No nit” policies are more harmful to education than helpful for prevention of investation.³⁷

Pediculosis corporis may transmit infectious agents including Bartonella quintana, (trench fever, endocarditis, bacillary angiomatosis), Borrelia recurrentis (louse-borne relapsing fever), and Rickettsia prowazekii (epidemic typhus).^31,38,39 Additionally, severe pediculosis infestations have the potential to cause chronic blood loss in affected populations. In a study of patients with active pediculosis infestation, mean hemoglobin values were found to be 2.5 g/dL lower than a matched population without infestation.⁴⁰ It is important to consider pediculosis as a risk for iron-deficiency anemia in populations who are known to lack access to regular medical evaluation.⁴¹

Future Considerations

Increased access to tools and education for clinicians treating refugee populations is key to reducing the burden of parasitic skin disease and related morbidity and mortality in vulnerable groups both domestically and globally. One such tool, the Skin NTDs App, was launched by the World Health Organization in 2020. It is available for free for Android and iOS devices to assist clinicians in the field with the diagnosis and treatment of neglected tropical diseases—including scabies—that may affect refugee populations.⁴²

Additionally, to both improve access and limit preventable sequelae, future investigations into appropriate models of community-based care are paramount. The model of community-based care is centered on the idea of care provision that prioritizes safety, accessibility, affordability, and acceptability in an environment closest to vulnerable populations. The largest dermatologic society, the International League of Dermatological Societies, formed a Migrant Health Dermatology Working Group that prioritizes understanding and improving care for refugee and migrant populations; this group hosted a summit in 2022, bringing together international subject matter leaders to discuss such models of care and set goals for the creation of tool kits for patients, frontline health care workers, and dermatologists.⁴³

Conclusion

Improvement in dermatologic care of refugee populations includes provision of culturally and linguistically appropriate care by trained clinicians, adequate access to the most essential medications, and basic physical or legal access to health care systems in general.^8,11,44 Parasitic infestations have the potential to remain asymptomatic for extended periods of time and result in spread to potentially nonendemic regions of resettlement.⁴⁵ Additionally, the psychosocial well-being of refugee populations upon resettlement may be negatively affected by stigma of disease processes such as scabies and pediculosis, leading to additional barriers to successful re-entry into the patient’s new environment.⁴⁶ Therefore, proper screening, diagnosis, and treatment of the most common parasitic infestations in this population have great potential to improve outcomes for large groups across the globe.

Approximately 108 million individuals have been forcibly displaced across the globe as of 2022, 35 million of whom are formally designated as refugees.^1,2 The United States has coordinated resettlement of more refugee populations than any other country; the most common countries of origin are the Democratic Republic of the Congo, Syria, Afghanistan, and Myanmar.³ In 2021, policy to increase the number of refugees resettled in the United States by more than 700% (from 15,000 up to 125,000) was established; since enactment, the United States has seen more than double the refugee arrivals in 2023 than the prior year, making medical care for this population increasingly relevant for the dermatologist.⁴

Understanding how to care for this population begins with an accurate understanding of the term refugee. The United Nations defines a refugee as a person who is unwilling or unable to return to their country of nationality because of persecution or well-founded fear of persecution due to race, religion, nationality, membership in a particular social group, or political opinion. This term grants a protected status under international law and encompasses access to travel assistance, housing, cultural orientation, and medical evaluation upon resettlement.^5,6

The burden of treatable dermatologic conditions in refugee populations ranges from 19% to 96% in the literature^7,8 and varies from inflammatory disorders to infectious and parasitic diseases.⁹ In one study of 6899 displaced individuals in Greece, the prevalence of dermatologic conditions was higher than traumatic injury, cardiac disease, psychological conditions, and dental disease.¹⁰

When outlining differential diagnoses for parasitic infestations of the skin that affect refugee populations, helpful considerations include the individual’s country of origin, route traveled, and method of travel.¹¹ Parasitic infestations specifically are more common in refugee populations when there are barriers to basic hygiene, crowded living or travel conditions, or lack of access to health care, which they may experience at any point in their home country, during travel, or in resettlement housing.⁸

Even with limited examination and diagnostic resources, the skin is the most accessible first indication of patients’ overall well-being and often provides simple diagnostic clues—in combination with contextualization of the patient’s unique circumstances—necessary for successful diagnosis and treatment of scabies and pediculosis.¹² The dermatologist working with refugee populations may be the first set of eyes available and trained to discern skin infestations and therefore has the potential to improve overall outcomes.

Some parasitic infestations in refugee populations may fall under the category of neglected tropical diseases, including scabies, ascariasis, trypanosomiasis, leishmaniasis, and schistosomiasis; they affect an estimated 1 billion individuals across the globe but historically have been underrepresented in the literature and in health policy due in part to limited access to care.¹³ This review will focus on infestations by the scabies mite (Sarcoptes scabiei var hominis) and the human louse, as these frequently are encountered, easily diagnosed, and treatable by trained clinicians, even in resource-limited settings.

Scabies

Scabies is a parasitic skin infestation caused by the 8-legged mite Sarcoptes scabiei var hominis. The female mite begins the infestation process via penetration of the epidermis, particularly the stratum corneum, and commences laying eggs (Figure 1). The subsequent larvae emerge 48 to 72 hours later and remain burrowed in the epidermis. The larvae mature over the next 10 to 14 days and continue the reproductive cycle.^14,15 Symptoms of infestation occurs due to a hypersensitivity reaction to the mite and its by-products.¹⁶ Transmission of the mite primarily occurs via direct (skin-to-skin) contact with infected individuals or environmental surfaces for 24 to36 hours in specific conditions, though the latter source has been debated in the literature.

