Cutis

The Diagnosis: Cutaneous Metaplastic Synovial Cyst 

Gross examination of the excised nodule revealed a 2.5×1.2×1.0-cm, intact, gray-white, thin-walled, smooth-lined nodule filled with clear mucinouslike material. Hematoxylin and eosin-stained sections demonstrated a dermal-based cystlike structure composed of a lining of connective tissue with hyalinized material and fibrin as well as spindle and epithelioid cells with a mild mixed inflammatory infiltrate (Figure). These histopathologic findings led to the diagnosis of cutaneous metaplastic synovial cyst (CMSC).  

Cutaneous metaplastic synovial cyst, also known as synovial metaplasia of the skin, is an uncommon benign cystic lesion that was first reported by Gonzalez et al¹ in 1987. Histologically, CMSC lacks an epithelial lining and therefore is not a true cyst but rather a pseudocyst.² Clinically, the lesion typically presents as a solitary subcutaneous nodule that may be tender or painless. In a literature review of CMSC cases performed by Fukuyama et al,³ distribution of reported cases according to body site varied; however, limbs were found to be the most commonly involved area. A PubMed search of articles indexed for MEDLINE as well as a Google Scholar search using the term cutaneous metaplastic synovial cyst revealed at least 37 cases reported in the English-language literature,^3-9 including our present case. The pathogenesis remains uncertain; however, a majority of previously reported cases of CMSC characteristically have been associated with a pre-existing lesion, with most presentations developing at surgical scar sites secondary to operation or trauma.⁵ Relative tissue fragility secondary to rheumatoid arthritis¹⁰ and Ehlers-Danlos syndrome^9,11,12 has been linked to CMSC in some documented reports, while a minority of cases report no antecedent events triggering formation of the lesion.^13-15 

As evidenced by our patient, CMSC clinically mimics several other benign entities; histopathologic examination is necessary to confirm the diagnosis. Although nodular hidradenoma also may clinically present as a solitary firm intradermal nodule, microscopy reveals a dermal-based lobulated tumor containing cystic spaces and solid areas composed of basophilic polyhedral cells and round glycogen-filled clear cells.¹⁶ Epidermoid cysts are differentiated from CMSC by the presence of a cyst wall lining composed of stratified squamous epithelium and associated laminated keratin within the lumen,¹⁷ which corresponds to its pearly white appearance on gross examination. Cutaneous ciliated cysts predominantly occur on the lower extremities of young women and are lined by simple cuboidal or columnar ciliated cells that resemble müllerian epithelium.¹⁸ Similar to CMSC, ganglion cysts are pseudocysts that lack a true epithelial lining but differ in appearance due to their mucin-filled synovial-lined sac.¹⁹ Additionally, ganglion cysts most often occur on the dorsal and volar aspects of the wrist. 

Excisional biopsy is indicated as the preferred treatment of CMSC, given the lesion's benign behavior and low recurrence rate.⁶ Our case highlights this rare entity and reinforces its inclusion in the differential diagnosis of subcutaneous mobile nodules, especially in the setting of prior tissue injury secondary to trauma, surgical procedures, or conditions such as rheumatoid arthritis or Ehlers-Danlos syndrome. Unlike most previously reported cases, our patient reported no preceding tissue injury associated with formation of the lesion, and she was largely asymptomatic on presentation. Considering the limited number of CMSC cases demonstrated in the literature, it is important to continue reporting new cases to better understand characteristics and presentations of this uncommon lesion. 

The Diagnosis: Cutaneous Metaplastic Synovial Cyst 

Gross examination of the excised nodule revealed a 2.5×1.2×1.0-cm, intact, gray-white, thin-walled, smooth-lined nodule filled with clear mucinouslike material. Hematoxylin and eosin-stained sections demonstrated a dermal-based cystlike structure composed of a lining of connective tissue with hyalinized material and fibrin as well as spindle and epithelioid cells with a mild mixed inflammatory infiltrate (Figure). These histopathologic findings led to the diagnosis of cutaneous metaplastic synovial cyst (CMSC).  

Cutaneous metaplastic synovial cyst, also known as synovial metaplasia of the skin, is an uncommon benign cystic lesion that was first reported by Gonzalez et al¹ in 1987. Histologically, CMSC lacks an epithelial lining and therefore is not a true cyst but rather a pseudocyst.² Clinically, the lesion typically presents as a solitary subcutaneous nodule that may be tender or painless. In a literature review of CMSC cases performed by Fukuyama et al,³ distribution of reported cases according to body site varied; however, limbs were found to be the most commonly involved area. A PubMed search of articles indexed for MEDLINE as well as a Google Scholar search using the term cutaneous metaplastic synovial cyst revealed at least 37 cases reported in the English-language literature,^3-9 including our present case. The pathogenesis remains uncertain; however, a majority of previously reported cases of CMSC characteristically have been associated with a pre-existing lesion, with most presentations developing at surgical scar sites secondary to operation or trauma.⁵ Relative tissue fragility secondary to rheumatoid arthritis¹⁰ and Ehlers-Danlos syndrome^9,11,12 has been linked to CMSC in some documented reports, while a minority of cases report no antecedent events triggering formation of the lesion.^13-15 

As evidenced by our patient, CMSC clinically mimics several other benign entities; histopathologic examination is necessary to confirm the diagnosis. Although nodular hidradenoma also may clinically present as a solitary firm intradermal nodule, microscopy reveals a dermal-based lobulated tumor containing cystic spaces and solid areas composed of basophilic polyhedral cells and round glycogen-filled clear cells.¹⁶ Epidermoid cysts are differentiated from CMSC by the presence of a cyst wall lining composed of stratified squamous epithelium and associated laminated keratin within the lumen,¹⁷ which corresponds to its pearly white appearance on gross examination. Cutaneous ciliated cysts predominantly occur on the lower extremities of young women and are lined by simple cuboidal or columnar ciliated cells that resemble müllerian epithelium.¹⁸ Similar to CMSC, ganglion cysts are pseudocysts that lack a true epithelial lining but differ in appearance due to their mucin-filled synovial-lined sac.¹⁹ Additionally, ganglion cysts most often occur on the dorsal and volar aspects of the wrist. 

Excisional biopsy is indicated as the preferred treatment of CMSC, given the lesion's benign behavior and low recurrence rate.⁶ Our case highlights this rare entity and reinforces its inclusion in the differential diagnosis of subcutaneous mobile nodules, especially in the setting of prior tissue injury secondary to trauma, surgical procedures, or conditions such as rheumatoid arthritis or Ehlers-Danlos syndrome. Unlike most previously reported cases, our patient reported no preceding tissue injury associated with formation of the lesion, and she was largely asymptomatic on presentation. Considering the limited number of CMSC cases demonstrated in the literature, it is important to continue reporting new cases to better understand characteristics and presentations of this uncommon lesion. 

The Diagnosis: Cutaneous Metaplastic Synovial Cyst 

Gross examination of the excised nodule revealed a 2.5×1.2×1.0-cm, intact, gray-white, thin-walled, smooth-lined nodule filled with clear mucinouslike material. Hematoxylin and eosin-stained sections demonstrated a dermal-based cystlike structure composed of a lining of connective tissue with hyalinized material and fibrin as well as spindle and epithelioid cells with a mild mixed inflammatory infiltrate (Figure). These histopathologic findings led to the diagnosis of cutaneous metaplastic synovial cyst (CMSC).  

Cutaneous metaplastic synovial cyst, also known as synovial metaplasia of the skin, is an uncommon benign cystic lesion that was first reported by Gonzalez et al¹ in 1987. Histologically, CMSC lacks an epithelial lining and therefore is not a true cyst but rather a pseudocyst.² Clinically, the lesion typically presents as a solitary subcutaneous nodule that may be tender or painless. In a literature review of CMSC cases performed by Fukuyama et al,³ distribution of reported cases according to body site varied; however, limbs were found to be the most commonly involved area. A PubMed search of articles indexed for MEDLINE as well as a Google Scholar search using the term cutaneous metaplastic synovial cyst revealed at least 37 cases reported in the English-language literature,^3-9 including our present case. The pathogenesis remains uncertain; however, a majority of previously reported cases of CMSC characteristically have been associated with a pre-existing lesion, with most presentations developing at surgical scar sites secondary to operation or trauma.⁵ Relative tissue fragility secondary to rheumatoid arthritis¹⁰ and Ehlers-Danlos syndrome^9,11,12 has been linked to CMSC in some documented reports, while a minority of cases report no antecedent events triggering formation of the lesion.^13-15 

As evidenced by our patient, CMSC clinically mimics several other benign entities; histopathologic examination is necessary to confirm the diagnosis. Although nodular hidradenoma also may clinically present as a solitary firm intradermal nodule, microscopy reveals a dermal-based lobulated tumor containing cystic spaces and solid areas composed of basophilic polyhedral cells and round glycogen-filled clear cells.¹⁶ Epidermoid cysts are differentiated from CMSC by the presence of a cyst wall lining composed of stratified squamous epithelium and associated laminated keratin within the lumen,¹⁷ which corresponds to its pearly white appearance on gross examination. Cutaneous ciliated cysts predominantly occur on the lower extremities of young women and are lined by simple cuboidal or columnar ciliated cells that resemble müllerian epithelium.¹⁸ Similar to CMSC, ganglion cysts are pseudocysts that lack a true epithelial lining but differ in appearance due to their mucin-filled synovial-lined sac.¹⁹ Additionally, ganglion cysts most often occur on the dorsal and volar aspects of the wrist. 

Excisional biopsy is indicated as the preferred treatment of CMSC, given the lesion's benign behavior and low recurrence rate.⁶ Our case highlights this rare entity and reinforces its inclusion in the differential diagnosis of subcutaneous mobile nodules, especially in the setting of prior tissue injury secondary to trauma, surgical procedures, or conditions such as rheumatoid arthritis or Ehlers-Danlos syndrome. Unlike most previously reported cases, our patient reported no preceding tissue injury associated with formation of the lesion, and she was largely asymptomatic on presentation. Considering the limited number of CMSC cases demonstrated in the literature, it is important to continue reporting new cases to better understand characteristics and presentations of this uncommon lesion. 

To the Editor:

The evolution in the understanding of psoriasis and psoriatic arthritis has unfolded many new facets of this immune-mediated inflammatory disease. Once considered to be just a cutaneous disease, psoriasis is not actually confined to skin but can involve almost any other system of the body. Cardiovascular morbidity and mortality are the major concerns in patients with psoriasis. We report the sudden death of a young man with severe psoriasis.

A 31-year-old man was admitted for severe psoriasis with pustular exacerbation (Figures 1A and 1B). He had moderate to severe unstable disease during the last 8 years and was managed with oral methotrexate (0.3–0.5 mg/kg/wk). He was not compliant with treatment, which led to multiple relapses. There was no personal or family history of risk factors for cardiovascular events (CVEs). At the time of present hospitalization, his vital parameters were normal. Physical examination revealed erythematous scaly plaques on more than 75% of the body surface area. Multiple pustules also were noted, often coalescing to form plaques (Figure 1C). Baseline investigations consisting of complete blood cell count, lipid profile, liver and renal functions, and chest radiography were within reference range. Baseline electrocardiogram (ECG) at admission was unremarkable (Figure 2A), except for sinus tachycardia. Low-voltage complexes in limb leads were appreciated as well as a corrected QT interval of 420 milliseconds (within reference range). Echocardiography was normal (visual ejection fraction of 60%).

The patient was unable to tolerate methotrexate due to excessive nausea; he was started on oral acitretin 25 mg once daily. There was no improvement in psoriasis over the following week, and he reported mild upper abdominal discomfort. He did not have any chest pain or dyspnea, and his pulse and blood pressure were normal. Serum electrolytes, liver function, lipid profile, and an ultrasound of the abdomen revealed no abnormalities. A repeat ECG showed no changes, and cardiac biomarkers were not elevated. Two days later, the patient collapsed while still in the hospital. A cardiac monitor and ECG showed ventricular tachycardia (VT)(Figure 2B); however, serum electrolytes, calcium, magnesium, and phosphorus levels were within reference range. Aggressive resuscitative measures including multiple attempts at cardioversion with up to 200 J (biphasic) and intravenous amiodarone infusion failed to revive the patient, and he died.

Proinflammatory cytokines such as IL-6 and tumor necrosis factor α are increased in young people with ventricular arrhythmias who have no evidence of myocardial injury (MI), suggesting an inflammatory background is involved.¹ Psoriasis, a common immune-mediated inflammatory disease, has a chronic state of systemic inflammation with notably higher serum levels of tumor necrosis factor α, IFN-γ, IL-6, IL-8, IL-12, and IL-18 compared to controls.² This inflammation is not confined to skin but can involve blood vessels, joints, and the liver, as demonstrated by increased fluorodeoxyglucose uptake.³ It also seems to exert its influence on supraventricular beat development in patients with psoriasis who do not have a history of CVEs.⁴ Tumor necrosis factor α is one of the major cytokines playing a role in the inflammatory process of psoriasis. Studies have shown serum levels of tumor necrosis factor α to correlate with the clinical symptoms of heart failure and to supraventricular arrhythmia in animal models.⁴ Various extreme CVEs can be an expression of this ongoing dynamic process. It would be interesting to know which specific factors among these inflammatory cytokines lead to rhythm irregularities.

Another theory is that young patients may experience micro-MI during the disease course. These small infarcted areas may act as aberrant pulse generators or lead to conduction disturbances. One study found increased correct QT interval dispersion, a predictor of ventricular arrhythmias, to be associated with psoriasis.⁵ A nationwide population-based matched cohort study by Chiu et al⁶ revealed that patients with psoriasis have a higher risk for arrhythmia independent of traditional cardiovascular risk factors. Our patient also had severe unstable psoriasis for 8 years that may have led to increased accumulation of proarrhythmogenic cytokines in the heart and could have led to VT.

Acitretin as a potential cause of sudden cardiac death remains a possibility in our case; however, the exact mechanism leading to such sudden arrhythmia is lacking. Acitretin is known to increase serum triglycerides and cholesterol, specifically by shifting high-density lipoproteins to low-density lipoproteins, thereby increasing the risk for CVE. However, it takes time for such derangement to occur, eventually leading to CVE. Mittal et al⁷ reported a psoriasis patient who died secondary to MI after 5 days of low-dose acitretin. Lack of evidence makes acitretin a less likely cause of mortality.

We present a case of sudden cardiac death secondary to VT in a young patient with psoriasis and no other traditional cardiovascular risk factors. This case highlights the importance of being vigilant for adverse CVEs such as arrhythmia in psoriatic patients, especially in younger patients with severe unstable disease.

To the Editor:

The evolution in the understanding of psoriasis and psoriatic arthritis has unfolded many new facets of this immune-mediated inflammatory disease. Once considered to be just a cutaneous disease, psoriasis is not actually confined to skin but can involve almost any other system of the body. Cardiovascular morbidity and mortality are the major concerns in patients with psoriasis. We report the sudden death of a young man with severe psoriasis.

A 31-year-old man was admitted for severe psoriasis with pustular exacerbation (Figures 1A and 1B). He had moderate to severe unstable disease during the last 8 years and was managed with oral methotrexate (0.3–0.5 mg/kg/wk). He was not compliant with treatment, which led to multiple relapses. There was no personal or family history of risk factors for cardiovascular events (CVEs). At the time of present hospitalization, his vital parameters were normal. Physical examination revealed erythematous scaly plaques on more than 75% of the body surface area. Multiple pustules also were noted, often coalescing to form plaques (Figure 1C). Baseline investigations consisting of complete blood cell count, lipid profile, liver and renal functions, and chest radiography were within reference range. Baseline electrocardiogram (ECG) at admission was unremarkable (Figure 2A), except for sinus tachycardia. Low-voltage complexes in limb leads were appreciated as well as a corrected QT interval of 420 milliseconds (within reference range). Echocardiography was normal (visual ejection fraction of 60%).

The patient was unable to tolerate methotrexate due to excessive nausea; he was started on oral acitretin 25 mg once daily. There was no improvement in psoriasis over the following week, and he reported mild upper abdominal discomfort. He did not have any chest pain or dyspnea, and his pulse and blood pressure were normal. Serum electrolytes, liver function, lipid profile, and an ultrasound of the abdomen revealed no abnormalities. A repeat ECG showed no changes, and cardiac biomarkers were not elevated. Two days later, the patient collapsed while still in the hospital. A cardiac monitor and ECG showed ventricular tachycardia (VT)(Figure 2B); however, serum electrolytes, calcium, magnesium, and phosphorus levels were within reference range. Aggressive resuscitative measures including multiple attempts at cardioversion with up to 200 J (biphasic) and intravenous amiodarone infusion failed to revive the patient, and he died.

Proinflammatory cytokines such as IL-6 and tumor necrosis factor α are increased in young people with ventricular arrhythmias who have no evidence of myocardial injury (MI), suggesting an inflammatory background is involved.¹ Psoriasis, a common immune-mediated inflammatory disease, has a chronic state of systemic inflammation with notably higher serum levels of tumor necrosis factor α, IFN-γ, IL-6, IL-8, IL-12, and IL-18 compared to controls.² This inflammation is not confined to skin but can involve blood vessels, joints, and the liver, as demonstrated by increased fluorodeoxyglucose uptake.³ It also seems to exert its influence on supraventricular beat development in patients with psoriasis who do not have a history of CVEs.⁴ Tumor necrosis factor α is one of the major cytokines playing a role in the inflammatory process of psoriasis. Studies have shown serum levels of tumor necrosis factor α to correlate with the clinical symptoms of heart failure and to supraventricular arrhythmia in animal models.⁴ Various extreme CVEs can be an expression of this ongoing dynamic process. It would be interesting to know which specific factors among these inflammatory cytokines lead to rhythm irregularities.

Another theory is that young patients may experience micro-MI during the disease course. These small infarcted areas may act as aberrant pulse generators or lead to conduction disturbances. One study found increased correct QT interval dispersion, a predictor of ventricular arrhythmias, to be associated with psoriasis.⁵ A nationwide population-based matched cohort study by Chiu et al⁶ revealed that patients with psoriasis have a higher risk for arrhythmia independent of traditional cardiovascular risk factors. Our patient also had severe unstable psoriasis for 8 years that may have led to increased accumulation of proarrhythmogenic cytokines in the heart and could have led to VT.

Acitretin as a potential cause of sudden cardiac death remains a possibility in our case; however, the exact mechanism leading to such sudden arrhythmia is lacking. Acitretin is known to increase serum triglycerides and cholesterol, specifically by shifting high-density lipoproteins to low-density lipoproteins, thereby increasing the risk for CVE. However, it takes time for such derangement to occur, eventually leading to CVE. Mittal et al⁷ reported a psoriasis patient who died secondary to MI after 5 days of low-dose acitretin. Lack of evidence makes acitretin a less likely cause of mortality.

We present a case of sudden cardiac death secondary to VT in a young patient with psoriasis and no other traditional cardiovascular risk factors. This case highlights the importance of being vigilant for adverse CVEs such as arrhythmia in psoriatic patients, especially in younger patients with severe unstable disease.

To the Editor:

The evolution in the understanding of psoriasis and psoriatic arthritis has unfolded many new facets of this immune-mediated inflammatory disease. Once considered to be just a cutaneous disease, psoriasis is not actually confined to skin but can involve almost any other system of the body. Cardiovascular morbidity and mortality are the major concerns in patients with psoriasis. We report the sudden death of a young man with severe psoriasis.

A 31-year-old man was admitted for severe psoriasis with pustular exacerbation (Figures 1A and 1B). He had moderate to severe unstable disease during the last 8 years and was managed with oral methotrexate (0.3–0.5 mg/kg/wk). He was not compliant with treatment, which led to multiple relapses. There was no personal or family history of risk factors for cardiovascular events (CVEs). At the time of present hospitalization, his vital parameters were normal. Physical examination revealed erythematous scaly plaques on more than 75% of the body surface area. Multiple pustules also were noted, often coalescing to form plaques (Figure 1C). Baseline investigations consisting of complete blood cell count, lipid profile, liver and renal functions, and chest radiography were within reference range. Baseline electrocardiogram (ECG) at admission was unremarkable (Figure 2A), except for sinus tachycardia. Low-voltage complexes in limb leads were appreciated as well as a corrected QT interval of 420 milliseconds (within reference range). Echocardiography was normal (visual ejection fraction of 60%).

The patient was unable to tolerate methotrexate due to excessive nausea; he was started on oral acitretin 25 mg once daily. There was no improvement in psoriasis over the following week, and he reported mild upper abdominal discomfort. He did not have any chest pain or dyspnea, and his pulse and blood pressure were normal. Serum electrolytes, liver function, lipid profile, and an ultrasound of the abdomen revealed no abnormalities. A repeat ECG showed no changes, and cardiac biomarkers were not elevated. Two days later, the patient collapsed while still in the hospital. A cardiac monitor and ECG showed ventricular tachycardia (VT)(Figure 2B); however, serum electrolytes, calcium, magnesium, and phosphorus levels were within reference range. Aggressive resuscitative measures including multiple attempts at cardioversion with up to 200 J (biphasic) and intravenous amiodarone infusion failed to revive the patient, and he died.

Proinflammatory cytokines such as IL-6 and tumor necrosis factor α are increased in young people with ventricular arrhythmias who have no evidence of myocardial injury (MI), suggesting an inflammatory background is involved.¹ Psoriasis, a common immune-mediated inflammatory disease, has a chronic state of systemic inflammation with notably higher serum levels of tumor necrosis factor α, IFN-γ, IL-6, IL-8, IL-12, and IL-18 compared to controls.² This inflammation is not confined to skin but can involve blood vessels, joints, and the liver, as demonstrated by increased fluorodeoxyglucose uptake.³ It also seems to exert its influence on supraventricular beat development in patients with psoriasis who do not have a history of CVEs.⁴ Tumor necrosis factor α is one of the major cytokines playing a role in the inflammatory process of psoriasis. Studies have shown serum levels of tumor necrosis factor α to correlate with the clinical symptoms of heart failure and to supraventricular arrhythmia in animal models.⁴ Various extreme CVEs can be an expression of this ongoing dynamic process. It would be interesting to know which specific factors among these inflammatory cytokines lead to rhythm irregularities.

Another theory is that young patients may experience micro-MI during the disease course. These small infarcted areas may act as aberrant pulse generators or lead to conduction disturbances. One study found increased correct QT interval dispersion, a predictor of ventricular arrhythmias, to be associated with psoriasis.⁵ A nationwide population-based matched cohort study by Chiu et al⁶ revealed that patients with psoriasis have a higher risk for arrhythmia independent of traditional cardiovascular risk factors. Our patient also had severe unstable psoriasis for 8 years that may have led to increased accumulation of proarrhythmogenic cytokines in the heart and could have led to VT.

Acitretin as a potential cause of sudden cardiac death remains a possibility in our case; however, the exact mechanism leading to such sudden arrhythmia is lacking. Acitretin is known to increase serum triglycerides and cholesterol, specifically by shifting high-density lipoproteins to low-density lipoproteins, thereby increasing the risk for CVE. However, it takes time for such derangement to occur, eventually leading to CVE. Mittal et al⁷ reported a psoriasis patient who died secondary to MI after 5 days of low-dose acitretin. Lack of evidence makes acitretin a less likely cause of mortality.

We present a case of sudden cardiac death secondary to VT in a young patient with psoriasis and no other traditional cardiovascular risk factors. This case highlights the importance of being vigilant for adverse CVEs such as arrhythmia in psoriatic patients, especially in younger patients with severe unstable disease.

To the Editor:

We report the case of an 83-year-old male nursing home resident with a history of end-stage renal disease who presented with multiple small white islands on the surface of the nail plate, similar to those seen in white superficial onychomycosis (Figure 1). Minimal subungual hyperkeratosis of the fingernails also was observed. Three digits were affected with no toenail involvement. Wet mount examination with potassium hydroxide 20% showed a mite (Figure 2A) and multiple eggs (Figure 2B). Treatment consisted of oral ivermectin 3 mg immediately and permethrin solution 5% applied under occlusion to each of the affected nails for 5 consecutive nights, which resulted in complete clearance of the lesion on the nail plate after 2 weeks.

Crusted scabies was first described as Norwegian scabies in 1848 by Danielsen and Boeck,¹ and the name was later changed to crusted scabies in 1976 by Parish and Lumholt² because there was no inherent connection between Norway and Norwegian scabies. It is a skin infestation of Sarcoptes scabiei var hominis and more commonly is seen in immunocompromised individuals such as the elderly and malnourished patients as well as those with diabetes mellitus and alcoholism.^3,4 Patients typically present with widespread hyperkeratosis, mostly involving the palms and soles. Subungual hyperkeratosis and nail dystrophy also can be seen when nail involvement is present, and the scalp rarely is involved.⁵ Unlike common scabies, skin burrows and pruritus may be minimal or absent, thus making the diagnosis of crusted scabies more difficult than normal scabies.⁶ Diagnosis of crusted scabies is confirmed by direct microscopy, which demonstrates mites, eggs, or feces. Strict isolation of the patient is necessary, as the disease is very contagious. Treatment with oral ivermectin (1–3 doses of 3 mg at 14-day intervals) in combination with topical permethrin is effective.⁷

We present a case of crusted scabies with nail involvement that presented with white superficial onychomycosislike lesions. The patient’s nails were successfully treated with a combination of oral ivermectin and topical permethrin occlusion of the nails. In cases with subungual hyperkeratosis, nonsurgical nail avulsion with 40% urea cream or ointment has been used to improve the penetration of permethrin. Partial nail avulsion may be necessary if subungual hyperkeratosis or nail dystrophy becomes extreme.⁸

To the Editor:

We report the case of an 83-year-old male nursing home resident with a history of end-stage renal disease who presented with multiple small white islands on the surface of the nail plate, similar to those seen in white superficial onychomycosis (Figure 1). Minimal subungual hyperkeratosis of the fingernails also was observed. Three digits were affected with no toenail involvement. Wet mount examination with potassium hydroxide 20% showed a mite (Figure 2A) and multiple eggs (Figure 2B). Treatment consisted of oral ivermectin 3 mg immediately and permethrin solution 5% applied under occlusion to each of the affected nails for 5 consecutive nights, which resulted in complete clearance of the lesion on the nail plate after 2 weeks.

Crusted scabies was first described as Norwegian scabies in 1848 by Danielsen and Boeck,¹ and the name was later changed to crusted scabies in 1976 by Parish and Lumholt² because there was no inherent connection between Norway and Norwegian scabies. It is a skin infestation of Sarcoptes scabiei var hominis and more commonly is seen in immunocompromised individuals such as the elderly and malnourished patients as well as those with diabetes mellitus and alcoholism.^3,4 Patients typically present with widespread hyperkeratosis, mostly involving the palms and soles. Subungual hyperkeratosis and nail dystrophy also can be seen when nail involvement is present, and the scalp rarely is involved.⁵ Unlike common scabies, skin burrows and pruritus may be minimal or absent, thus making the diagnosis of crusted scabies more difficult than normal scabies.⁶ Diagnosis of crusted scabies is confirmed by direct microscopy, which demonstrates mites, eggs, or feces. Strict isolation of the patient is necessary, as the disease is very contagious. Treatment with oral ivermectin (1–3 doses of 3 mg at 14-day intervals) in combination with topical permethrin is effective.⁷

We present a case of crusted scabies with nail involvement that presented with white superficial onychomycosislike lesions. The patient’s nails were successfully treated with a combination of oral ivermectin and topical permethrin occlusion of the nails. In cases with subungual hyperkeratosis, nonsurgical nail avulsion with 40% urea cream or ointment has been used to improve the penetration of permethrin. Partial nail avulsion may be necessary if subungual hyperkeratosis or nail dystrophy becomes extreme.⁸

To the Editor:

We report the case of an 83-year-old male nursing home resident with a history of end-stage renal disease who presented with multiple small white islands on the surface of the nail plate, similar to those seen in white superficial onychomycosis (Figure 1). Minimal subungual hyperkeratosis of the fingernails also was observed. Three digits were affected with no toenail involvement. Wet mount examination with potassium hydroxide 20% showed a mite (Figure 2A) and multiple eggs (Figure 2B). Treatment consisted of oral ivermectin 3 mg immediately and permethrin solution 5% applied under occlusion to each of the affected nails for 5 consecutive nights, which resulted in complete clearance of the lesion on the nail plate after 2 weeks.

Crusted scabies was first described as Norwegian scabies in 1848 by Danielsen and Boeck,¹ and the name was later changed to crusted scabies in 1976 by Parish and Lumholt² because there was no inherent connection between Norway and Norwegian scabies. It is a skin infestation of Sarcoptes scabiei var hominis and more commonly is seen in immunocompromised individuals such as the elderly and malnourished patients as well as those with diabetes mellitus and alcoholism.^3,4 Patients typically present with widespread hyperkeratosis, mostly involving the palms and soles. Subungual hyperkeratosis and nail dystrophy also can be seen when nail involvement is present, and the scalp rarely is involved.⁵ Unlike common scabies, skin burrows and pruritus may be minimal or absent, thus making the diagnosis of crusted scabies more difficult than normal scabies.⁶ Diagnosis of crusted scabies is confirmed by direct microscopy, which demonstrates mites, eggs, or feces. Strict isolation of the patient is necessary, as the disease is very contagious. Treatment with oral ivermectin (1–3 doses of 3 mg at 14-day intervals) in combination with topical permethrin is effective.⁷

We present a case of crusted scabies with nail involvement that presented with white superficial onychomycosislike lesions. The patient’s nails were successfully treated with a combination of oral ivermectin and topical permethrin occlusion of the nails. In cases with subungual hyperkeratosis, nonsurgical nail avulsion with 40% urea cream or ointment has been used to improve the penetration of permethrin. Partial nail avulsion may be necessary if subungual hyperkeratosis or nail dystrophy becomes extreme.⁸

To the Editor:

A 28-year-old man presented to the dermatology clinic with red, tender, swollen nodules on the left arm of 5 days’ duration, which had been a recurrent issue involving both arms. He also experienced intermittent fatigue and mild myalgia but denied associated fevers or chills. Oral clindamycin prescribed by a local emergency department provided some improvement. Upon further questioning, the patient admitted to injecting an unknown substance into the muscles 10 years prior for the purpose of enhancing their volume and appearance. Physical examination revealed large bilateral biceps with firm, mobile, nontender, subcutaneous nodules and mild erythema on the inner aspects of the arms. An incisional biopsy of a left arm nodule was performed with tissue culture (Figure 1). Microscopic evaluation revealed mild dermal sclerosis with edema and sclerosis of fat septae (Figure 2A). The fat lobules contained granulomas with surrounding lymphocytes and clear holes noted within the histiocytic giant cells, indicating a likely foreign substance (Figure 2B). Immunohistochemical staining of the histiocytes with CD68 highlighted the clear vacuoles (Figure 3). Polarization examination, Alcian blue, periodic acid–Schiff, and acid-fast bacilli staining were negative. Bacterial, fungal, and mycobacterial tissue cultures and staining also were negative. The histologic findings of septal and lobular panniculitis with sclerosis and granulomatous inflammation in the clinical setting were consistent with a foreign body reaction secondary to synthol injection.

The willingness of athletes in competitive sports to undergo procedures or utilize substances for a competitive advantage despite both immediate and long-term consequences is well documented.^1,2 In bodybuilding, use of anabolic steroids and intramuscular oil injections has been documented.³ The use of site enhancements in the form of “fillers” such as petroleum jelly and paraffin have been used for more than 100 years.⁴ The use of oil for volumetric site enhancement began in the 1960s in Italy with formebolone and evolved to the use of synthol in the 1990s.⁵ Synthol is a substance composed of 85% oil in the form of medium-chain triglycerides, 7.5% alcohol, and 7.5% lidocaine.⁶ The presumed mechanism of action of injected oils consists of an initial inflammatory response followed by fibrosis and chronic macrophagocytosis, ultimately leading to expanded volume in the subcutaneous tissue.⁷ These procedures are purely aesthetic with no increase in muscle strength or performance.