The method of transmission is particularly important when considering care for refugee populations. Scabies is found most often in those living in or traveling from tropical regions including East Asia, Southeast Asia, Oceania, and Latin America.¹⁷ In displaced or refugee populations, a lack of access to basic hygiene, extended travel in close quarters, and suboptimal health care access all may lead to an increased incidence of untreated scabies infestations.¹⁸ Scabies is more prevalent in children, with increased potential for secondary bacterial infections with Streptococcus and Staphylococcus species due to excoriation in unsanitary conditions. Secondary infection with Streptococcus pyogenes can lead to acute poststreptococcal glomerulonephritis, which accounts for a large burden of chronic kidney disease in affected populations.¹⁹ However, scabies may be found in any population, regardless of hygiene or health care access. Treating health care providers should keep a broad differential.

Presentation—The latency of scabies symptoms is 2 to 6 weeks in a primary outbreak and may be as short as 1 to 3 days with re-infestation, following the course of delayed-type hypersensitivity.²⁰ The initial hallmark symptom is pruritus with increased severity in the evening. Visible lesions, excoriations, and burrows associated with scattered vesicles or pustules may be seen over the web spaces of the hands and feet, volar surfaces of the wrists, axillae, waist, genitalia, inner thighs, or buttocks.¹⁹ Chronic infestation often manifests with genital nodules. In populations with limited access to health care, there are reports of a sensitization phenomenon in which the individual may become less symptomatic after 4 to 6 weeks and yet be a potential carrier of the mite.²¹

Those with compromised immune function, such as individuals living with HIV or severe malnutrition, may present with crusted scabies, a variant that manifests as widespread hyperkeratotic scaling with more pronounced involvement of the head, neck, and acral areas. In contrast to classic scabies, crusted scabies is associated with minimal pruritus.²²

Diagnosis—The diagnosis of scabies is largely clinical with confirmation through skin scrapings. The International Alliance for Control of Scabies has established diagnostic criteria that include a combination of clinical findings, history, and visualization of mites.²³ A dermatologist working with refugee populations may employ any combination of history (eg, nocturnal itch, exposure to an affected individual) or clinical findings along with a high degree of suspicion in those with elevated risk. Visualization of mites is helpful to confirm the diagnosis and may be completed with the application of mineral oil at the terminal end of a burrow, skin scraping with a surgical blade or needle, and examination under light microscopy.

Treatment—First-line treatment for scabies consists of application of permethrin cream 5% on the skin of the neck to the soles of the feet, which is to be left on for 8 to 14 hours followed by rinsing. Re-application is recommended in 1 to 2 weeks. Oral ivermectin is a reasonable alternative to permethrin cream due to its low cost and easy administration in large affected groups. It is not labeled for use in pregnant women or children weighing less than 15 kg but has no selective fetal toxicity. Treatment of scabies with ivermectin has the benefit of treating many other parasitic infections. Both medications are on the World Health Organization Model List of Essential Medications and are widely available for treating providers, even in resource-limited settings.²⁴

Much of the world still uses benzyl benzoate or precipitated sulfur ointment to treat scabies, and some botanicals used in folk medicine have genuine antiscabetic properties. Pruritus may persist for 1 to 4 weeks following treatment and does not indicate treatment failure. Topical camphor and menthol preparations, low-potency topical corticosteroids, or emollients all may be employed for relief.²⁵Sarna is a Spanish term for scabies and has become the proprietary name for topical antipruritic agents. Additional methods of treatment and prevention include washing clothes and linens in hot water and drying on high heat. If machine washing is not available, clothing and linens may be sealed in a plastic bag for 72 hours.

Pediculosis

Pediculosis is an infestation caused by the ectoparasite Pediculus humanus, an obligate, sesame seed–sized louse that feeds exclusively on the blood of its host (Figure 2).²⁶ Of the lice species, 2 require humans as hosts; one is P humanus and the other is Pthirus pubis (pubic lice). Pediculus humanus may be further classified into morphologies based largely on the affected area: body (P humanus corporis) or head (P humanus capitis), both of which will be discussed.²⁷

Lice primarily attach to clothing and hair shafts, then transfer to the skin for blood feeds. Females lay eggs that hatch 6 to 10 days later, subsequently maturing into adults. The lifespan of these parasites with regular access to a host is 1 to 3 months for head lice and 18 days for body lice vs only 3 to 5 days without a host.²⁸ Transmission of P humanus capitis primarily occurs via direct contact with affected individuals, either head-to-head contact or sharing of items such as brushes and headscarves; P humanus corporis also may be transmitted via direct contact with affected individuals or clothing.

Pediculosis is an important infestation to consider when providing care for refugee populations. Risk factors include lack of access to basic hygiene, including regular bathing or laundering of clothing, and crowded conditions that make direct person-to-person contact with affected individuals more likely.²⁹ Body lice are associated more often with domestic turbulence and displaced populations³⁰ in comparison to head lice, which have broad demographic variables, most often affecting females and children.²⁸ Fatty acids in adult male sebum make the scalp less hospitable to lice.

Presentation—The most common clinical manifestation of pediculosis is pruritus. Cutaneous findings can include papules, wheals, or hemorrhagic puncta secondary to the louse bite. Due to the Tyndall effect of deep hemosiderin pigment, blue-grey macules termed maculae ceruleae (Figure 3) also may be present in chronic infestations of pediculosis pubis, in contrast to pediculosis capitis or corporis.³¹ Body louse infestation is associated with a general pruritus concentrated on the neck, shoulders, and waist—areas where clothing makes the most direct contact. Lesions may be visible and include eczematous patches with excoriation and possible secondary bacterial infection. Chronic infestation may exhibit lichenification or hyperpigmentation in associated areas. Head lice most often manifest with localized scalp pruritus and associated excoriation and cervical or occipital lymphadenopathy.³²

Diagnosis—The diagnosis of pediculosis is clinical, with confirmation requiring direct examination of the insect or nits (the egg case of the parasite)(Figure 4). Body lice and associated nits can be visualized on clothing seams near areas of highest body temperature, particularly the waistband. Head lice may be visualized crawling on hair shafts or on a louse comb. Nits are firmly attached to hair shafts and are visible to the naked eye, whereas pseudonits slide freely along the hair shaft and are not a manifestation of louse infestation (Figure 5).³¹

Treatment—Treatment varies by affected area. Pediculosis corporis may be treated with permethrin cream 5% applied to the entire body and left on for 8 to 10 hours, but this may not be necessary if facilities are available to wash and dry clothing.³³ The use of oral ivermectin and permethrin-impregnated underwear both have been proposed.^34,35 Treatment of pediculosis capitis may be accomplished with a variety of topical pediculicides including permethrin, pyrethrum with piperonyl butoxide, dimethicone, malathion, benzyl alcohol, spinosad, and topical ivermectin.²² Topical corticosteroids or emollients may be employed for residual pruritus.