There are few cases in the literature of side effects from intramuscular synthol injections. In one report, a 29-year-old man presented with painful muscle fibrosis requiring open surgical excision of massively fibrotic bicep tissue.⁸ Another report documented a 45-year-old man who presented with spontaneous ulcerations on the biceps that initially were treated with antibiotics and compression therapy but eventually required surgical intervention and skin grafting.⁹ Complications have been more frequently reported from injections of other oils such as paraffin and sesame.^10,11 Given the similar underlying mechanisms of action, injected oils share the local side effects of inflammation, infection, chronic wounds, and ulceration,^9,10 as well as a systemic risk for embolization leading to pulmonary emboli, myocardial infarction, and stroke.⁶ Although no standard of care exists for the management of complications arising from intramuscular oil injections, treatments that have been employed include antibiotics, corticosteroids, wound care, and compression therapy; definitive treatment typically is surgical excision.^6,8,9,11,12 Psychiatric evaluation also should be considered to evaluate for the possibility of body dysmorphic disorder and other associated psychiatric conditions.¹¹

Pressure for a particular aesthetic appearance, both within and outside the world of competitive sports, has driven individuals to various methods of muscular enhancement. Volumetric site enhancements have become increasingly popular, in part due to the perceived lack of systemic side effects, such as those associated with anabolic steroids.⁸ However, most users are unaware of the notable short-term and long-term risks associated with intramuscular oil injections. Synthol is widely available on the Internet and easily can be purchased and injected by anyone.¹³ Medical providers should be aware of the possibility of aesthetic site enhancement use in their patients and be able to recognize and intervene in these cases to prevent chronic damage to muscle tissue and accompanying complications. Despite extensive commercialization of these products, few reports in the medical literature exist detailing the side effects of intramuscular oil injections, which may be contributing to the trivialization of these procedures by the general public.¹²

To the Editor:

A 28-year-old man presented to the dermatology clinic with red, tender, swollen nodules on the left arm of 5 days’ duration, which had been a recurrent issue involving both arms. He also experienced intermittent fatigue and mild myalgia but denied associated fevers or chills. Oral clindamycin prescribed by a local emergency department provided some improvement. Upon further questioning, the patient admitted to injecting an unknown substance into the muscles 10 years prior for the purpose of enhancing their volume and appearance. Physical examination revealed large bilateral biceps with firm, mobile, nontender, subcutaneous nodules and mild erythema on the inner aspects of the arms. An incisional biopsy of a left arm nodule was performed with tissue culture (Figure 1). Microscopic evaluation revealed mild dermal sclerosis with edema and sclerosis of fat septae (Figure 2A). The fat lobules contained granulomas with surrounding lymphocytes and clear holes noted within the histiocytic giant cells, indicating a likely foreign substance (Figure 2B). Immunohistochemical staining of the histiocytes with CD68 highlighted the clear vacuoles (Figure 3). Polarization examination, Alcian blue, periodic acid–Schiff, and acid-fast bacilli staining were negative. Bacterial, fungal, and mycobacterial tissue cultures and staining also were negative. The histologic findings of septal and lobular panniculitis with sclerosis and granulomatous inflammation in the clinical setting were consistent with a foreign body reaction secondary to synthol injection.

The willingness of athletes in competitive sports to undergo procedures or utilize substances for a competitive advantage despite both immediate and long-term consequences is well documented.^1,2 In bodybuilding, use of anabolic steroids and intramuscular oil injections has been documented.³ The use of site enhancements in the form of “fillers” such as petroleum jelly and paraffin have been used for more than 100 years.⁴ The use of oil for volumetric site enhancement began in the 1960s in Italy with formebolone and evolved to the use of synthol in the 1990s.⁵ Synthol is a substance composed of 85% oil in the form of medium-chain triglycerides, 7.5% alcohol, and 7.5% lidocaine.⁶ The presumed mechanism of action of injected oils consists of an initial inflammatory response followed by fibrosis and chronic macrophagocytosis, ultimately leading to expanded volume in the subcutaneous tissue.⁷ These procedures are purely aesthetic with no increase in muscle strength or performance.

There are few cases in the literature of side effects from intramuscular synthol injections. In one report, a 29-year-old man presented with painful muscle fibrosis requiring open surgical excision of massively fibrotic bicep tissue.⁸ Another report documented a 45-year-old man who presented with spontaneous ulcerations on the biceps that initially were treated with antibiotics and compression therapy but eventually required surgical intervention and skin grafting.⁹ Complications have been more frequently reported from injections of other oils such as paraffin and sesame.^10,11 Given the similar underlying mechanisms of action, injected oils share the local side effects of inflammation, infection, chronic wounds, and ulceration,^9,10 as well as a systemic risk for embolization leading to pulmonary emboli, myocardial infarction, and stroke.⁶ Although no standard of care exists for the management of complications arising from intramuscular oil injections, treatments that have been employed include antibiotics, corticosteroids, wound care, and compression therapy; definitive treatment typically is surgical excision.^6,8,9,11,12 Psychiatric evaluation also should be considered to evaluate for the possibility of body dysmorphic disorder and other associated psychiatric conditions.¹¹

Pressure for a particular aesthetic appearance, both within and outside the world of competitive sports, has driven individuals to various methods of muscular enhancement. Volumetric site enhancements have become increasingly popular, in part due to the perceived lack of systemic side effects, such as those associated with anabolic steroids.⁸ However, most users are unaware of the notable short-term and long-term risks associated with intramuscular oil injections. Synthol is widely available on the Internet and easily can be purchased and injected by anyone.¹³ Medical providers should be aware of the possibility of aesthetic site enhancement use in their patients and be able to recognize and intervene in these cases to prevent chronic damage to muscle tissue and accompanying complications. Despite extensive commercialization of these products, few reports in the medical literature exist detailing the side effects of intramuscular oil injections, which may be contributing to the trivialization of these procedures by the general public.¹²

To the Editor:

A 28-year-old man presented to the dermatology clinic with red, tender, swollen nodules on the left arm of 5 days’ duration, which had been a recurrent issue involving both arms. He also experienced intermittent fatigue and mild myalgia but denied associated fevers or chills. Oral clindamycin prescribed by a local emergency department provided some improvement. Upon further questioning, the patient admitted to injecting an unknown substance into the muscles 10 years prior for the purpose of enhancing their volume and appearance. Physical examination revealed large bilateral biceps with firm, mobile, nontender, subcutaneous nodules and mild erythema on the inner aspects of the arms. An incisional biopsy of a left arm nodule was performed with tissue culture (Figure 1). Microscopic evaluation revealed mild dermal sclerosis with edema and sclerosis of fat septae (Figure 2A). The fat lobules contained granulomas with surrounding lymphocytes and clear holes noted within the histiocytic giant cells, indicating a likely foreign substance (Figure 2B). Immunohistochemical staining of the histiocytes with CD68 highlighted the clear vacuoles (Figure 3). Polarization examination, Alcian blue, periodic acid–Schiff, and acid-fast bacilli staining were negative. Bacterial, fungal, and mycobacterial tissue cultures and staining also were negative. The histologic findings of septal and lobular panniculitis with sclerosis and granulomatous inflammation in the clinical setting were consistent with a foreign body reaction secondary to synthol injection.

The willingness of athletes in competitive sports to undergo procedures or utilize substances for a competitive advantage despite both immediate and long-term consequences is well documented.^1,2 In bodybuilding, use of anabolic steroids and intramuscular oil injections has been documented.³ The use of site enhancements in the form of “fillers” such as petroleum jelly and paraffin have been used for more than 100 years.⁴ The use of oil for volumetric site enhancement began in the 1960s in Italy with formebolone and evolved to the use of synthol in the 1990s.⁵ Synthol is a substance composed of 85% oil in the form of medium-chain triglycerides, 7.5% alcohol, and 7.5% lidocaine.⁶ The presumed mechanism of action of injected oils consists of an initial inflammatory response followed by fibrosis and chronic macrophagocytosis, ultimately leading to expanded volume in the subcutaneous tissue.⁷ These procedures are purely aesthetic with no increase in muscle strength or performance.

There are few cases in the literature of side effects from intramuscular synthol injections. In one report, a 29-year-old man presented with painful muscle fibrosis requiring open surgical excision of massively fibrotic bicep tissue.⁸ Another report documented a 45-year-old man who presented with spontaneous ulcerations on the biceps that initially were treated with antibiotics and compression therapy but eventually required surgical intervention and skin grafting.⁹ Complications have been more frequently reported from injections of other oils such as paraffin and sesame.^10,11 Given the similar underlying mechanisms of action, injected oils share the local side effects of inflammation, infection, chronic wounds, and ulceration,^9,10 as well as a systemic risk for embolization leading to pulmonary emboli, myocardial infarction, and stroke.⁶ Although no standard of care exists for the management of complications arising from intramuscular oil injections, treatments that have been employed include antibiotics, corticosteroids, wound care, and compression therapy; definitive treatment typically is surgical excision.^6,8,9,11,12 Psychiatric evaluation also should be considered to evaluate for the possibility of body dysmorphic disorder and other associated psychiatric conditions.¹¹

Pressure for a particular aesthetic appearance, both within and outside the world of competitive sports, has driven individuals to various methods of muscular enhancement. Volumetric site enhancements have become increasingly popular, in part due to the perceived lack of systemic side effects, such as those associated with anabolic steroids.⁸ However, most users are unaware of the notable short-term and long-term risks associated with intramuscular oil injections. Synthol is widely available on the Internet and easily can be purchased and injected by anyone.¹³ Medical providers should be aware of the possibility of aesthetic site enhancement use in their patients and be able to recognize and intervene in these cases to prevent chronic damage to muscle tissue and accompanying complications. Despite extensive commercialization of these products, few reports in the medical literature exist detailing the side effects of intramuscular oil injections, which may be contributing to the trivialization of these procedures by the general public.¹²

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The Diagnosis: Epidermodysplasia Verruciformis 

Histopathologic examination of our patient's biopsy specimen revealed mild acanthosis with prominent hypergranulosis and enlarged keratinocytes with blue-gray cytoplasm (Figure). A diagnosis of acquired epidermodysplasia verruciformis (EV) was rendered. The patient was treated with photodynamic therapy utilizing 5-aminolevulinic acid. 

Epidermodysplasia verruciformis is characterized by susceptibility to human papillomavirus (HPV) infections via a defect in cellular immunity. Epidermodysplasia verruciformis was first described as an autosomal-recessive genodermatosis, but it can be acquired in immunosuppressed states with an atypical clinical appearance.¹ There are few case reports in skin of color. Acquired EV appears in patients with acquired immunodeficiencies that are susceptible to EV-causing HPVs via a similar mechanism found in inherited EV.² The most common HPV serotypes involved in EV are HPV-5 and HPV-8. The duration of immunosuppression has been found to be positively correlated with the risk for EV development, with the majority of patients developing lesions after 5 years of immunosuppression.³ There is an approximately 60% risk of malignant transformation of EV lesions into nonmelanoma skin cancer.² This risk is believed to be lower in patients with darker skin.⁴  

Preventative measures including sun protection and annual surveillance are crucial in EV patients given the high rate of malignant transformation in sun-exposed lesions.⁵ Treatment options for EV are anecdotal and have variable results, ranging from topicals including 5-fluorouracil and imiquimod to systemic medications including acitretin and interferon.³ Photodynamic therapy can be used for extensive EV. Surgical modalities and other destructive methods also have been tried.⁶ 

Epidermodysplasia verruciformis often can be confused with similar dermatoses. Porokeratosis appears as annular pink papules with waferlike peripheral scales. Tinea versicolor is a dermatophyte infection caused by Malassezia furfur and presents as multiple dyspigmented, finely scaling, thin papules and plaques. Subacute cutaneous lupus erythematosus presents as pink, scaly, annular or psoriasiform papules and plaques most commonly on the trunk. Discoid lupus erythematosus presents as pink, hypopigmented or depigmented, atrophic plaques with a peripheral rim of erythema that indicates activity. Secondary syphilis, commonly denoted as the "great mimicker," presents as psoriasiform papules and plaques among other variable morphologies. 

The Diagnosis: Epidermodysplasia Verruciformis 

Histopathologic examination of our patient's biopsy specimen revealed mild acanthosis with prominent hypergranulosis and enlarged keratinocytes with blue-gray cytoplasm (Figure). A diagnosis of acquired epidermodysplasia verruciformis (EV) was rendered. The patient was treated with photodynamic therapy utilizing 5-aminolevulinic acid. 

Epidermodysplasia verruciformis is characterized by susceptibility to human papillomavirus (HPV) infections via a defect in cellular immunity. Epidermodysplasia verruciformis was first described as an autosomal-recessive genodermatosis, but it can be acquired in immunosuppressed states with an atypical clinical appearance.¹ There are few case reports in skin of color. Acquired EV appears in patients with acquired immunodeficiencies that are susceptible to EV-causing HPVs via a similar mechanism found in inherited EV.² The most common HPV serotypes involved in EV are HPV-5 and HPV-8. The duration of immunosuppression has been found to be positively correlated with the risk for EV development, with the majority of patients developing lesions after 5 years of immunosuppression.³ There is an approximately 60% risk of malignant transformation of EV lesions into nonmelanoma skin cancer.² This risk is believed to be lower in patients with darker skin.⁴  

Preventative measures including sun protection and annual surveillance are crucial in EV patients given the high rate of malignant transformation in sun-exposed lesions.⁵ Treatment options for EV are anecdotal and have variable results, ranging from topicals including 5-fluorouracil and imiquimod to systemic medications including acitretin and interferon.³ Photodynamic therapy can be used for extensive EV. Surgical modalities and other destructive methods also have been tried.⁶ 

Epidermodysplasia verruciformis often can be confused with similar dermatoses. Porokeratosis appears as annular pink papules with waferlike peripheral scales. Tinea versicolor is a dermatophyte infection caused by Malassezia furfur and presents as multiple dyspigmented, finely scaling, thin papules and plaques. Subacute cutaneous lupus erythematosus presents as pink, scaly, annular or psoriasiform papules and plaques most commonly on the trunk. Discoid lupus erythematosus presents as pink, hypopigmented or depigmented, atrophic plaques with a peripheral rim of erythema that indicates activity. Secondary syphilis, commonly denoted as the "great mimicker," presents as psoriasiform papules and plaques among other variable morphologies. 

The Diagnosis: Epidermodysplasia Verruciformis 

Histopathologic examination of our patient's biopsy specimen revealed mild acanthosis with prominent hypergranulosis and enlarged keratinocytes with blue-gray cytoplasm (Figure). A diagnosis of acquired epidermodysplasia verruciformis (EV) was rendered. The patient was treated with photodynamic therapy utilizing 5-aminolevulinic acid. 

Epidermodysplasia verruciformis is characterized by susceptibility to human papillomavirus (HPV) infections via a defect in cellular immunity. Epidermodysplasia verruciformis was first described as an autosomal-recessive genodermatosis, but it can be acquired in immunosuppressed states with an atypical clinical appearance.¹ There are few case reports in skin of color. Acquired EV appears in patients with acquired immunodeficiencies that are susceptible to EV-causing HPVs via a similar mechanism found in inherited EV.² The most common HPV serotypes involved in EV are HPV-5 and HPV-8. The duration of immunosuppression has been found to be positively correlated with the risk for EV development, with the majority of patients developing lesions after 5 years of immunosuppression.³ There is an approximately 60% risk of malignant transformation of EV lesions into nonmelanoma skin cancer.² This risk is believed to be lower in patients with darker skin.⁴  

Preventative measures including sun protection and annual surveillance are crucial in EV patients given the high rate of malignant transformation in sun-exposed lesions.⁵ Treatment options for EV are anecdotal and have variable results, ranging from topicals including 5-fluorouracil and imiquimod to systemic medications including acitretin and interferon.³ Photodynamic therapy can be used for extensive EV. Surgical modalities and other destructive methods also have been tried.⁶ 

Epidermodysplasia verruciformis often can be confused with similar dermatoses. Porokeratosis appears as annular pink papules with waferlike peripheral scales. Tinea versicolor is a dermatophyte infection caused by Malassezia furfur and presents as multiple dyspigmented, finely scaling, thin papules and plaques. Subacute cutaneous lupus erythematosus presents as pink, scaly, annular or psoriasiform papules and plaques most commonly on the trunk. Discoid lupus erythematosus presents as pink, hypopigmented or depigmented, atrophic plaques with a peripheral rim of erythema that indicates activity. Secondary syphilis, commonly denoted as the "great mimicker," presents as psoriasiform papules and plaques among other variable morphologies. 