Equally important is environmental elimination of infestation. Clothing should be discarded if possible or washed and dried using high heat. If neither approach is possible or appropriate, clothing may be sealed in a plastic bag for 2 weeks or treated with a pediculicide. Nit combing is an important adjunct in the treatment of pediculosis capitis.³⁶ It is important to encourage return to work and/or school immediately after treatment. “No nit” policies are more harmful to education than helpful for prevention of investation.³⁷

Pediculosis corporis may transmit infectious agents including Bartonella quintana, (trench fever, endocarditis, bacillary angiomatosis), Borrelia recurrentis (louse-borne relapsing fever), and Rickettsia prowazekii (epidemic typhus).^31,38,39 Additionally, severe pediculosis infestations have the potential to cause chronic blood loss in affected populations. In a study of patients with active pediculosis infestation, mean hemoglobin values were found to be 2.5 g/dL lower than a matched population without infestation.⁴⁰ It is important to consider pediculosis as a risk for iron-deficiency anemia in populations who are known to lack access to regular medical evaluation.⁴¹

Future Considerations

Increased access to tools and education for clinicians treating refugee populations is key to reducing the burden of parasitic skin disease and related morbidity and mortality in vulnerable groups both domestically and globally. One such tool, the Skin NTDs App, was launched by the World Health Organization in 2020. It is available for free for Android and iOS devices to assist clinicians in the field with the diagnosis and treatment of neglected tropical diseases—including scabies—that may affect refugee populations.⁴²

Additionally, to both improve access and limit preventable sequelae, future investigations into appropriate models of community-based care are paramount. The model of community-based care is centered on the idea of care provision that prioritizes safety, accessibility, affordability, and acceptability in an environment closest to vulnerable populations. The largest dermatologic society, the International League of Dermatological Societies, formed a Migrant Health Dermatology Working Group that prioritizes understanding and improving care for refugee and migrant populations; this group hosted a summit in 2022, bringing together international subject matter leaders to discuss such models of care and set goals for the creation of tool kits for patients, frontline health care workers, and dermatologists.⁴³

Conclusion

Improvement in dermatologic care of refugee populations includes provision of culturally and linguistically appropriate care by trained clinicians, adequate access to the most essential medications, and basic physical or legal access to health care systems in general.^8,11,44 Parasitic infestations have the potential to remain asymptomatic for extended periods of time and result in spread to potentially nonendemic regions of resettlement.⁴⁵ Additionally, the psychosocial well-being of refugee populations upon resettlement may be negatively affected by stigma of disease processes such as scabies and pediculosis, leading to additional barriers to successful re-entry into the patient’s new environment.⁴⁶ Therefore, proper screening, diagnosis, and treatment of the most common parasitic infestations in this population have great potential to improve outcomes for large groups across the globe.

Approximately 108 million individuals have been forcibly displaced across the globe as of 2022, 35 million of whom are formally designated as refugees.^1,2 The United States has coordinated resettlement of more refugee populations than any other country; the most common countries of origin are the Democratic Republic of the Congo, Syria, Afghanistan, and Myanmar.³ In 2021, policy to increase the number of refugees resettled in the United States by more than 700% (from 15,000 up to 125,000) was established; since enactment, the United States has seen more than double the refugee arrivals in 2023 than the prior year, making medical care for this population increasingly relevant for the dermatologist.⁴

Understanding how to care for this population begins with an accurate understanding of the term refugee. The United Nations defines a refugee as a person who is unwilling or unable to return to their country of nationality because of persecution or well-founded fear of persecution due to race, religion, nationality, membership in a particular social group, or political opinion. This term grants a protected status under international law and encompasses access to travel assistance, housing, cultural orientation, and medical evaluation upon resettlement.^5,6

The burden of treatable dermatologic conditions in refugee populations ranges from 19% to 96% in the literature^7,8 and varies from inflammatory disorders to infectious and parasitic diseases.⁹ In one study of 6899 displaced individuals in Greece, the prevalence of dermatologic conditions was higher than traumatic injury, cardiac disease, psychological conditions, and dental disease.¹⁰

When outlining differential diagnoses for parasitic infestations of the skin that affect refugee populations, helpful considerations include the individual’s country of origin, route traveled, and method of travel.¹¹ Parasitic infestations specifically are more common in refugee populations when there are barriers to basic hygiene, crowded living or travel conditions, or lack of access to health care, which they may experience at any point in their home country, during travel, or in resettlement housing.⁸

Even with limited examination and diagnostic resources, the skin is the most accessible first indication of patients’ overall well-being and often provides simple diagnostic clues—in combination with contextualization of the patient’s unique circumstances—necessary for successful diagnosis and treatment of scabies and pediculosis.¹² The dermatologist working with refugee populations may be the first set of eyes available and trained to discern skin infestations and therefore has the potential to improve overall outcomes.

Some parasitic infestations in refugee populations may fall under the category of neglected tropical diseases, including scabies, ascariasis, trypanosomiasis, leishmaniasis, and schistosomiasis; they affect an estimated 1 billion individuals across the globe but historically have been underrepresented in the literature and in health policy due in part to limited access to care.¹³ This review will focus on infestations by the scabies mite (Sarcoptes scabiei var hominis) and the human louse, as these frequently are encountered, easily diagnosed, and treatable by trained clinicians, even in resource-limited settings.

Scabies

Scabies is a parasitic skin infestation caused by the 8-legged mite Sarcoptes scabiei var hominis. The female mite begins the infestation process via penetration of the epidermis, particularly the stratum corneum, and commences laying eggs (Figure 1). The subsequent larvae emerge 48 to 72 hours later and remain burrowed in the epidermis. The larvae mature over the next 10 to 14 days and continue the reproductive cycle.^14,15 Symptoms of infestation occurs due to a hypersensitivity reaction to the mite and its by-products.¹⁶ Transmission of the mite primarily occurs via direct (skin-to-skin) contact with infected individuals or environmental surfaces for 24 to36 hours in specific conditions, though the latter source has been debated in the literature.

The method of transmission is particularly important when considering care for refugee populations. Scabies is found most often in those living in or traveling from tropical regions including East Asia, Southeast Asia, Oceania, and Latin America.¹⁷ In displaced or refugee populations, a lack of access to basic hygiene, extended travel in close quarters, and suboptimal health care access all may lead to an increased incidence of untreated scabies infestations.¹⁸ Scabies is more prevalent in children, with increased potential for secondary bacterial infections with Streptococcus and Staphylococcus species due to excoriation in unsanitary conditions. Secondary infection with Streptococcus pyogenes can lead to acute poststreptococcal glomerulonephritis, which accounts for a large burden of chronic kidney disease in affected populations.¹⁹ However, scabies may be found in any population, regardless of hygiene or health care access. Treating health care providers should keep a broad differential.

Presentation—The latency of scabies symptoms is 2 to 6 weeks in a primary outbreak and may be as short as 1 to 3 days with re-infestation, following the course of delayed-type hypersensitivity.²⁰ The initial hallmark symptom is pruritus with increased severity in the evening. Visible lesions, excoriations, and burrows associated with scattered vesicles or pustules may be seen over the web spaces of the hands and feet, volar surfaces of the wrists, axillae, waist, genitalia, inner thighs, or buttocks.¹⁹ Chronic infestation often manifests with genital nodules. In populations with limited access to health care, there are reports of a sensitization phenomenon in which the individual may become less symptomatic after 4 to 6 weeks and yet be a potential carrier of the mite.²¹

Those with compromised immune function, such as individuals living with HIV or severe malnutrition, may present with crusted scabies, a variant that manifests as widespread hyperkeratotic scaling with more pronounced involvement of the head, neck, and acral areas. In contrast to classic scabies, crusted scabies is associated with minimal pruritus.²²

Diagnosis—The diagnosis of scabies is largely clinical with confirmation through skin scrapings. The International Alliance for Control of Scabies has established diagnostic criteria that include a combination of clinical findings, history, and visualization of mites.²³ A dermatologist working with refugee populations may employ any combination of history (eg, nocturnal itch, exposure to an affected individual) or clinical findings along with a high degree of suspicion in those with elevated risk. Visualization of mites is helpful to confirm the diagnosis and may be completed with the application of mineral oil at the terminal end of a burrow, skin scraping with a surgical blade or needle, and examination under light microscopy.

Treatment—First-line treatment for scabies consists of application of permethrin cream 5% on the skin of the neck to the soles of the feet, which is to be left on for 8 to 14 hours followed by rinsing. Re-application is recommended in 1 to 2 weeks. Oral ivermectin is a reasonable alternative to permethrin cream due to its low cost and easy administration in large affected groups. It is not labeled for use in pregnant women or children weighing less than 15 kg but has no selective fetal toxicity. Treatment of scabies with ivermectin has the benefit of treating many other parasitic infections. Both medications are on the World Health Organization Model List of Essential Medications and are widely available for treating providers, even in resource-limited settings.²⁴

Much of the world still uses benzyl benzoate or precipitated sulfur ointment to treat scabies, and some botanicals used in folk medicine have genuine antiscabetic properties. Pruritus may persist for 1 to 4 weeks following treatment and does not indicate treatment failure. Topical camphor and menthol preparations, low-potency topical corticosteroids, or emollients all may be employed for relief.²⁵Sarna is a Spanish term for scabies and has become the proprietary name for topical antipruritic agents. Additional methods of treatment and prevention include washing clothes and linens in hot water and drying on high heat. If machine washing is not available, clothing and linens may be sealed in a plastic bag for 72 hours.

Pediculosis

Pediculosis is an infestation caused by the ectoparasite Pediculus humanus, an obligate, sesame seed–sized louse that feeds exclusively on the blood of its host (Figure 2).²⁶ Of the lice species, 2 require humans as hosts; one is P humanus and the other is Pthirus pubis (pubic lice). Pediculus humanus may be further classified into morphologies based largely on the affected area: body (P humanus corporis) or head (P humanus capitis), both of which will be discussed.²⁷

Lice primarily attach to clothing and hair shafts, then transfer to the skin for blood feeds. Females lay eggs that hatch 6 to 10 days later, subsequently maturing into adults. The lifespan of these parasites with regular access to a host is 1 to 3 months for head lice and 18 days for body lice vs only 3 to 5 days without a host.²⁸ Transmission of P humanus capitis primarily occurs via direct contact with affected individuals, either head-to-head contact or sharing of items such as brushes and headscarves; P humanus corporis also may be transmitted via direct contact with affected individuals or clothing.

Pediculosis is an important infestation to consider when providing care for refugee populations. Risk factors include lack of access to basic hygiene, including regular bathing or laundering of clothing, and crowded conditions that make direct person-to-person contact with affected individuals more likely.²⁹ Body lice are associated more often with domestic turbulence and displaced populations³⁰ in comparison to head lice, which have broad demographic variables, most often affecting females and children.²⁸ Fatty acids in adult male sebum make the scalp less hospitable to lice.