Vibrio vulnificus is a member of the Vibrio genus. Most Vibrio species are nonpathogenic in humans; however, V vulnificus is one of the pathogenic strains.¹ In Latin, the term vulnificus means “wounding,” and V vulnificus can cause life-threatening infections in patients. The mortality rate of V vulnificus infections is approximately 33% in the United States.²Vibrio vulnificus is a gram-negative bacterium that was first isolated by the Centers for Disease Control and Prevention in 1964 and was given its current name in 1979.^3-6 It has been found in numerous organisms, including oysters, crabs, clams, shrimp, mussels, mullets, and sea bass.⁴ The vast majority of infections in the United States are due to oyster exposure and consumption.^2,7Vibrio vulnificus is responsible for more than 95% of seafood-related deaths in the United States and has the highest mortality rate of all food-borne illness in the United States.^2,5 It also has the highest per-case economic impact of all food-related diseases in the United States.¹

What distinguishes a pathogenic vs nonpathogenic Vibrio isolate remains unknown; Vibrio species rapidly undergo horizontal gene transfer, making DNA isolation difficult.¹ Some characteristics of V vulnificus that may confer virulence are the capsular polysaccharide, lipopolysaccharide, binding proteins, and tissue-degrading enzymes.^1,5 First, encapsulated strains are more virulent and invasive than unencapsulated strains.¹ The mucopolysaccharide capsule protects the bacterium from the immune system, allowing it to evade immune surveillance, cause more severe infection, and invade into the subcutaneous tissue.^3,5 Second, production of sialic acid–like molecules alter the lipopolysaccharide, allowing for motility and biofilm formation.¹ This allows the bacterium to survive in marine waters and within the bloodstream, the latter leading to sepsis in humans. Third, production of N-acetylglucosamine–binding protein A allows for adhesion to chitin. Shellfish consume chitin, and chitin accumulates in shellfish. N-acetylglucosamine–binding protein A also binds mucin; this may be how V vulnificus binds to mucin in the gastrointestinal tract in humans, causing gastroenteritis.¹ Binding to the human mucosae also may allow the bacteria to gain access to the blood supply, leading to septicemia.⁴ Finally, tissue-degrading enzymes such as proteases are responsible for necrotizing wound infections associated with V vulnificus, as the enzymes allow for invasion into the skin and subcutaneous tissues. Proteases also increase vascular permeability and lead to edema.³ Hence, these virulence factors may provide V vulnificus the pathogenicity to cause infection in humans.

Three biotypes of V vulnificus have been discovered. Biotype 1 is the most common and is found worldwide in brackish water.⁸ It can cause the entire spectrum of illnesses, and it has a case fatality rate of 50% in humans. Biotype 1 is presumably responsible for all infections in the United States. Biotype 2 is found in the Far East and Western Europe; it inhabits a unique niche—saltwater used for eel farming. It typically causes infection in eels, but rarely it can cause wound infections in humans. Biotype 3 is found in freshwater fish farming in Israel, and it is a hybrid of biotypes 1 and 2.It can cause severe soft tissue infections in humans, sometimes requiring amputation.⁸

Epidemiology

Vibrio vulnificus is a motile, gram-negative, halophilic, aquatic bacterium.^1,4,5,8,9 It is part of the normal estuarine microbiome and typically is found in warm coastal waters.^1,5,10 The ideal conditions for growth and survival of V vulnificus are water temperatures at 18 °C (64.4 °F) and water salinities between 15 to 25 parts per thousand.^2,8,9 These conditions are found in tropical and subtropical regions.²Vibrio vulnificus is found all over the world, including Denmark, Italy, Japan, Australia, Brazil, and the United States,² where most infections come from oyster exposure and consumption in the Gulf of Mexico.^2,8,11 The incidence of infection in the United States is highest between April and October.^8,11

Some populations are at a higher risk of infection. Risk factors include male sex, liver cirrhosis, hemochromatosis, end-stage renal disease, immunosuppression, and diabetes mellitus.^1,8,11 Healthy patients with no risk factors account for less than 5% of US V vulnificus infections.⁸

Male Predilection
Men are 6 times more likely to be affected by V vulnificus than women.Some hypotheses for this discrepancy are that estrogen is protective againstV vulnificus and that women may be less likely to engage in risky water activities and seafood handling.⁵ Additionally, older males (aged >60 years) are most often affected,^1,8 likely due to the association between increasing age with number of comorbidities, such as diabetes mellitus, heart disease, and chronic disease.⁸

Iron Levels
Iron appears to play an important role in V vulnificus infection. Iron is essential for bacterial growth, and the ability to obtain iron from a host increases the organism’s pathogenicity.³Vibrio vulnificus rapidly grows when transferrin saturation exceeds 70%.⁸ Additionally, iron overload decreases the inoculum needed to cause sepsis in animal studies, which could play a role in human pathogenesis.⁴ Iron levels are elevated in patients with hemochromatosis due to increased iron absorption, cirrhosis and chronic liver disease due to impaired iron metabolism, and end-stage renal disease, especially in patients receiving parenteral iron.⁸

Immunosuppression
Patients who are immunocompromised and those with chronic liver disease are at an increased risk of infection because of neutrophils having decreased phagocytic activity.⁴

Diabetes Mellitus
Patients with diabetes mellitus may have peripheral neuropathy and may be unaware of pre-existing wounds that serve as entry points for V vulnificus.¹²

Etiology

Vibrio vulnificus infects humans via seafood consumption and handling as well as exposure to contaminated water.^2,5 With respect to seafood consumption, raw shellfish are the primary type of seafood that harbor high levels of V vulnificus.⁵ Oysters are the most common etiology, but consumption of crabs, clams, and shrimp also can lead to infection.^5,7Vibrio vulnificus contamination does not change the appearance, taste, or odor of shellfish, making it hard to detect.⁸ An inoculate of 1 million bacteria typically is necessary for infection after consumption.⁵ Contaminated seawater is another primary cause of V vulnificus infection. When open wounds are exposed to seawater harboring the bacteria, wound infections can arise.⁷ Infections can be acquired when swimming, fishing, or participating in water sports. Wound infections also occur while handling contaminated seafood, such as oyster shucking.⁵ There is a short incubation period for V vulnificus infections; the onset of symptoms and clinical outcome typically occur within 24 hours.⁵

Clinical Presentation

Vibrio vulnificus infections can have numerous clinical presentations, including gastroenteritis, wound infections, necrotizing fasciitis, and sepsis.^1,8 There also is a spectrum of clinical outcomes; for instance, gastroenteritis typically is self-limited, whereas necrotizing fasciitis or sepsis can be fatal.²

Gastroenteritis
Vibrio vulnificus gastroenteritis is due to ingestion of contaminated shellfish.^2,9 Symptoms typically are mild to moderate and include nausea, vomiting, diarrhea, fever, chills, abdominal pain, and cramping.^2,4,8 Cases likely are underreported in the United States because gastroenteritis is self-limited, and many patients do not seek treatment.^2,11

Wound Infections
Wound infections with V vulnificus have a cutaneous port of entry. Exposure to contaminated seawater or seafood can inoculate an open wound, leading to infection.^7,8 Wound infections usually stem from 1 of 2 routes: (1) a pre-existing open wound gets infected while the patient is swimming in contaminated water, or (2) a traumatic injury occurs while the patient is handling contaminated shellfish, knives, or fishhooks. Many shellfish, such as oysters, have sharp points on their shells that can lacerate the skin.⁸ A wound on the hand can be contaminated by V vulnificus while handling contaminated seafood (eg, oyster shucking).¹³ Minor abrasions should not be dismissed; in fact, a small puncture or skin break often acts as the port of entry.^9,11 Wound infections tend to arise within 7 days of exposure, though they can manifest up to 12 days after exposure.⁸ Wound infections can present as cellulitis, bullae, or ecchymoses.⁷ Lesions are exquisitely tender, and the skin is erythematous with marked surrounding soft tissue edema.^3,4,8 Cellulitis typically arises first, with hemorrhagic bullae rapidly following.¹⁴ Lesions are limited to the affected extremity or area of inoculation.⁸ Systemic symptoms are rare, but fever and chills may accompany the infection.^8,14 Unfortunately, lesions can become necrotic and progress rapidly to necrotizing fasciitis if left untreated.^4,7,11 In these cases, secondary sepsis can occur.⁸

Necrotizing Fasciitis
Wound infections caused by V vulnificus can progress to necrotizing skin and soft tissue infections, such as necrotizing fasciitis and gangrene.⁵ Necrotizing fasciitis accounts for approximately one-third of V vulnificus infections.⁹ It usually stems from an open wound that is inoculated by contact with contaminated seafood or seawater.^2,9 The wound infection begins as cellulitis with extreme tenderness, erythematous skin, and marked soft tissue edema, then rapidly progresses, becoming necrotic. These necrotic lesions present as black and purple eschars as the skin, blood supply, and subcutaneous tissues are infiltrated by the bacteria and destroyed. Lesions may have blistering or exudation. Many patients have accompanying systemic symptoms, including fever, chills, abdominal pain, diarrhea, hypotension, and sepsis.^11,14 However, some patients may not present with systemic symptoms, so it is important to maintain a high index of suspicion even in the absence of these symptoms. The infection typically is limited to the affected extremity; necrotizing infections can lead to amputation and even death, depending on the extent of destruction and spread of the bacteria.^11,13 The infection may spread beyond the inoculated extremity if the bacteria gains access to the bloodstream.^8,9 In these cases, fulminant purpura or secondary septicemia can occur.^8,15 Fatalityrates in the United States for necrotizing V vulnificus infections approach 30%.² Necrotizing fasciitis accounts for approximately 8% of deaths associated with the pathogen in the United States.⁹

Interestingly, one reported case of necrotizing fasciitis associated with V vulnificus infection was triggered by acupuncture.¹⁶ The patient worked in a fish hatchery, where he was exposed to V vulnificus, and subsequent acupuncture led to the inoculation of bacteria into his bloodstream. This case raises the important point that we typically sequence the pathogenesis of V vulnificus infection as a patient having an open wound that is subsequently exposed to contaminated water; however, it also can follow the reverse sequence. Thus, proper cleansing of the skin after swimming in brackish water or handling shellfish is important to prevent V vulnificus infection.¹⁶ Additionally, dermatologists should be sure to cleanse patients’ skin thoroughly before performing procedures that could cause breaks in the skin.

Septicemia
Primary septicemia is the most common presentation of V vulnificus infection.^2,8 Septicemia accounts for approximately 58% of V vulnificus infections in the United States.⁹ Infection typically occurs after ingestion of contaminated oysters, with subsequent absorption into the bloodstream through the ileum or cecum.^2,8,9 Patients with chronic liver disease are 80 times more likely to develop primary sepsis than healthy individuals.⁸ Patients typically present with sudden-onset fever and chills, vomiting, diarrhea, and pain in the abdomen and/or extremities within hours to days of ingestion.^4,8,9 The median time from ingestion to symptom onset is 18 hours.^4,16 However, symptoms can be delayed up to 14 days.² Progression is rapid; secondary lesions such as bullae, ecchymoses, cellulitis, purpura, macular or maculopapular eruptions, pustules, vasculitis, urticaria, and erythema multiforme–like lesions appear on the extremities within 24 hours of symptom onset. ^2,3,4,8,17 Hemorrhagic bullae are the most common cutaneous manifestation of sepsis.⁴ Lesions are extremely tender to palpation.³ Cutaneous lesions can progress to necrotic ulcers, necrotizing fasciitis, gangrene, necrotizing vasculitis, or myonecrosis.^4,8 Evidence of petechiae may indicate progression to disseminated intravascular coagulation (DIC). Elevated D-dimer and fibrin split products also may indicate DIC, and elevated creatine kinase may signify rhabdomyolysis.³ Unfortunately, septicemia has the worst outcomes of all V vulnificus presentations, with morality rates greater than 50% in the United States.^1,2,4Vibrio vulnificus septicemia has a similar case-fatality rate to pathogens such as anthrax, Ebola virus disease, and the bubonic plague.⁵ Septicemia accounts for approximately 80% of the deaths associated with V vulnificus in the United States.^8,9

Septicemia due to V vulnificus progresses to septic shock in two-thirds of cases.⁸ Septic shock presents with hypotension, mental status changes, and thrombocytopenia.^2,8,17 Patients can become tachycardic, tachypneic, and hypoxic. Intubation may be required for resuscitation. In cases of septic shock secondary to V vulnificus infection, mortality rates reach 92%.³ Hypotension with a systolic blood pressure less than 90 mm Hg is a poor prognostic factor; patients presenting with hypotension secondary to V vulnificus infection have a fatality rate approaching 75% within 12 hours.²

Atypical Presentations
Rare atypical presentations of V vulnificus infection that have been reported in the literature include meningitis, corneal ulcers, epiglottitis, tonsillitis, spontaneous bacterial peritonitis, pneumonia, endometritis, septic arthritis, osteomyelitis, rhabdomyolysis endophthalmitis, and keratitis.^{2,4,6,13,18,19}

Diagnosis

When diagnosing V vulnificus, providers need to obtain a thorough patient history, including any history of consumption or handling of raw seafood and recent water activities. Providers practicing in tropical climates or in warm summer months should keep V vulnificus in mind, as it is the ideal climate for the pathogen.⁹ Vital signs can range from unremarkable to fever, hypotension, tachycardia, and/or hypoxia. Skin examination may show exquisitely tender, erythematous skin with marked soft tissue edema, hemorrhagic bullae, ecchymoses, and/or necrosis. As physical examination findings can be nonspecific, wound cultures, blood cultures, and skin biopsies should be taken.

A wound culture and blood culture should be taken immediately if V vulnificus is suspected.^8,11 A wound culture using discharge or fluid from necrotic or bullous lesions should be analyzed via gram stain.^8,9 Gram stains of V vulnificus show short, slim, curved gram-negative rods under light microscopy.^9,20 Special stains also can be done on cultures; V vulnificus is an oxidase-positive, lactose-positive, lysine-positive, salicin-positive, and arginine-negative organism. This knowledge can help differentiate V vulnificus from other gram-negative rods.¹³ Blood cultures will be positive in approximately 97% of patients with primary septicemia and 30% of patients with septicemia secondary to V vulnificus wound infections.^3,9

Histologically, perilesional skin biopsies show epidermal necrosis with dermal and subcutaneous inflammation.^12,17 There typically is an inflammatory infiltrate with neutrophilic abscesses and extensive tissue destruction in the subcutaneous tissue extending into the deep dermis.^12,17 The superficial dermis is edematous but can lack the inflammatory infiltrate found in the subcutaneous tissue.¹⁷ Subepidermal bullae can form with numerous organisms within the fluid of the bullae. There also may be evidence of leukocytoclastic vasculitis with accompanying vessel wall necrosis. Fibrin clot formation and extravasated red blood cells may be visualized with few inflammatory cells but numerous organisms around the involved vessels.¹⁷

Management

Early diagnosis and treatment are vital.^5,17 Cultures should be taken before aggressive treatment is started.³ Treatment is multifaceted; it requires antibiotics and wound care, except in cases of self-limited gastroenteritis.^2,11 Aggressive debridement, fasciotomy, amputation, and supportive measures also may be necessary depending on the patient’s presentation.^2,3,8,9 Establishing 2 peripheral intravenous lines is important in case rapid resuscitation becomes necessary.

Antibiotics
Primary cellulitis wound infections should be treated with doxycycline or a quinolone. If untreated, the wound can rapidly progress to necrotizing fasciitis.¹¹ For necrotizing fasciitis and septicemia, broader-spectrum antibiotics are needed. For adults, ceftazidime plus doxycycline is the mainstay of antibiotic treatment for V vulnificus.^2,9,11 For children, trimethoprim-sulfamethoxazole plus an aminoglycoside is preferred (Table).^2,11

Antibiotic treatment has become more difficult as resistance arises. Antibiotic resistance likely is due to extensive antibiotic use in health care along with the agriculture and aquaculture industries using prophylactic and therapeutic antibiotics that wash into or are directly added to marine waters, where V vulnificus resides. Thus, antibiotic treatment should be tailored to the resistance profile of V vulnificus in various regions; for example, ceftazidime has an intermediate resistance profile in the United States, so cefotaxime and ceftriaxone may be better options.²

Wound Care
Wound infections must be extensively irrigated.^9,21 For mild wound infections, proper wound care and oral antibiotics are appropriate (Table).²¹ Mild wounds should be irrigated thoroughly and followed by wound coverage to prevent progression, secondary infection, and necrosis. The dressing of choice will depend on the presenting lesion and provider preference; nonadherent, occlusive, or wet-to-dry dressings often are the best choices.²² Nonadherent dressings, such as petrolatum-covered gauze, do not pull off the newly formed epithelium when removed, making them beneficial to the skin’s healing process. Another option is occlusive dressings, which maintain a moist environment to hasten healing. They also enhance the autodigestion of necrotic tissue, which can be beneficial for necrotizing V vulnificus infections. Wet-to-dry dressings also may be used; these typically are comprised of gauze soaked with water, an astringent, and an antimicrobial or antiseptic solution. These dressings help to treat acute inflammation and also remove any exudate from the wound.²²

Soft tissue and necrotizing infections require debridement.^2,8 Early debridement decreases mortality rates.^2,8,9 Necrotizing fasciitis often requires serial debridement to clear all the dead tissue and reduce the bacterial burden.^8,9 Debridement prevents contiguous spread and metastatic seeding of the bacteria; it is important to prevent spread to the blood vessels, as vasculitis can necrose vessels, preventing antibiotics from reaching the dead tissue.¹⁷ Providers also should monitor for compartment syndrome, which should be treated with fasciotomy to decrease mortality.^9,23 Many physicians leave V vulnificus–infected wounds open in order to heal by secondary intention.⁹ Hyperbaric oxygen therapy may be helpful as an adjunct to aggressive antimicrobial treatment for wound healing.⁸

Supportive Measures
Supportive care for dehydration, sepsis, DIC, and septic shock may be necessary, depending on the patient’s course. Treatment for severe V vulnificus infection includes intravenous fluids, crystalloids, oxygen, and/or intubation. Furthermore, if DIC develops, fresh frozen plasma, cryoprecipitate, a packed red blood cell transfusion, and/or anticoagulation may be required for resuscitation.³

Timing
Time to treatment and fatality rate are directly proportional in V vulnificus infection; the greater the delay in treatment, the higher the fatality rate.² A 24-hour delay in antibiotic treatment is associated with a 33% case-fatality rate, and a 72-hour delay is associated with a 100% case-fatality rate.⁹ Even with early, appropriate treatment, mortality rates remain high.⁴

Prevention

Prevention of V vulnificus infections is an important consideration, especially for patients with chronic liver disease, immunosuppression, and hemochromatosis. Public education about the risks of eating raw shellfish is important.⁴ Oysters need to be treated properly to prevent growth and survival of V vulnificus.² The most reliable method for destroying the bacteria is cooking shellfish.^8,13 Only 15% of high-risk patients in the United States are aware of the risks associated with raw oyster consumption.³ High-risk patients should avoid eating raw oysters and shellfish and should cook seafood thoroughly before consumption.^2,8 They also should wear protective clothing (ie, gloves) and eye protection when handling seafood and protective footwear (ie, wading shoes) while in seawater.^2,8,13 It also is important to avoid contact with brackish water if one has any open wounds and to cleanse properly after exposure to brackish water or shellfish.^2,8,16 Because severe V vulnificus infections can lead to death, prevention should be strongly encouraged by providers.²

Conclusion

Vibrio vulnificus infection typically occurs due to consumption of contaminated seafood or exposure to contaminated seawater. It most frequently affects older male patients with chronic liver disease, immunosuppression, hemochromatosis, or diabetes mellitus. Vibrio vulnificus can cause a vast spectrum of diseases, including gastroenteritis, wound infections, necrotizing fasciitis, and sepsis. Septicemia is the most common presentation of V vulnificus infection and accounts for the most fatalities from the bacteria. Septicemia often presents with fever, chills, vomiting, diarrhea, and hemorrhagic bullae. Vibrio vulnificus also commonly causes necrotizing fasciitis, which initially presents as cellulitis and rapidly progresses to hemorrhagic bullae or necrosis with accompanying systemic symptoms. Prompt diagnosis and treatment are vital to prevent mortality.

Interestingly, regions impacted by V vulnificus are expanding because of global warming.^5,7Vibrio vulnificus thrives in warm waters, and increasing water temperatures are enhancing V vulnificus growth and survival.^1,9 As global warming continues, the incidence of V vulnificus infections may rise. In fact, the number of infections increased by 78% between 1996 and 2006 in the United States.⁵ This rise likely was due to a combination of factors, including an aging population with more comorbidities, improvements in diagnosis, and climate change. Thus, as the number of V vulnificus infections rises, so too must providers’ suspicion for the pathogen.

Vibrio vulnificus is a member of the Vibrio genus. Most Vibrio species are nonpathogenic in humans; however, V vulnificus is one of the pathogenic strains.¹ In Latin, the term vulnificus means “wounding,” and V vulnificus can cause life-threatening infections in patients. The mortality rate of V vulnificus infections is approximately 33% in the United States.²Vibrio vulnificus is a gram-negative bacterium that was first isolated by the Centers for Disease Control and Prevention in 1964 and was given its current name in 1979.^3-6 It has been found in numerous organisms, including oysters, crabs, clams, shrimp, mussels, mullets, and sea bass.⁴ The vast majority of infections in the United States are due to oyster exposure and consumption.^2,7Vibrio vulnificus is responsible for more than 95% of seafood-related deaths in the United States and has the highest mortality rate of all food-borne illness in the United States.^2,5 It also has the highest per-case economic impact of all food-related diseases in the United States.¹

What distinguishes a pathogenic vs nonpathogenic Vibrio isolate remains unknown; Vibrio species rapidly undergo horizontal gene transfer, making DNA isolation difficult.¹ Some characteristics of V vulnificus that may confer virulence are the capsular polysaccharide, lipopolysaccharide, binding proteins, and tissue-degrading enzymes.^1,5 First, encapsulated strains are more virulent and invasive than unencapsulated strains.¹ The mucopolysaccharide capsule protects the bacterium from the immune system, allowing it to evade immune surveillance, cause more severe infection, and invade into the subcutaneous tissue.^3,5 Second, production of sialic acid–like molecules alter the lipopolysaccharide, allowing for motility and biofilm formation.¹ This allows the bacterium to survive in marine waters and within the bloodstream, the latter leading to sepsis in humans. Third, production of N-acetylglucosamine–binding protein A allows for adhesion to chitin. Shellfish consume chitin, and chitin accumulates in shellfish. N-acetylglucosamine–binding protein A also binds mucin; this may be how V vulnificus binds to mucin in the gastrointestinal tract in humans, causing gastroenteritis.¹ Binding to the human mucosae also may allow the bacteria to gain access to the blood supply, leading to septicemia.⁴ Finally, tissue-degrading enzymes such as proteases are responsible for necrotizing wound infections associated with V vulnificus, as the enzymes allow for invasion into the skin and subcutaneous tissues. Proteases also increase vascular permeability and lead to edema.³ Hence, these virulence factors may provide V vulnificus the pathogenicity to cause infection in humans.

Three biotypes of V vulnificus have been discovered. Biotype 1 is the most common and is found worldwide in brackish water.⁸ It can cause the entire spectrum of illnesses, and it has a case fatality rate of 50% in humans. Biotype 1 is presumably responsible for all infections in the United States. Biotype 2 is found in the Far East and Western Europe; it inhabits a unique niche—saltwater used for eel farming. It typically causes infection in eels, but rarely it can cause wound infections in humans. Biotype 3 is found in freshwater fish farming in Israel, and it is a hybrid of biotypes 1 and 2.It can cause severe soft tissue infections in humans, sometimes requiring amputation.⁸

Epidemiology

Vibrio vulnificus is a motile, gram-negative, halophilic, aquatic bacterium.^1,4,5,8,9 It is part of the normal estuarine microbiome and typically is found in warm coastal waters.^1,5,10 The ideal conditions for growth and survival of V vulnificus are water temperatures at 18 °C (64.4 °F) and water salinities between 15 to 25 parts per thousand.^2,8,9 These conditions are found in tropical and subtropical regions.²Vibrio vulnificus is found all over the world, including Denmark, Italy, Japan, Australia, Brazil, and the United States,² where most infections come from oyster exposure and consumption in the Gulf of Mexico.^2,8,11 The incidence of infection in the United States is highest between April and October.^8,11

Some populations are at a higher risk of infection. Risk factors include male sex, liver cirrhosis, hemochromatosis, end-stage renal disease, immunosuppression, and diabetes mellitus.^1,8,11 Healthy patients with no risk factors account for less than 5% of US V vulnificus infections.⁸

Male Predilection
Men are 6 times more likely to be affected by V vulnificus than women.Some hypotheses for this discrepancy are that estrogen is protective againstV vulnificus and that women may be less likely to engage in risky water activities and seafood handling.⁵ Additionally, older males (aged >60 years) are most often affected,^1,8 likely due to the association between increasing age with number of comorbidities, such as diabetes mellitus, heart disease, and chronic disease.⁸

Iron Levels
Iron appears to play an important role in V vulnificus infection. Iron is essential for bacterial growth, and the ability to obtain iron from a host increases the organism’s pathogenicity.³Vibrio vulnificus rapidly grows when transferrin saturation exceeds 70%.⁸ Additionally, iron overload decreases the inoculum needed to cause sepsis in animal studies, which could play a role in human pathogenesis.⁴ Iron levels are elevated in patients with hemochromatosis due to increased iron absorption, cirrhosis and chronic liver disease due to impaired iron metabolism, and end-stage renal disease, especially in patients receiving parenteral iron.⁸

Immunosuppression
Patients who are immunocompromised and those with chronic liver disease are at an increased risk of infection because of neutrophils having decreased phagocytic activity.⁴

Diabetes Mellitus
Patients with diabetes mellitus may have peripheral neuropathy and may be unaware of pre-existing wounds that serve as entry points for V vulnificus.¹²

Etiology

Vibrio vulnificus infects humans via seafood consumption and handling as well as exposure to contaminated water.^2,5 With respect to seafood consumption, raw shellfish are the primary type of seafood that harbor high levels of V vulnificus.⁵ Oysters are the most common etiology, but consumption of crabs, clams, and shrimp also can lead to infection.^5,7Vibrio vulnificus contamination does not change the appearance, taste, or odor of shellfish, making it hard to detect.⁸ An inoculate of 1 million bacteria typically is necessary for infection after consumption.⁵ Contaminated seawater is another primary cause of V vulnificus infection. When open wounds are exposed to seawater harboring the bacteria, wound infections can arise.⁷ Infections can be acquired when swimming, fishing, or participating in water sports. Wound infections also occur while handling contaminated seafood, such as oyster shucking.⁵ There is a short incubation period for V vulnificus infections; the onset of symptoms and clinical outcome typically occur within 24 hours.⁵

Clinical Presentation

Vibrio vulnificus infections can have numerous clinical presentations, including gastroenteritis, wound infections, necrotizing fasciitis, and sepsis.^1,8 There also is a spectrum of clinical outcomes; for instance, gastroenteritis typically is self-limited, whereas necrotizing fasciitis or sepsis can be fatal.²

Gastroenteritis
Vibrio vulnificus gastroenteritis is due to ingestion of contaminated shellfish.^2,9 Symptoms typically are mild to moderate and include nausea, vomiting, diarrhea, fever, chills, abdominal pain, and cramping.^2,4,8 Cases likely are underreported in the United States because gastroenteritis is self-limited, and many patients do not seek treatment.^2,11

Wound Infections
Wound infections with V vulnificus have a cutaneous port of entry. Exposure to contaminated seawater or seafood can inoculate an open wound, leading to infection.^7,8 Wound infections usually stem from 1 of 2 routes: (1) a pre-existing open wound gets infected while the patient is swimming in contaminated water, or (2) a traumatic injury occurs while the patient is handling contaminated shellfish, knives, or fishhooks. Many shellfish, such as oysters, have sharp points on their shells that can lacerate the skin.⁸ A wound on the hand can be contaminated by V vulnificus while handling contaminated seafood (eg, oyster shucking).¹³ Minor abrasions should not be dismissed; in fact, a small puncture or skin break often acts as the port of entry.^9,11 Wound infections tend to arise within 7 days of exposure, though they can manifest up to 12 days after exposure.⁸ Wound infections can present as cellulitis, bullae, or ecchymoses.⁷ Lesions are exquisitely tender, and the skin is erythematous with marked surrounding soft tissue edema.^3,4,8 Cellulitis typically arises first, with hemorrhagic bullae rapidly following.¹⁴ Lesions are limited to the affected extremity or area of inoculation.⁸ Systemic symptoms are rare, but fever and chills may accompany the infection.^8,14 Unfortunately, lesions can become necrotic and progress rapidly to necrotizing fasciitis if left untreated.^4,7,11 In these cases, secondary sepsis can occur.⁸

Necrotizing Fasciitis
Wound infections caused by V vulnificus can progress to necrotizing skin and soft tissue infections, such as necrotizing fasciitis and gangrene.⁵ Necrotizing fasciitis accounts for approximately one-third of V vulnificus infections.⁹ It usually stems from an open wound that is inoculated by contact with contaminated seafood or seawater.^2,9 The wound infection begins as cellulitis with extreme tenderness, erythematous skin, and marked soft tissue edema, then rapidly progresses, becoming necrotic. These necrotic lesions present as black and purple eschars as the skin, blood supply, and subcutaneous tissues are infiltrated by the bacteria and destroyed. Lesions may have blistering or exudation. Many patients have accompanying systemic symptoms, including fever, chills, abdominal pain, diarrhea, hypotension, and sepsis.^11,14 However, some patients may not present with systemic symptoms, so it is important to maintain a high index of suspicion even in the absence of these symptoms. The infection typically is limited to the affected extremity; necrotizing infections can lead to amputation and even death, depending on the extent of destruction and spread of the bacteria.^11,13 The infection may spread beyond the inoculated extremity if the bacteria gains access to the bloodstream.^8,9 In these cases, fulminant purpura or secondary septicemia can occur.^8,15 Fatalityrates in the United States for necrotizing V vulnificus infections approach 30%.² Necrotizing fasciitis accounts for approximately 8% of deaths associated with the pathogen in the United States.⁹

Interestingly, one reported case of necrotizing fasciitis associated with V vulnificus infection was triggered by acupuncture.¹⁶ The patient worked in a fish hatchery, where he was exposed to V vulnificus, and subsequent acupuncture led to the inoculation of bacteria into his bloodstream. This case raises the important point that we typically sequence the pathogenesis of V vulnificus infection as a patient having an open wound that is subsequently exposed to contaminated water; however, it also can follow the reverse sequence. Thus, proper cleansing of the skin after swimming in brackish water or handling shellfish is important to prevent V vulnificus infection.¹⁶ Additionally, dermatologists should be sure to cleanse patients’ skin thoroughly before performing procedures that could cause breaks in the skin.

Septicemia
Primary septicemia is the most common presentation of V vulnificus infection.^2,8 Septicemia accounts for approximately 58% of V vulnificus infections in the United States.⁹ Infection typically occurs after ingestion of contaminated oysters, with subsequent absorption into the bloodstream through the ileum or cecum.^2,8,9 Patients with chronic liver disease are 80 times more likely to develop primary sepsis than healthy individuals.⁸ Patients typically present with sudden-onset fever and chills, vomiting, diarrhea, and pain in the abdomen and/or extremities within hours to days of ingestion.^4,8,9 The median time from ingestion to symptom onset is 18 hours.^4,16 However, symptoms can be delayed up to 14 days.² Progression is rapid; secondary lesions such as bullae, ecchymoses, cellulitis, purpura, macular or maculopapular eruptions, pustules, vasculitis, urticaria, and erythema multiforme–like lesions appear on the extremities within 24 hours of symptom onset. ^2,3,4,8,17 Hemorrhagic bullae are the most common cutaneous manifestation of sepsis.⁴ Lesions are extremely tender to palpation.³ Cutaneous lesions can progress to necrotic ulcers, necrotizing fasciitis, gangrene, necrotizing vasculitis, or myonecrosis.^4,8 Evidence of petechiae may indicate progression to disseminated intravascular coagulation (DIC). Elevated D-dimer and fibrin split products also may indicate DIC, and elevated creatine kinase may signify rhabdomyolysis.³ Unfortunately, septicemia has the worst outcomes of all V vulnificus presentations, with morality rates greater than 50% in the United States.^1,2,4Vibrio vulnificus septicemia has a similar case-fatality rate to pathogens such as anthrax, Ebola virus disease, and the bubonic plague.⁵ Septicemia accounts for approximately 80% of the deaths associated with V vulnificus in the United States.^8,9

Septicemia due to V vulnificus progresses to septic shock in two-thirds of cases.⁸ Septic shock presents with hypotension, mental status changes, and thrombocytopenia.^2,8,17 Patients can become tachycardic, tachypneic, and hypoxic. Intubation may be required for resuscitation. In cases of septic shock secondary to V vulnificus infection, mortality rates reach 92%.³ Hypotension with a systolic blood pressure less than 90 mm Hg is a poor prognostic factor; patients presenting with hypotension secondary to V vulnificus infection have a fatality rate approaching 75% within 12 hours.²

Atypical Presentations
Rare atypical presentations of V vulnificus infection that have been reported in the literature include meningitis, corneal ulcers, epiglottitis, tonsillitis, spontaneous bacterial peritonitis, pneumonia, endometritis, septic arthritis, osteomyelitis, rhabdomyolysis endophthalmitis, and keratitis.^{2,4,6,13,18,19}

Diagnosis

When diagnosing V vulnificus, providers need to obtain a thorough patient history, including any history of consumption or handling of raw seafood and recent water activities. Providers practicing in tropical climates or in warm summer months should keep V vulnificus in mind, as it is the ideal climate for the pathogen.⁹ Vital signs can range from unremarkable to fever, hypotension, tachycardia, and/or hypoxia. Skin examination may show exquisitely tender, erythematous skin with marked soft tissue edema, hemorrhagic bullae, ecchymoses, and/or necrosis. As physical examination findings can be nonspecific, wound cultures, blood cultures, and skin biopsies should be taken.