Presentation—The most common clinical manifestation of pediculosis is pruritus. Cutaneous findings can include papules, wheals, or hemorrhagic puncta secondary to the louse bite. Due to the Tyndall effect of deep hemosiderin pigment, blue-grey macules termed maculae ceruleae (Figure 3) also may be present in chronic infestations of pediculosis pubis, in contrast to pediculosis capitis or corporis.³¹ Body louse infestation is associated with a general pruritus concentrated on the neck, shoulders, and waist—areas where clothing makes the most direct contact. Lesions may be visible and include eczematous patches with excoriation and possible secondary bacterial infection. Chronic infestation may exhibit lichenification or hyperpigmentation in associated areas. Head lice most often manifest with localized scalp pruritus and associated excoriation and cervical or occipital lymphadenopathy.³²

Diagnosis—The diagnosis of pediculosis is clinical, with confirmation requiring direct examination of the insect or nits (the egg case of the parasite)(Figure 4). Body lice and associated nits can be visualized on clothing seams near areas of highest body temperature, particularly the waistband. Head lice may be visualized crawling on hair shafts or on a louse comb. Nits are firmly attached to hair shafts and are visible to the naked eye, whereas pseudonits slide freely along the hair shaft and are not a manifestation of louse infestation (Figure 5).³¹

Treatment—Treatment varies by affected area. Pediculosis corporis may be treated with permethrin cream 5% applied to the entire body and left on for 8 to 10 hours, but this may not be necessary if facilities are available to wash and dry clothing.³³ The use of oral ivermectin and permethrin-impregnated underwear both have been proposed.^34,35 Treatment of pediculosis capitis may be accomplished with a variety of topical pediculicides including permethrin, pyrethrum with piperonyl butoxide, dimethicone, malathion, benzyl alcohol, spinosad, and topical ivermectin.²² Topical corticosteroids or emollients may be employed for residual pruritus.

Equally important is environmental elimination of infestation. Clothing should be discarded if possible or washed and dried using high heat. If neither approach is possible or appropriate, clothing may be sealed in a plastic bag for 2 weeks or treated with a pediculicide. Nit combing is an important adjunct in the treatment of pediculosis capitis.³⁶ It is important to encourage return to work and/or school immediately after treatment. “No nit” policies are more harmful to education than helpful for prevention of investation.³⁷

Pediculosis corporis may transmit infectious agents including Bartonella quintana, (trench fever, endocarditis, bacillary angiomatosis), Borrelia recurrentis (louse-borne relapsing fever), and Rickettsia prowazekii (epidemic typhus).^31,38,39 Additionally, severe pediculosis infestations have the potential to cause chronic blood loss in affected populations. In a study of patients with active pediculosis infestation, mean hemoglobin values were found to be 2.5 g/dL lower than a matched population without infestation.⁴⁰ It is important to consider pediculosis as a risk for iron-deficiency anemia in populations who are known to lack access to regular medical evaluation.⁴¹

Future Considerations

Increased access to tools and education for clinicians treating refugee populations is key to reducing the burden of parasitic skin disease and related morbidity and mortality in vulnerable groups both domestically and globally. One such tool, the Skin NTDs App, was launched by the World Health Organization in 2020. It is available for free for Android and iOS devices to assist clinicians in the field with the diagnosis and treatment of neglected tropical diseases—including scabies—that may affect refugee populations.⁴²

Additionally, to both improve access and limit preventable sequelae, future investigations into appropriate models of community-based care are paramount. The model of community-based care is centered on the idea of care provision that prioritizes safety, accessibility, affordability, and acceptability in an environment closest to vulnerable populations. The largest dermatologic society, the International League of Dermatological Societies, formed a Migrant Health Dermatology Working Group that prioritizes understanding and improving care for refugee and migrant populations; this group hosted a summit in 2022, bringing together international subject matter leaders to discuss such models of care and set goals for the creation of tool kits for patients, frontline health care workers, and dermatologists.⁴³

Conclusion

Improvement in dermatologic care of refugee populations includes provision of culturally and linguistically appropriate care by trained clinicians, adequate access to the most essential medications, and basic physical or legal access to health care systems in general.^8,11,44 Parasitic infestations have the potential to remain asymptomatic for extended periods of time and result in spread to potentially nonendemic regions of resettlement.⁴⁵ Additionally, the psychosocial well-being of refugee populations upon resettlement may be negatively affected by stigma of disease processes such as scabies and pediculosis, leading to additional barriers to successful re-entry into the patient’s new environment.⁴⁶ Therefore, proper screening, diagnosis, and treatment of the most common parasitic infestations in this population have great potential to improve outcomes for large groups across the globe.

Plant Parts and Nomenclature

Ficus carica (common fig) is a deciduous shrub or small tree with smooth gray bark that can grow up to 10 m in height (Figure 1). It is characterized by many spreading branches, but the trunk rarely grows beyond a diameter of 7 in. Its hairy leaves are coarse on the upper side and soft underneath with 3 to 7 deep lobes that can extend up to 25 cm in length or width; the leaves grow individually, alternating along the sides of the branches. Fig trees often can be seen adorning yards, gardens, and parks, especially in tropical and subtropical climates. Ficus carica should not be confused with Ficus benjamina (weeping fig), a common ornamental tree that also is used to provide shade in hot climates, though both can cause phototoxic skin eruptions.

The common fig tree originated in the Mediterranean and western Asia¹ and has been cultivated by humans since the second and third millennia bc for its fruit, which commonly is used to sweeten cookies, cakes, and jams.² Figs are the most commonly mentioned food plant in the Bible, with at least 56 references in the Old and New Testaments.³ The “fruit” technically is a syconium—a hollow fleshy receptacle with a small opening at the apex partly closed by small scales. It can be obovoid, turbinate, or pear shaped; can be 1 to 4 inches long; and can vary in color from yellowish green to coppery, bronze, or dark purple (Figure 2).

Ficus carica is a member of the Moraceae family (derived from the Latin name for the mulberry tree), which includes 53 genera and approximately 1400 species, of which about 850 belong to the genus Ficus (the Latin name for a fig tree). The term carica likely comes from the Latin word carricare (to load) to describe a tree loaded with figs. Family members include trees, shrubs, lianas, and herbs that usually contain laticifers with a milky latex.

Traditional Uses

For centuries, components of the fig tree have been used in herbal teas and pastes to treat ailments ranging from sore throats to diarrhea, though there is no evidence to support their efficacy.⁴ Ancient Indians and Egyptians used plants such as the common fig tree containing furocoumarins to induce hyperpigmentation in vitiligo.⁵

Phototoxic Components

The leaves and sap of the common fig tree contain psoralens, which are members of the furocoumarin group of chemical compounds and are the source of its phototoxicity. The fruit does not contain psoralens.^6-9 The tree also produces proteolytic enzymes such as protease, amylase, ficin, triterpenoids, and lipodiastase that enhance its phototoxic effects.⁸ Exposure to UV light between 320 and 400 nm following contact with these phototoxic components triggers a reaction in the skin over the course of 1 to 3 days.⁵ The psoralens bind in epidermal cells, cross-link the DNA, and cause cell-membrane destruction, leading to edema and necrosis.¹⁰ The delay in symptoms may be attributed to the time needed to synthesize acute-phase reaction proteins such as tumor necrosis factor α and IL-1.¹¹ In spring and summer months, an increased concentration of psoralens in the leaves and sap contribute to an increased incidence of phytophotodermatitis.⁹ Humidity and sweat also increase the percutaneous absorption of psoralens.^12,13

Allergens

Fig trees produce a latex protein that can cause cross-reactive hypersensitivity reactions in those allergic to F benjamina latex and rubber latex.⁶ The latex proteins in fig trees can act as airborne respiratory allergens. Ingestion of figs can produce anaphylactic reactions in those sensitized to rubber latex and F benjamina latex.⁷ Other plant families associated with phototoxic reactions include Rutaceae (lemon, lime, bitter orange), Apiaceae (formerly Umbelliferae)(carrot, parsnip, parsley, dill, celery, hogweed), and Fabaceae (prairie turnip).

Most cases of fig phytophotodermatitis begin with burning, pain, and/or itching within hours of sunlight exposure in areas of the skin that encountered components of the fig tree, often in a linear pattern. The affected areas become erythematous and edematous with formation of bullae and unilocular vesicles over the course of 1 to 3 days.^12,14,15 Lesions may extend beyond the region of contact with the fig tree as they spread across the skin due to sweat or friction, and pain may linger even after the lesions resolve.^12,13,16 Adults who handle fig trees (eg, pruning) are susceptible to phototoxic reactions, especially those using chain saws or other mechanisms that result in spray exposure, as the photosensitizing sap permeates the wood and bark of the entire tree.¹⁷ Similarly, children who handle fig leaves or sap during outdoor play can develop bullous eruptions. Severe cases have resulted in hospital admission after prolonged exposure.¹⁶ Additionally, irritant dermatitis may arise from contact with the trichomes or “hairs” on various parts of the plant.

Image provided with permission by Scott Norton, MD, MPH, MSc (Washington, DC).

Patients who use natural remedies containing components of the fig tree without the supervision of a medical provider put themselves at risk for unsafe or unwanted adverse effects, such as phytophotodermatitis.^12,15,16,18 An entire family presented with burns after they applied fig leaf extract to the skin prior to tanning outside in the sun.¹⁹ A 42-year-old woman acquired a severe burn covering 81% of the body surface after topically applying fig leaf tea to the skin as a tanning agent.²⁰ A subset of patients ingesting or applying fig tree components for conditions such as vitiligo, dermatitis, onychomycosis, and motor retardation developed similar cutaneous reactions.^13,14,21,22 Lesions resembling finger marks can raise concerns for potential abuse or neglect in children.²²

The differential diagnosis for fig phytophotodermatitis includes sunburn, chemical burns, drug-related photosensitivity, infectious lesions (eg, herpes simplex, bullous impetigo, Lyme disease, superficial lymphangitis), connective tissue disease (eg, systemic lupus erythematosus), contact dermatitis, and nonaccidental trauma.^12,15,18 Compared to sunburn, phytophotodermatitis tends to increase in severity over days following exposure and heals with dramatic hyperpigmentation, which also prompts visits to dermatology.¹²

Treatment

Treatment of fig phytophotodermatitis chiefly is symptomatic, including analgesia, appropriate wound care, and infection prophylaxis. Topical and systemic corticosteroids may aid in the resolution of moderate to severe reactions.^15,23,24 Even severe injuries over small areas or mild injuries to a high percentage of the total body surface area may require treatment in a burn unit. Patients should be encouraged to use mineral-based sunscreens on the affected areas to reduce the risk for hyperpigmentation. Individuals who regularly handle fig trees should use contact barriers including gloves and protective clothing (eg, long-sleeved shirts, long pants).

Plant Parts and Nomenclature

Ficus carica (common fig) is a deciduous shrub or small tree with smooth gray bark that can grow up to 10 m in height (Figure 1). It is characterized by many spreading branches, but the trunk rarely grows beyond a diameter of 7 in. Its hairy leaves are coarse on the upper side and soft underneath with 3 to 7 deep lobes that can extend up to 25 cm in length or width; the leaves grow individually, alternating along the sides of the branches. Fig trees often can be seen adorning yards, gardens, and parks, especially in tropical and subtropical climates. Ficus carica should not be confused with Ficus benjamina (weeping fig), a common ornamental tree that also is used to provide shade in hot climates, though both can cause phototoxic skin eruptions.