A wound culture and blood culture should be taken immediately if V vulnificus is suspected.^8,11 A wound culture using discharge or fluid from necrotic or bullous lesions should be analyzed via gram stain.^8,9 Gram stains of V vulnificus show short, slim, curved gram-negative rods under light microscopy.^9,20 Special stains also can be done on cultures; V vulnificus is an oxidase-positive, lactose-positive, lysine-positive, salicin-positive, and arginine-negative organism. This knowledge can help differentiate V vulnificus from other gram-negative rods.¹³ Blood cultures will be positive in approximately 97% of patients with primary septicemia and 30% of patients with septicemia secondary to V vulnificus wound infections.^3,9

Histologically, perilesional skin biopsies show epidermal necrosis with dermal and subcutaneous inflammation.^12,17 There typically is an inflammatory infiltrate with neutrophilic abscesses and extensive tissue destruction in the subcutaneous tissue extending into the deep dermis.^12,17 The superficial dermis is edematous but can lack the inflammatory infiltrate found in the subcutaneous tissue.¹⁷ Subepidermal bullae can form with numerous organisms within the fluid of the bullae. There also may be evidence of leukocytoclastic vasculitis with accompanying vessel wall necrosis. Fibrin clot formation and extravasated red blood cells may be visualized with few inflammatory cells but numerous organisms around the involved vessels.¹⁷

Management

Early diagnosis and treatment are vital.^5,17 Cultures should be taken before aggressive treatment is started.³ Treatment is multifaceted; it requires antibiotics and wound care, except in cases of self-limited gastroenteritis.^2,11 Aggressive debridement, fasciotomy, amputation, and supportive measures also may be necessary depending on the patient’s presentation.^2,3,8,9 Establishing 2 peripheral intravenous lines is important in case rapid resuscitation becomes necessary.

Antibiotics
Primary cellulitis wound infections should be treated with doxycycline or a quinolone. If untreated, the wound can rapidly progress to necrotizing fasciitis.¹¹ For necrotizing fasciitis and septicemia, broader-spectrum antibiotics are needed. For adults, ceftazidime plus doxycycline is the mainstay of antibiotic treatment for V vulnificus.^2,9,11 For children, trimethoprim-sulfamethoxazole plus an aminoglycoside is preferred (Table).^2,11

Antibiotic treatment has become more difficult as resistance arises. Antibiotic resistance likely is due to extensive antibiotic use in health care along with the agriculture and aquaculture industries using prophylactic and therapeutic antibiotics that wash into or are directly added to marine waters, where V vulnificus resides. Thus, antibiotic treatment should be tailored to the resistance profile of V vulnificus in various regions; for example, ceftazidime has an intermediate resistance profile in the United States, so cefotaxime and ceftriaxone may be better options.²

Wound Care
Wound infections must be extensively irrigated.^9,21 For mild wound infections, proper wound care and oral antibiotics are appropriate (Table).²¹ Mild wounds should be irrigated thoroughly and followed by wound coverage to prevent progression, secondary infection, and necrosis. The dressing of choice will depend on the presenting lesion and provider preference; nonadherent, occlusive, or wet-to-dry dressings often are the best choices.²² Nonadherent dressings, such as petrolatum-covered gauze, do not pull off the newly formed epithelium when removed, making them beneficial to the skin’s healing process. Another option is occlusive dressings, which maintain a moist environment to hasten healing. They also enhance the autodigestion of necrotic tissue, which can be beneficial for necrotizing V vulnificus infections. Wet-to-dry dressings also may be used; these typically are comprised of gauze soaked with water, an astringent, and an antimicrobial or antiseptic solution. These dressings help to treat acute inflammation and also remove any exudate from the wound.²²

Soft tissue and necrotizing infections require debridement.^2,8 Early debridement decreases mortality rates.^2,8,9 Necrotizing fasciitis often requires serial debridement to clear all the dead tissue and reduce the bacterial burden.^8,9 Debridement prevents contiguous spread and metastatic seeding of the bacteria; it is important to prevent spread to the blood vessels, as vasculitis can necrose vessels, preventing antibiotics from reaching the dead tissue.¹⁷ Providers also should monitor for compartment syndrome, which should be treated with fasciotomy to decrease mortality.^9,23 Many physicians leave V vulnificus–infected wounds open in order to heal by secondary intention.⁹ Hyperbaric oxygen therapy may be helpful as an adjunct to aggressive antimicrobial treatment for wound healing.⁸

Supportive Measures
Supportive care for dehydration, sepsis, DIC, and septic shock may be necessary, depending on the patient’s course. Treatment for severe V vulnificus infection includes intravenous fluids, crystalloids, oxygen, and/or intubation. Furthermore, if DIC develops, fresh frozen plasma, cryoprecipitate, a packed red blood cell transfusion, and/or anticoagulation may be required for resuscitation.³

Timing
Time to treatment and fatality rate are directly proportional in V vulnificus infection; the greater the delay in treatment, the higher the fatality rate.² A 24-hour delay in antibiotic treatment is associated with a 33% case-fatality rate, and a 72-hour delay is associated with a 100% case-fatality rate.⁹ Even with early, appropriate treatment, mortality rates remain high.⁴

Prevention

Prevention of V vulnificus infections is an important consideration, especially for patients with chronic liver disease, immunosuppression, and hemochromatosis. Public education about the risks of eating raw shellfish is important.⁴ Oysters need to be treated properly to prevent growth and survival of V vulnificus.² The most reliable method for destroying the bacteria is cooking shellfish.^8,13 Only 15% of high-risk patients in the United States are aware of the risks associated with raw oyster consumption.³ High-risk patients should avoid eating raw oysters and shellfish and should cook seafood thoroughly before consumption.^2,8 They also should wear protective clothing (ie, gloves) and eye protection when handling seafood and protective footwear (ie, wading shoes) while in seawater.^2,8,13 It also is important to avoid contact with brackish water if one has any open wounds and to cleanse properly after exposure to brackish water or shellfish.^2,8,16 Because severe V vulnificus infections can lead to death, prevention should be strongly encouraged by providers.²

Conclusion

Vibrio vulnificus infection typically occurs due to consumption of contaminated seafood or exposure to contaminated seawater. It most frequently affects older male patients with chronic liver disease, immunosuppression, hemochromatosis, or diabetes mellitus. Vibrio vulnificus can cause a vast spectrum of diseases, including gastroenteritis, wound infections, necrotizing fasciitis, and sepsis. Septicemia is the most common presentation of V vulnificus infection and accounts for the most fatalities from the bacteria. Septicemia often presents with fever, chills, vomiting, diarrhea, and hemorrhagic bullae. Vibrio vulnificus also commonly causes necrotizing fasciitis, which initially presents as cellulitis and rapidly progresses to hemorrhagic bullae or necrosis with accompanying systemic symptoms. Prompt diagnosis and treatment are vital to prevent mortality.

Interestingly, regions impacted by V vulnificus are expanding because of global warming.^5,7Vibrio vulnificus thrives in warm waters, and increasing water temperatures are enhancing V vulnificus growth and survival.^1,9 As global warming continues, the incidence of V vulnificus infections may rise. In fact, the number of infections increased by 78% between 1996 and 2006 in the United States.⁵ This rise likely was due to a combination of factors, including an aging population with more comorbidities, improvements in diagnosis, and climate change. Thus, as the number of V vulnificus infections rises, so too must providers’ suspicion for the pathogen.

Vibrio vulnificus is a member of the Vibrio genus. Most Vibrio species are nonpathogenic in humans; however, V vulnificus is one of the pathogenic strains.¹ In Latin, the term vulnificus means “wounding,” and V vulnificus can cause life-threatening infections in patients. The mortality rate of V vulnificus infections is approximately 33% in the United States.²Vibrio vulnificus is a gram-negative bacterium that was first isolated by the Centers for Disease Control and Prevention in 1964 and was given its current name in 1979.^3-6 It has been found in numerous organisms, including oysters, crabs, clams, shrimp, mussels, mullets, and sea bass.⁴ The vast majority of infections in the United States are due to oyster exposure and consumption.^2,7Vibrio vulnificus is responsible for more than 95% of seafood-related deaths in the United States and has the highest mortality rate of all food-borne illness in the United States.^2,5 It also has the highest per-case economic impact of all food-related diseases in the United States.¹

What distinguishes a pathogenic vs nonpathogenic Vibrio isolate remains unknown; Vibrio species rapidly undergo horizontal gene transfer, making DNA isolation difficult.¹ Some characteristics of V vulnificus that may confer virulence are the capsular polysaccharide, lipopolysaccharide, binding proteins, and tissue-degrading enzymes.^1,5 First, encapsulated strains are more virulent and invasive than unencapsulated strains.¹ The mucopolysaccharide capsule protects the bacterium from the immune system, allowing it to evade immune surveillance, cause more severe infection, and invade into the subcutaneous tissue.^3,5 Second, production of sialic acid–like molecules alter the lipopolysaccharide, allowing for motility and biofilm formation.¹ This allows the bacterium to survive in marine waters and within the bloodstream, the latter leading to sepsis in humans. Third, production of N-acetylglucosamine–binding protein A allows for adhesion to chitin. Shellfish consume chitin, and chitin accumulates in shellfish. N-acetylglucosamine–binding protein A also binds mucin; this may be how V vulnificus binds to mucin in the gastrointestinal tract in humans, causing gastroenteritis.¹ Binding to the human mucosae also may allow the bacteria to gain access to the blood supply, leading to septicemia.⁴ Finally, tissue-degrading enzymes such as proteases are responsible for necrotizing wound infections associated with V vulnificus, as the enzymes allow for invasion into the skin and subcutaneous tissues. Proteases also increase vascular permeability and lead to edema.³ Hence, these virulence factors may provide V vulnificus the pathogenicity to cause infection in humans.

Three biotypes of V vulnificus have been discovered. Biotype 1 is the most common and is found worldwide in brackish water.⁸ It can cause the entire spectrum of illnesses, and it has a case fatality rate of 50% in humans. Biotype 1 is presumably responsible for all infections in the United States. Biotype 2 is found in the Far East and Western Europe; it inhabits a unique niche—saltwater used for eel farming. It typically causes infection in eels, but rarely it can cause wound infections in humans. Biotype 3 is found in freshwater fish farming in Israel, and it is a hybrid of biotypes 1 and 2.It can cause severe soft tissue infections in humans, sometimes requiring amputation.⁸

Epidemiology

Vibrio vulnificus is a motile, gram-negative, halophilic, aquatic bacterium.^1,4,5,8,9 It is part of the normal estuarine microbiome and typically is found in warm coastal waters.^1,5,10 The ideal conditions for growth and survival of V vulnificus are water temperatures at 18 °C (64.4 °F) and water salinities between 15 to 25 parts per thousand.^2,8,9 These conditions are found in tropical and subtropical regions.²Vibrio vulnificus is found all over the world, including Denmark, Italy, Japan, Australia, Brazil, and the United States,² where most infections come from oyster exposure and consumption in the Gulf of Mexico.^2,8,11 The incidence of infection in the United States is highest between April and October.^8,11

Some populations are at a higher risk of infection. Risk factors include male sex, liver cirrhosis, hemochromatosis, end-stage renal disease, immunosuppression, and diabetes mellitus.^1,8,11 Healthy patients with no risk factors account for less than 5% of US V vulnificus infections.⁸

Male Predilection
Men are 6 times more likely to be affected by V vulnificus than women.Some hypotheses for this discrepancy are that estrogen is protective againstV vulnificus and that women may be less likely to engage in risky water activities and seafood handling.⁵ Additionally, older males (aged >60 years) are most often affected,^1,8 likely due to the association between increasing age with number of comorbidities, such as diabetes mellitus, heart disease, and chronic disease.⁸

Iron Levels
Iron appears to play an important role in V vulnificus infection. Iron is essential for bacterial growth, and the ability to obtain iron from a host increases the organism’s pathogenicity.³Vibrio vulnificus rapidly grows when transferrin saturation exceeds 70%.⁸ Additionally, iron overload decreases the inoculum needed to cause sepsis in animal studies, which could play a role in human pathogenesis.⁴ Iron levels are elevated in patients with hemochromatosis due to increased iron absorption, cirrhosis and chronic liver disease due to impaired iron metabolism, and end-stage renal disease, especially in patients receiving parenteral iron.⁸

Immunosuppression
Patients who are immunocompromised and those with chronic liver disease are at an increased risk of infection because of neutrophils having decreased phagocytic activity.⁴

Diabetes Mellitus
Patients with diabetes mellitus may have peripheral neuropathy and may be unaware of pre-existing wounds that serve as entry points for V vulnificus.¹²

Etiology

Vibrio vulnificus infects humans via seafood consumption and handling as well as exposure to contaminated water.^2,5 With respect to seafood consumption, raw shellfish are the primary type of seafood that harbor high levels of V vulnificus.⁵ Oysters are the most common etiology, but consumption of crabs, clams, and shrimp also can lead to infection.^5,7Vibrio vulnificus contamination does not change the appearance, taste, or odor of shellfish, making it hard to detect.⁸ An inoculate of 1 million bacteria typically is necessary for infection after consumption.⁵ Contaminated seawater is another primary cause of V vulnificus infection. When open wounds are exposed to seawater harboring the bacteria, wound infections can arise.⁷ Infections can be acquired when swimming, fishing, or participating in water sports. Wound infections also occur while handling contaminated seafood, such as oyster shucking.⁵ There is a short incubation period for V vulnificus infections; the onset of symptoms and clinical outcome typically occur within 24 hours.⁵

Clinical Presentation

Vibrio vulnificus infections can have numerous clinical presentations, including gastroenteritis, wound infections, necrotizing fasciitis, and sepsis.^1,8 There also is a spectrum of clinical outcomes; for instance, gastroenteritis typically is self-limited, whereas necrotizing fasciitis or sepsis can be fatal.²

Gastroenteritis
Vibrio vulnificus gastroenteritis is due to ingestion of contaminated shellfish.^2,9 Symptoms typically are mild to moderate and include nausea, vomiting, diarrhea, fever, chills, abdominal pain, and cramping.^2,4,8 Cases likely are underreported in the United States because gastroenteritis is self-limited, and many patients do not seek treatment.^2,11