The common fig tree originated in the Mediterranean and western Asia¹ and has been cultivated by humans since the second and third millennia bc for its fruit, which commonly is used to sweeten cookies, cakes, and jams.² Figs are the most commonly mentioned food plant in the Bible, with at least 56 references in the Old and New Testaments.³ The “fruit” technically is a syconium—a hollow fleshy receptacle with a small opening at the apex partly closed by small scales. It can be obovoid, turbinate, or pear shaped; can be 1 to 4 inches long; and can vary in color from yellowish green to coppery, bronze, or dark purple (Figure 2).

Ficus carica is a member of the Moraceae family (derived from the Latin name for the mulberry tree), which includes 53 genera and approximately 1400 species, of which about 850 belong to the genus Ficus (the Latin name for a fig tree). The term carica likely comes from the Latin word carricare (to load) to describe a tree loaded with figs. Family members include trees, shrubs, lianas, and herbs that usually contain laticifers with a milky latex.

Traditional Uses

For centuries, components of the fig tree have been used in herbal teas and pastes to treat ailments ranging from sore throats to diarrhea, though there is no evidence to support their efficacy.⁴ Ancient Indians and Egyptians used plants such as the common fig tree containing furocoumarins to induce hyperpigmentation in vitiligo.⁵

Phototoxic Components

The leaves and sap of the common fig tree contain psoralens, which are members of the furocoumarin group of chemical compounds and are the source of its phototoxicity. The fruit does not contain psoralens.^6-9 The tree also produces proteolytic enzymes such as protease, amylase, ficin, triterpenoids, and lipodiastase that enhance its phototoxic effects.⁸ Exposure to UV light between 320 and 400 nm following contact with these phototoxic components triggers a reaction in the skin over the course of 1 to 3 days.⁵ The psoralens bind in epidermal cells, cross-link the DNA, and cause cell-membrane destruction, leading to edema and necrosis.¹⁰ The delay in symptoms may be attributed to the time needed to synthesize acute-phase reaction proteins such as tumor necrosis factor α and IL-1.¹¹ In spring and summer months, an increased concentration of psoralens in the leaves and sap contribute to an increased incidence of phytophotodermatitis.⁹ Humidity and sweat also increase the percutaneous absorption of psoralens.^12,13

Allergens

Fig trees produce a latex protein that can cause cross-reactive hypersensitivity reactions in those allergic to F benjamina latex and rubber latex.⁶ The latex proteins in fig trees can act as airborne respiratory allergens. Ingestion of figs can produce anaphylactic reactions in those sensitized to rubber latex and F benjamina latex.⁷ Other plant families associated with phototoxic reactions include Rutaceae (lemon, lime, bitter orange), Apiaceae (formerly Umbelliferae)(carrot, parsnip, parsley, dill, celery, hogweed), and Fabaceae (prairie turnip).

Most cases of fig phytophotodermatitis begin with burning, pain, and/or itching within hours of sunlight exposure in areas of the skin that encountered components of the fig tree, often in a linear pattern. The affected areas become erythematous and edematous with formation of bullae and unilocular vesicles over the course of 1 to 3 days.^12,14,15 Lesions may extend beyond the region of contact with the fig tree as they spread across the skin due to sweat or friction, and pain may linger even after the lesions resolve.^12,13,16 Adults who handle fig trees (eg, pruning) are susceptible to phototoxic reactions, especially those using chain saws or other mechanisms that result in spray exposure, as the photosensitizing sap permeates the wood and bark of the entire tree.¹⁷ Similarly, children who handle fig leaves or sap during outdoor play can develop bullous eruptions. Severe cases have resulted in hospital admission after prolonged exposure.¹⁶ Additionally, irritant dermatitis may arise from contact with the trichomes or “hairs” on various parts of the plant.

Image provided with permission by Scott Norton, MD, MPH, MSc (Washington, DC).

Patients who use natural remedies containing components of the fig tree without the supervision of a medical provider put themselves at risk for unsafe or unwanted adverse effects, such as phytophotodermatitis.^12,15,16,18 An entire family presented with burns after they applied fig leaf extract to the skin prior to tanning outside in the sun.¹⁹ A 42-year-old woman acquired a severe burn covering 81% of the body surface after topically applying fig leaf tea to the skin as a tanning agent.²⁰ A subset of patients ingesting or applying fig tree components for conditions such as vitiligo, dermatitis, onychomycosis, and motor retardation developed similar cutaneous reactions.^13,14,21,22 Lesions resembling finger marks can raise concerns for potential abuse or neglect in children.²²

The differential diagnosis for fig phytophotodermatitis includes sunburn, chemical burns, drug-related photosensitivity, infectious lesions (eg, herpes simplex, bullous impetigo, Lyme disease, superficial lymphangitis), connective tissue disease (eg, systemic lupus erythematosus), contact dermatitis, and nonaccidental trauma.^12,15,18 Compared to sunburn, phytophotodermatitis tends to increase in severity over days following exposure and heals with dramatic hyperpigmentation, which also prompts visits to dermatology.¹²

Treatment

Treatment of fig phytophotodermatitis chiefly is symptomatic, including analgesia, appropriate wound care, and infection prophylaxis. Topical and systemic corticosteroids may aid in the resolution of moderate to severe reactions.^15,23,24 Even severe injuries over small areas or mild injuries to a high percentage of the total body surface area may require treatment in a burn unit. Patients should be encouraged to use mineral-based sunscreens on the affected areas to reduce the risk for hyperpigmentation. Individuals who regularly handle fig trees should use contact barriers including gloves and protective clothing (eg, long-sleeved shirts, long pants).

Plant Parts and Nomenclature

Ficus carica (common fig) is a deciduous shrub or small tree with smooth gray bark that can grow up to 10 m in height (Figure 1). It is characterized by many spreading branches, but the trunk rarely grows beyond a diameter of 7 in. Its hairy leaves are coarse on the upper side and soft underneath with 3 to 7 deep lobes that can extend up to 25 cm in length or width; the leaves grow individually, alternating along the sides of the branches. Fig trees often can be seen adorning yards, gardens, and parks, especially in tropical and subtropical climates. Ficus carica should not be confused with Ficus benjamina (weeping fig), a common ornamental tree that also is used to provide shade in hot climates, though both can cause phototoxic skin eruptions.