Wound Infections
Wound infections with V vulnificus have a cutaneous port of entry. Exposure to contaminated seawater or seafood can inoculate an open wound, leading to infection.^7,8 Wound infections usually stem from 1 of 2 routes: (1) a pre-existing open wound gets infected while the patient is swimming in contaminated water, or (2) a traumatic injury occurs while the patient is handling contaminated shellfish, knives, or fishhooks. Many shellfish, such as oysters, have sharp points on their shells that can lacerate the skin.⁸ A wound on the hand can be contaminated by V vulnificus while handling contaminated seafood (eg, oyster shucking).¹³ Minor abrasions should not be dismissed; in fact, a small puncture or skin break often acts as the port of entry.^9,11 Wound infections tend to arise within 7 days of exposure, though they can manifest up to 12 days after exposure.⁸ Wound infections can present as cellulitis, bullae, or ecchymoses.⁷ Lesions are exquisitely tender, and the skin is erythematous with marked surrounding soft tissue edema.^3,4,8 Cellulitis typically arises first, with hemorrhagic bullae rapidly following.¹⁴ Lesions are limited to the affected extremity or area of inoculation.⁸ Systemic symptoms are rare, but fever and chills may accompany the infection.^8,14 Unfortunately, lesions can become necrotic and progress rapidly to necrotizing fasciitis if left untreated.^4,7,11 In these cases, secondary sepsis can occur.⁸

Necrotizing Fasciitis
Wound infections caused by V vulnificus can progress to necrotizing skin and soft tissue infections, such as necrotizing fasciitis and gangrene.⁵ Necrotizing fasciitis accounts for approximately one-third of V vulnificus infections.⁹ It usually stems from an open wound that is inoculated by contact with contaminated seafood or seawater.^2,9 The wound infection begins as cellulitis with extreme tenderness, erythematous skin, and marked soft tissue edema, then rapidly progresses, becoming necrotic. These necrotic lesions present as black and purple eschars as the skin, blood supply, and subcutaneous tissues are infiltrated by the bacteria and destroyed. Lesions may have blistering or exudation. Many patients have accompanying systemic symptoms, including fever, chills, abdominal pain, diarrhea, hypotension, and sepsis.^11,14 However, some patients may not present with systemic symptoms, so it is important to maintain a high index of suspicion even in the absence of these symptoms. The infection typically is limited to the affected extremity; necrotizing infections can lead to amputation and even death, depending on the extent of destruction and spread of the bacteria.^11,13 The infection may spread beyond the inoculated extremity if the bacteria gains access to the bloodstream.^8,9 In these cases, fulminant purpura or secondary septicemia can occur.^8,15 Fatalityrates in the United States for necrotizing V vulnificus infections approach 30%.² Necrotizing fasciitis accounts for approximately 8% of deaths associated with the pathogen in the United States.⁹

Interestingly, one reported case of necrotizing fasciitis associated with V vulnificus infection was triggered by acupuncture.¹⁶ The patient worked in a fish hatchery, where he was exposed to V vulnificus, and subsequent acupuncture led to the inoculation of bacteria into his bloodstream. This case raises the important point that we typically sequence the pathogenesis of V vulnificus infection as a patient having an open wound that is subsequently exposed to contaminated water; however, it also can follow the reverse sequence. Thus, proper cleansing of the skin after swimming in brackish water or handling shellfish is important to prevent V vulnificus infection.¹⁶ Additionally, dermatologists should be sure to cleanse patients’ skin thoroughly before performing procedures that could cause breaks in the skin.

Septicemia
Primary septicemia is the most common presentation of V vulnificus infection.^2,8 Septicemia accounts for approximately 58% of V vulnificus infections in the United States.⁹ Infection typically occurs after ingestion of contaminated oysters, with subsequent absorption into the bloodstream through the ileum or cecum.^2,8,9 Patients with chronic liver disease are 80 times more likely to develop primary sepsis than healthy individuals.⁸ Patients typically present with sudden-onset fever and chills, vomiting, diarrhea, and pain in the abdomen and/or extremities within hours to days of ingestion.^4,8,9 The median time from ingestion to symptom onset is 18 hours.^4,16 However, symptoms can be delayed up to 14 days.² Progression is rapid; secondary lesions such as bullae, ecchymoses, cellulitis, purpura, macular or maculopapular eruptions, pustules, vasculitis, urticaria, and erythema multiforme–like lesions appear on the extremities within 24 hours of symptom onset. ^2,3,4,8,17 Hemorrhagic bullae are the most common cutaneous manifestation of sepsis.⁴ Lesions are extremely tender to palpation.³ Cutaneous lesions can progress to necrotic ulcers, necrotizing fasciitis, gangrene, necrotizing vasculitis, or myonecrosis.^4,8 Evidence of petechiae may indicate progression to disseminated intravascular coagulation (DIC). Elevated D-dimer and fibrin split products also may indicate DIC, and elevated creatine kinase may signify rhabdomyolysis.³ Unfortunately, septicemia has the worst outcomes of all V vulnificus presentations, with morality rates greater than 50% in the United States.^1,2,4Vibrio vulnificus septicemia has a similar case-fatality rate to pathogens such as anthrax, Ebola virus disease, and the bubonic plague.⁵ Septicemia accounts for approximately 80% of the deaths associated with V vulnificus in the United States.^8,9

Septicemia due to V vulnificus progresses to septic shock in two-thirds of cases.⁸ Septic shock presents with hypotension, mental status changes, and thrombocytopenia.^2,8,17 Patients can become tachycardic, tachypneic, and hypoxic. Intubation may be required for resuscitation. In cases of septic shock secondary to V vulnificus infection, mortality rates reach 92%.³ Hypotension with a systolic blood pressure less than 90 mm Hg is a poor prognostic factor; patients presenting with hypotension secondary to V vulnificus infection have a fatality rate approaching 75% within 12 hours.²

Atypical Presentations
Rare atypical presentations of V vulnificus infection that have been reported in the literature include meningitis, corneal ulcers, epiglottitis, tonsillitis, spontaneous bacterial peritonitis, pneumonia, endometritis, septic arthritis, osteomyelitis, rhabdomyolysis endophthalmitis, and keratitis.^{2,4,6,13,18,19}

Diagnosis

When diagnosing V vulnificus, providers need to obtain a thorough patient history, including any history of consumption or handling of raw seafood and recent water activities. Providers practicing in tropical climates or in warm summer months should keep V vulnificus in mind, as it is the ideal climate for the pathogen.⁹ Vital signs can range from unremarkable to fever, hypotension, tachycardia, and/or hypoxia. Skin examination may show exquisitely tender, erythematous skin with marked soft tissue edema, hemorrhagic bullae, ecchymoses, and/or necrosis. As physical examination findings can be nonspecific, wound cultures, blood cultures, and skin biopsies should be taken.

A wound culture and blood culture should be taken immediately if V vulnificus is suspected.^8,11 A wound culture using discharge or fluid from necrotic or bullous lesions should be analyzed via gram stain.^8,9 Gram stains of V vulnificus show short, slim, curved gram-negative rods under light microscopy.^9,20 Special stains also can be done on cultures; V vulnificus is an oxidase-positive, lactose-positive, lysine-positive, salicin-positive, and arginine-negative organism. This knowledge can help differentiate V vulnificus from other gram-negative rods.¹³ Blood cultures will be positive in approximately 97% of patients with primary septicemia and 30% of patients with septicemia secondary to V vulnificus wound infections.^3,9

Histologically, perilesional skin biopsies show epidermal necrosis with dermal and subcutaneous inflammation.^12,17 There typically is an inflammatory infiltrate with neutrophilic abscesses and extensive tissue destruction in the subcutaneous tissue extending into the deep dermis.^12,17 The superficial dermis is edematous but can lack the inflammatory infiltrate found in the subcutaneous tissue.¹⁷ Subepidermal bullae can form with numerous organisms within the fluid of the bullae. There also may be evidence of leukocytoclastic vasculitis with accompanying vessel wall necrosis. Fibrin clot formation and extravasated red blood cells may be visualized with few inflammatory cells but numerous organisms around the involved vessels.¹⁷

Management

Early diagnosis and treatment are vital.^5,17 Cultures should be taken before aggressive treatment is started.³ Treatment is multifaceted; it requires antibiotics and wound care, except in cases of self-limited gastroenteritis.^2,11 Aggressive debridement, fasciotomy, amputation, and supportive measures also may be necessary depending on the patient’s presentation.^2,3,8,9 Establishing 2 peripheral intravenous lines is important in case rapid resuscitation becomes necessary.

Antibiotics
Primary cellulitis wound infections should be treated with doxycycline or a quinolone. If untreated, the wound can rapidly progress to necrotizing fasciitis.¹¹ For necrotizing fasciitis and septicemia, broader-spectrum antibiotics are needed. For adults, ceftazidime plus doxycycline is the mainstay of antibiotic treatment for V vulnificus.^2,9,11 For children, trimethoprim-sulfamethoxazole plus an aminoglycoside is preferred (Table).^2,11

Antibiotic treatment has become more difficult as resistance arises. Antibiotic resistance likely is due to extensive antibiotic use in health care along with the agriculture and aquaculture industries using prophylactic and therapeutic antibiotics that wash into or are directly added to marine waters, where V vulnificus resides. Thus, antibiotic treatment should be tailored to the resistance profile of V vulnificus in various regions; for example, ceftazidime has an intermediate resistance profile in the United States, so cefotaxime and ceftriaxone may be better options.²

Wound Care
Wound infections must be extensively irrigated.^9,21 For mild wound infections, proper wound care and oral antibiotics are appropriate (Table).²¹ Mild wounds should be irrigated thoroughly and followed by wound coverage to prevent progression, secondary infection, and necrosis. The dressing of choice will depend on the presenting lesion and provider preference; nonadherent, occlusive, or wet-to-dry dressings often are the best choices.²² Nonadherent dressings, such as petrolatum-covered gauze, do not pull off the newly formed epithelium when removed, making them beneficial to the skin’s healing process. Another option is occlusive dressings, which maintain a moist environment to hasten healing. They also enhance the autodigestion of necrotic tissue, which can be beneficial for necrotizing V vulnificus infections. Wet-to-dry dressings also may be used; these typically are comprised of gauze soaked with water, an astringent, and an antimicrobial or antiseptic solution. These dressings help to treat acute inflammation and also remove any exudate from the wound.²²

Soft tissue and necrotizing infections require debridement.^2,8 Early debridement decreases mortality rates.^2,8,9 Necrotizing fasciitis often requires serial debridement to clear all the dead tissue and reduce the bacterial burden.^8,9 Debridement prevents contiguous spread and metastatic seeding of the bacteria; it is important to prevent spread to the blood vessels, as vasculitis can necrose vessels, preventing antibiotics from reaching the dead tissue.¹⁷ Providers also should monitor for compartment syndrome, which should be treated with fasciotomy to decrease mortality.^9,23 Many physicians leave V vulnificus–infected wounds open in order to heal by secondary intention.⁹ Hyperbaric oxygen therapy may be helpful as an adjunct to aggressive antimicrobial treatment for wound healing.⁸

Supportive Measures
Supportive care for dehydration, sepsis, DIC, and septic shock may be necessary, depending on the patient’s course. Treatment for severe V vulnificus infection includes intravenous fluids, crystalloids, oxygen, and/or intubation. Furthermore, if DIC develops, fresh frozen plasma, cryoprecipitate, a packed red blood cell transfusion, and/or anticoagulation may be required for resuscitation.³

Timing
Time to treatment and fatality rate are directly proportional in V vulnificus infection; the greater the delay in treatment, the higher the fatality rate.² A 24-hour delay in antibiotic treatment is associated with a 33% case-fatality rate, and a 72-hour delay is associated with a 100% case-fatality rate.⁹ Even with early, appropriate treatment, mortality rates remain high.⁴

Prevention

Prevention of V vulnificus infections is an important consideration, especially for patients with chronic liver disease, immunosuppression, and hemochromatosis. Public education about the risks of eating raw shellfish is important.⁴ Oysters need to be treated properly to prevent growth and survival of V vulnificus.² The most reliable method for destroying the bacteria is cooking shellfish.^8,13 Only 15% of high-risk patients in the United States are aware of the risks associated with raw oyster consumption.³ High-risk patients should avoid eating raw oysters and shellfish and should cook seafood thoroughly before consumption.^2,8 They also should wear protective clothing (ie, gloves) and eye protection when handling seafood and protective footwear (ie, wading shoes) while in seawater.^2,8,13 It also is important to avoid contact with brackish water if one has any open wounds and to cleanse properly after exposure to brackish water or shellfish.^2,8,16 Because severe V vulnificus infections can lead to death, prevention should be strongly encouraged by providers.²

Conclusion

Vibrio vulnificus infection typically occurs due to consumption of contaminated seafood or exposure to contaminated seawater. It most frequently affects older male patients with chronic liver disease, immunosuppression, hemochromatosis, or diabetes mellitus. Vibrio vulnificus can cause a vast spectrum of diseases, including gastroenteritis, wound infections, necrotizing fasciitis, and sepsis. Septicemia is the most common presentation of V vulnificus infection and accounts for the most fatalities from the bacteria. Septicemia often presents with fever, chills, vomiting, diarrhea, and hemorrhagic bullae. Vibrio vulnificus also commonly causes necrotizing fasciitis, which initially presents as cellulitis and rapidly progresses to hemorrhagic bullae or necrosis with accompanying systemic symptoms. Prompt diagnosis and treatment are vital to prevent mortality.

Interestingly, regions impacted by V vulnificus are expanding because of global warming.^5,7Vibrio vulnificus thrives in warm waters, and increasing water temperatures are enhancing V vulnificus growth and survival.^1,9 As global warming continues, the incidence of V vulnificus infections may rise. In fact, the number of infections increased by 78% between 1996 and 2006 in the United States.⁵ This rise likely was due to a combination of factors, including an aging population with more comorbidities, improvements in diagnosis, and climate change. Thus, as the number of V vulnificus infections rises, so too must providers’ suspicion for the pathogen.

Dermatologists must understand the religious and cultural practices of various populations in order to provide optimal patient-centered care. In particular, patients of South Asian background have specific traditions and needs that may be unfamiliar to many providers and may affect the approach to their dermatologic care. These include the strong role of traditional garments and hair practices, the cultural emphasis on modest dress and limiting skin exposure in South Asian society, and the presence of anti–South Asian racism and religious discrimination in the United States.¹ Sikhism, Islam, and Hinduism are the predominant religions among the South Asian population, and followers of these faiths constitute nearly 40% of the world population.^2,3 By becoming familiar with the unique health care needs of this patient population, dermatologists can become key players in reducing health care disparities.

Traditional garments are particularly important in both Sikhism and Islam. Sikhs began wearing symbolic garments in the 16th century as markers of their identity during periods of religious persecution. Today, many Sikhs continue to maintain this tradition of wearing the Five Ks—kesh (uncut hair, often tied in a turban), kanga (wooden hair comb), kirpan (symbolic dagger), kachha (cotton underwear), and kara (steel bracelet).² Similarly, Islamic traditions also provide guidance for clothing. Many Muslim women wear the hijab (headscarf), a garment that originated as protective headgear for nomadic desert cultures and has come to symbolize modest dress. Traditionally, the hijab is worn in the presence of all men who are not immediate relatives, although patients may make exceptions for medical care. Some Muslim men also may cover their heads with a skullcap and/or maintain long beards (occasionally dyed with henna pigment) as a way of keeping continuity with the tradition of the Prophet Muhammad and his companions.³

Certain styles of headwear can cause high tension on hair follicles and have been associated with traction alopecia.⁴ Persistent use of the same turban, hijab, or comb also may lead to seborrheic dermatitis or fungal scalp infections. Dermatologists should advise patients about these potential challenges and suggest modifications in accordance with the patient’s religious beliefs; for example, providers can suggest removing headwear at night, using prophylactic antifungal shampoos, and/or tying the hair in a ponytail or loosening the headgear to reduce traction.

Although Hinduism does not have a unifying garment or hair tradition in the vein of Sikhism or Islam, all 3 religions share a strong emphasis on bodily modesty, which may affect dermatologic examinations. Patients from all 3 religions may seek to expose as little skin as possible during a physical examination, and many patients may be uncomfortable with a physician of the opposite gender. Dermatologists may find the following practices to be helpful⁵:

• Talk through each aspect of the skin examination while it is being performed and expose the least amount of skin necessary during the process

• Offer the patient a chaperone or a same-gender provider, if possible

• Empower patients to assist in adjusting garments themselves to help the physician visualize all parts of the skin

Some Sikhs also may have specific concerns regarding cutting their hair. One aspect of kesh is that every hair is sacred, and thus, many Sikhs refrain from removing hair on any part of the body. As such, providers should carefully obtain the patient’s informed consent before performing any procedure or physical examination maneuvers (eg, hair pull test) that may result in loss of hair.²

Physicians of all disciplines can help address these challenges through increased outreach and cultural awareness; for example, dermatologists can create skin care pamphlets translated into various South Asian languages and distribute them at houses of worship or other community centers. This may help patients identify their skin needs and seek appropriate care. The onus must be on physicians to make these patients feel comfortable seeking care by creating nonjudgmental, culturally knowledgeable clinical environments. When asking about social history, the physician might consider asking an open-ended question such as, “What role does religion/spirituality play in your life?” They can then proceed to ask specific questions about practices that might affect the patient’s care.⁵

Given the current coronavirus disease 2019 pandemic, South Asian patients may be even further discouraged from seeking dermatologic care. By understanding religious traditions and taking steps to address biases, dermatologists can help mitigate health care disparities and provide culturally competent care to South Asian patients.