The common fig tree originated in the Mediterranean and western Asia¹ and has been cultivated by humans since the second and third millennia bc for its fruit, which commonly is used to sweeten cookies, cakes, and jams.² Figs are the most commonly mentioned food plant in the Bible, with at least 56 references in the Old and New Testaments.³ The “fruit” technically is a syconium—a hollow fleshy receptacle with a small opening at the apex partly closed by small scales. It can be obovoid, turbinate, or pear shaped; can be 1 to 4 inches long; and can vary in color from yellowish green to coppery, bronze, or dark purple (Figure 2).

Ficus carica is a member of the Moraceae family (derived from the Latin name for the mulberry tree), which includes 53 genera and approximately 1400 species, of which about 850 belong to the genus Ficus (the Latin name for a fig tree). The term carica likely comes from the Latin word carricare (to load) to describe a tree loaded with figs. Family members include trees, shrubs, lianas, and herbs that usually contain laticifers with a milky latex.

Traditional Uses

For centuries, components of the fig tree have been used in herbal teas and pastes to treat ailments ranging from sore throats to diarrhea, though there is no evidence to support their efficacy.⁴ Ancient Indians and Egyptians used plants such as the common fig tree containing furocoumarins to induce hyperpigmentation in vitiligo.⁵

Phototoxic Components

The leaves and sap of the common fig tree contain psoralens, which are members of the furocoumarin group of chemical compounds and are the source of its phototoxicity. The fruit does not contain psoralens.^6-9 The tree also produces proteolytic enzymes such as protease, amylase, ficin, triterpenoids, and lipodiastase that enhance its phototoxic effects.⁸ Exposure to UV light between 320 and 400 nm following contact with these phototoxic components triggers a reaction in the skin over the course of 1 to 3 days.⁵ The psoralens bind in epidermal cells, cross-link the DNA, and cause cell-membrane destruction, leading to edema and necrosis.¹⁰ The delay in symptoms may be attributed to the time needed to synthesize acute-phase reaction proteins such as tumor necrosis factor α and IL-1.¹¹ In spring and summer months, an increased concentration of psoralens in the leaves and sap contribute to an increased incidence of phytophotodermatitis.⁹ Humidity and sweat also increase the percutaneous absorption of psoralens.^12,13

Allergens

Fig trees produce a latex protein that can cause cross-reactive hypersensitivity reactions in those allergic to F benjamina latex and rubber latex.⁶ The latex proteins in fig trees can act as airborne respiratory allergens. Ingestion of figs can produce anaphylactic reactions in those sensitized to rubber latex and F benjamina latex.⁷ Other plant families associated with phototoxic reactions include Rutaceae (lemon, lime, bitter orange), Apiaceae (formerly Umbelliferae)(carrot, parsnip, parsley, dill, celery, hogweed), and Fabaceae (prairie turnip).

Most cases of fig phytophotodermatitis begin with burning, pain, and/or itching within hours of sunlight exposure in areas of the skin that encountered components of the fig tree, often in a linear pattern. The affected areas become erythematous and edematous with formation of bullae and unilocular vesicles over the course of 1 to 3 days.^12,14,15 Lesions may extend beyond the region of contact with the fig tree as they spread across the skin due to sweat or friction, and pain may linger even after the lesions resolve.^12,13,16 Adults who handle fig trees (eg, pruning) are susceptible to phototoxic reactions, especially those using chain saws or other mechanisms that result in spray exposure, as the photosensitizing sap permeates the wood and bark of the entire tree.¹⁷ Similarly, children who handle fig leaves or sap during outdoor play can develop bullous eruptions. Severe cases have resulted in hospital admission after prolonged exposure.¹⁶ Additionally, irritant dermatitis may arise from contact with the trichomes or “hairs” on various parts of the plant.

Image provided with permission by Scott Norton, MD, MPH, MSc (Washington, DC).

Patients who use natural remedies containing components of the fig tree without the supervision of a medical provider put themselves at risk for unsafe or unwanted adverse effects, such as phytophotodermatitis.^12,15,16,18 An entire family presented with burns after they applied fig leaf extract to the skin prior to tanning outside in the sun.¹⁹ A 42-year-old woman acquired a severe burn covering 81% of the body surface after topically applying fig leaf tea to the skin as a tanning agent.²⁰ A subset of patients ingesting or applying fig tree components for conditions such as vitiligo, dermatitis, onychomycosis, and motor retardation developed similar cutaneous reactions.^13,14,21,22 Lesions resembling finger marks can raise concerns for potential abuse or neglect in children.²²

The differential diagnosis for fig phytophotodermatitis includes sunburn, chemical burns, drug-related photosensitivity, infectious lesions (eg, herpes simplex, bullous impetigo, Lyme disease, superficial lymphangitis), connective tissue disease (eg, systemic lupus erythematosus), contact dermatitis, and nonaccidental trauma.^12,15,18 Compared to sunburn, phytophotodermatitis tends to increase in severity over days following exposure and heals with dramatic hyperpigmentation, which also prompts visits to dermatology.¹²

Treatment

Treatment of fig phytophotodermatitis chiefly is symptomatic, including analgesia, appropriate wound care, and infection prophylaxis. Topical and systemic corticosteroids may aid in the resolution of moderate to severe reactions.^15,23,24 Even severe injuries over small areas or mild injuries to a high percentage of the total body surface area may require treatment in a burn unit. Patients should be encouraged to use mineral-based sunscreens on the affected areas to reduce the risk for hyperpigmentation. Individuals who regularly handle fig trees should use contact barriers including gloves and protective clothing (eg, long-sleeved shirts, long pants).