Dermatologists must understand the religious and cultural practices of various populations in order to provide optimal patient-centered care. In particular, patients of South Asian background have specific traditions and needs that may be unfamiliar to many providers and may affect the approach to their dermatologic care. These include the strong role of traditional garments and hair practices, the cultural emphasis on modest dress and limiting skin exposure in South Asian society, and the presence of anti–South Asian racism and religious discrimination in the United States.¹ Sikhism, Islam, and Hinduism are the predominant religions among the South Asian population, and followers of these faiths constitute nearly 40% of the world population.^2,3 By becoming familiar with the unique health care needs of this patient population, dermatologists can become key players in reducing health care disparities.

Traditional garments are particularly important in both Sikhism and Islam. Sikhs began wearing symbolic garments in the 16th century as markers of their identity during periods of religious persecution. Today, many Sikhs continue to maintain this tradition of wearing the Five Ks—kesh (uncut hair, often tied in a turban), kanga (wooden hair comb), kirpan (symbolic dagger), kachha (cotton underwear), and kara (steel bracelet).² Similarly, Islamic traditions also provide guidance for clothing. Many Muslim women wear the hijab (headscarf), a garment that originated as protective headgear for nomadic desert cultures and has come to symbolize modest dress. Traditionally, the hijab is worn in the presence of all men who are not immediate relatives, although patients may make exceptions for medical care. Some Muslim men also may cover their heads with a skullcap and/or maintain long beards (occasionally dyed with henna pigment) as a way of keeping continuity with the tradition of the Prophet Muhammad and his companions.³

Certain styles of headwear can cause high tension on hair follicles and have been associated with traction alopecia.⁴ Persistent use of the same turban, hijab, or comb also may lead to seborrheic dermatitis or fungal scalp infections. Dermatologists should advise patients about these potential challenges and suggest modifications in accordance with the patient’s religious beliefs; for example, providers can suggest removing headwear at night, using prophylactic antifungal shampoos, and/or tying the hair in a ponytail or loosening the headgear to reduce traction.

Although Hinduism does not have a unifying garment or hair tradition in the vein of Sikhism or Islam, all 3 religions share a strong emphasis on bodily modesty, which may affect dermatologic examinations. Patients from all 3 religions may seek to expose as little skin as possible during a physical examination, and many patients may be uncomfortable with a physician of the opposite gender. Dermatologists may find the following practices to be helpful⁵:

• Talk through each aspect of the skin examination while it is being performed and expose the least amount of skin necessary during the process

• Offer the patient a chaperone or a same-gender provider, if possible

• Empower patients to assist in adjusting garments themselves to help the physician visualize all parts of the skin

Some Sikhs also may have specific concerns regarding cutting their hair. One aspect of kesh is that every hair is sacred, and thus, many Sikhs refrain from removing hair on any part of the body. As such, providers should carefully obtain the patient’s informed consent before performing any procedure or physical examination maneuvers (eg, hair pull test) that may result in loss of hair.²

Physicians of all disciplines can help address these challenges through increased outreach and cultural awareness; for example, dermatologists can create skin care pamphlets translated into various South Asian languages and distribute them at houses of worship or other community centers. This may help patients identify their skin needs and seek appropriate care. The onus must be on physicians to make these patients feel comfortable seeking care by creating nonjudgmental, culturally knowledgeable clinical environments. When asking about social history, the physician might consider asking an open-ended question such as, “What role does religion/spirituality play in your life?” They can then proceed to ask specific questions about practices that might affect the patient’s care.⁵

Given the current coronavirus disease 2019 pandemic, South Asian patients may be even further discouraged from seeking dermatologic care. By understanding religious traditions and taking steps to address biases, dermatologists can help mitigate health care disparities and provide culturally competent care to South Asian patients.

Dermatologists must understand the religious and cultural practices of various populations in order to provide optimal patient-centered care. In particular, patients of South Asian background have specific traditions and needs that may be unfamiliar to many providers and may affect the approach to their dermatologic care. These include the strong role of traditional garments and hair practices, the cultural emphasis on modest dress and limiting skin exposure in South Asian society, and the presence of anti–South Asian racism and religious discrimination in the United States.¹ Sikhism, Islam, and Hinduism are the predominant religions among the South Asian population, and followers of these faiths constitute nearly 40% of the world population.^2,3 By becoming familiar with the unique health care needs of this patient population, dermatologists can become key players in reducing health care disparities.

Traditional garments are particularly important in both Sikhism and Islam. Sikhs began wearing symbolic garments in the 16th century as markers of their identity during periods of religious persecution. Today, many Sikhs continue to maintain this tradition of wearing the Five Ks—kesh (uncut hair, often tied in a turban), kanga (wooden hair comb), kirpan (symbolic dagger), kachha (cotton underwear), and kara (steel bracelet).² Similarly, Islamic traditions also provide guidance for clothing. Many Muslim women wear the hijab (headscarf), a garment that originated as protective headgear for nomadic desert cultures and has come to symbolize modest dress. Traditionally, the hijab is worn in the presence of all men who are not immediate relatives, although patients may make exceptions for medical care. Some Muslim men also may cover their heads with a skullcap and/or maintain long beards (occasionally dyed with henna pigment) as a way of keeping continuity with the tradition of the Prophet Muhammad and his companions.³

Certain styles of headwear can cause high tension on hair follicles and have been associated with traction alopecia.⁴ Persistent use of the same turban, hijab, or comb also may lead to seborrheic dermatitis or fungal scalp infections. Dermatologists should advise patients about these potential challenges and suggest modifications in accordance with the patient’s religious beliefs; for example, providers can suggest removing headwear at night, using prophylactic antifungal shampoos, and/or tying the hair in a ponytail or loosening the headgear to reduce traction.

Although Hinduism does not have a unifying garment or hair tradition in the vein of Sikhism or Islam, all 3 religions share a strong emphasis on bodily modesty, which may affect dermatologic examinations. Patients from all 3 religions may seek to expose as little skin as possible during a physical examination, and many patients may be uncomfortable with a physician of the opposite gender. Dermatologists may find the following practices to be helpful⁵:

• Talk through each aspect of the skin examination while it is being performed and expose the least amount of skin necessary during the process

• Offer the patient a chaperone or a same-gender provider, if possible

• Empower patients to assist in adjusting garments themselves to help the physician visualize all parts of the skin

Some Sikhs also may have specific concerns regarding cutting their hair. One aspect of kesh is that every hair is sacred, and thus, many Sikhs refrain from removing hair on any part of the body. As such, providers should carefully obtain the patient’s informed consent before performing any procedure or physical examination maneuvers (eg, hair pull test) that may result in loss of hair.²

Physicians of all disciplines can help address these challenges through increased outreach and cultural awareness; for example, dermatologists can create skin care pamphlets translated into various South Asian languages and distribute them at houses of worship or other community centers. This may help patients identify their skin needs and seek appropriate care. The onus must be on physicians to make these patients feel comfortable seeking care by creating nonjudgmental, culturally knowledgeable clinical environments. When asking about social history, the physician might consider asking an open-ended question such as, “What role does religion/spirituality play in your life?” They can then proceed to ask specific questions about practices that might affect the patient’s care.⁵

Given the current coronavirus disease 2019 pandemic, South Asian patients may be even further discouraged from seeking dermatologic care. By understanding religious traditions and taking steps to address biases, dermatologists can help mitigate health care disparities and provide culturally competent care to South Asian patients.

The Diagnosis: Disseminated Erythema Chronicum Migrans 

Empiric treatment with doxycycline 100 mg twice daily for 14 days was initiated for suspected early disseminated Lyme disease manifesting as disseminated multifocal erythema chronicum migrans (Figure). Lyme screening immunoassay and confirmatory IgM Western blot testing subsequently were found to be positive. The clinical history of recent travel to an endemic area and tick bite combined with the recent onset of multifocal erythema migrans lesions, systemic symptoms, elevated erythrocyte sedimentation rate, and positive Lyme serology supported the diagnosis of Lyme disease.

The appropriate clinical context and cutaneous morphology are key when considering the differential diagnosis for multifocal annular lesions. Several entities comprised the differential diagnosis considered in our patient. Sweet syndrome is a neutrophilic dermatosis that can present with fever and varying painful cutaneous lesions. It often is associated with certain medications, underlying illnesses, and infections.¹ Our patient’s lesions were not painful, and she had no notable medical history, recent infections, or new medication use, making Sweet syndrome unlikely. A fixed drug eruption was low on the differential, as the patient denied starting any new medications within the 3 months prior to presentation. Erythema multiforme is an acute-onset immunemediated condition of the skin and mucous membranes that typically affects young adults and often is associated with infection (eg, herpes simplex virus, Mycoplasma pneumoniae) or medication use. Cutaneous lesions typically are self-limited, less than 3 cm targets with 3 concentric distinct color zones, often with central bullae or erosions. Although erythema multiforme was higher on the differential, it was less likely, as the patient lacked mucosal lesions and did not have symptoms of underlying herpetic or mycoplasma infection, and the clinical picture was more consistent with Lyme disease. Lastly, the failure for individual skin lesions to resolve within 
 24 hours excluded the diagnosis of urticaria.

Lyme disease is a tick-borne illness caused by 3 species of the Borrelia spirochete: Borrelia burgdorferi, Borrelia afzelii, and Borrelia garinii.² In the United States, the disease predominantly is caused by B burgdorferi that is endemic in the upper Midwest and Northeast regions.3 There are 3 stages of Lyme disease: early localized, early disseminated, and late disseminated disease. Early localized disease typically presents with a characteristic single erythema migrans (EM) lesion 3 to 30 days following a bite by the tick Ixodes scapularis.² The EM lesion gradually can enlarge over a period of several days, reaching up to 12 inches in diameter.² Early disseminated disease can occur weeks to months following a tick bite and may present with systemic symptoms, multiple widespread 
EM lesions, neurologic features such as meningitis or facial nerve palsy, and/or cardiac manifestations such as atrioventricular block or myocarditis. Late disseminated disease can present with chronic arthritis or encephalopathy after months to years if the disease is left untreated.⁴

Early localized Lyme disease can be diagnosed clinically if the characteristic EM lesion is present in a patient who visited an endemic area. Laboratory testing and Lyme serology are neither required nor recommended in these cases, as the lesion often appears before adequate time has lapsed to develop an adaptive immune response to the organism.5 In contrast, Lyme serology should be ordered in any patient who meets all of the following criteria: (1) patient lives in or has recently traveled to an area endemic for Lyme disease, (2) presence of a risk factor for tick exposure, and (3) symptoms consistent with early disseminated or late Lyme disease. Patients with signs of early or late disseminated disease typically are seropositive, as IgM antibodies can be detected within 2 weeks of onset of the EM lesion and IgG antibodies within 2 to 6 weeks.⁶ The Centers for Disease Control and Prevention recommends a 2-tiered approach when testing for Lyme disease.⁷ A screening test with high sensitivity such as an enzyme-linked immunosorbent assay or an immunofluorescence assay initially should be performed.⁷ If results of the screening test are equivocal or positive, secondary confirmatory testing should be performed via IgM, with or without IgG Western immunoblot assay.⁷ Biopsy with histologic evaluation can reveal nonspecific findings of vascular endothelial injury and increased mucin deposition. Patients with suspected Lyme disease should immediately be started on empiric treatment with doxycycline 100 mg twice daily for a minimum of 10 days (14–28 days if there is concern for dissemination) to prevent post-Lyme sequelae.⁵ Our patient’s cutaneous lesions responded to oral doxycycline. 

The Diagnosis: Disseminated Erythema Chronicum Migrans 

Empiric treatment with doxycycline 100 mg twice daily for 14 days was initiated for suspected early disseminated Lyme disease manifesting as disseminated multifocal erythema chronicum migrans (Figure). Lyme screening immunoassay and confirmatory IgM Western blot testing subsequently were found to be positive. The clinical history of recent travel to an endemic area and tick bite combined with the recent onset of multifocal erythema migrans lesions, systemic symptoms, elevated erythrocyte sedimentation rate, and positive Lyme serology supported the diagnosis of Lyme disease.

The appropriate clinical context and cutaneous morphology are key when considering the differential diagnosis for multifocal annular lesions. Several entities comprised the differential diagnosis considered in our patient. Sweet syndrome is a neutrophilic dermatosis that can present with fever and varying painful cutaneous lesions. It often is associated with certain medications, underlying illnesses, and infections.¹ Our patient’s lesions were not painful, and she had no notable medical history, recent infections, or new medication use, making Sweet syndrome unlikely. A fixed drug eruption was low on the differential, as the patient denied starting any new medications within the 3 months prior to presentation. Erythema multiforme is an acute-onset immunemediated condition of the skin and mucous membranes that typically affects young adults and often is associated with infection (eg, herpes simplex virus, Mycoplasma pneumoniae) or medication use. Cutaneous lesions typically are self-limited, less than 3 cm targets with 3 concentric distinct color zones, often with central bullae or erosions. Although erythema multiforme was higher on the differential, it was less likely, as the patient lacked mucosal lesions and did not have symptoms of underlying herpetic or mycoplasma infection, and the clinical picture was more consistent with Lyme disease. Lastly, the failure for individual skin lesions to resolve within 
 24 hours excluded the diagnosis of urticaria.

Lyme disease is a tick-borne illness caused by 3 species of the Borrelia spirochete: Borrelia burgdorferi, Borrelia afzelii, and Borrelia garinii.² In the United States, the disease predominantly is caused by B burgdorferi that is endemic in the upper Midwest and Northeast regions.3 There are 3 stages of Lyme disease: early localized, early disseminated, and late disseminated disease. Early localized disease typically presents with a characteristic single erythema migrans (EM) lesion 3 to 30 days following a bite by the tick Ixodes scapularis.² The EM lesion gradually can enlarge over a period of several days, reaching up to 12 inches in diameter.² Early disseminated disease can occur weeks to months following a tick bite and may present with systemic symptoms, multiple widespread 
EM lesions, neurologic features such as meningitis or facial nerve palsy, and/or cardiac manifestations such as atrioventricular block or myocarditis. Late disseminated disease can present with chronic arthritis or encephalopathy after months to years if the disease is left untreated.⁴

Early localized Lyme disease can be diagnosed clinically if the characteristic EM lesion is present in a patient who visited an endemic area. Laboratory testing and Lyme serology are neither required nor recommended in these cases, as the lesion often appears before adequate time has lapsed to develop an adaptive immune response to the organism.5 In contrast, Lyme serology should be ordered in any patient who meets all of the following criteria: (1) patient lives in or has recently traveled to an area endemic for Lyme disease, (2) presence of a risk factor for tick exposure, and (3) symptoms consistent with early disseminated or late Lyme disease. Patients with signs of early or late disseminated disease typically are seropositive, as IgM antibodies can be detected within 2 weeks of onset of the EM lesion and IgG antibodies within 2 to 6 weeks.⁶ The Centers for Disease Control and Prevention recommends a 2-tiered approach when testing for Lyme disease.⁷ A screening test with high sensitivity such as an enzyme-linked immunosorbent assay or an immunofluorescence assay initially should be performed.⁷ If results of the screening test are equivocal or positive, secondary confirmatory testing should be performed via IgM, with or without IgG Western immunoblot assay.⁷ Biopsy with histologic evaluation can reveal nonspecific findings of vascular endothelial injury and increased mucin deposition. Patients with suspected Lyme disease should immediately be started on empiric treatment with doxycycline 100 mg twice daily for a minimum of 10 days (14–28 days if there is concern for dissemination) to prevent post-Lyme sequelae.⁵ Our patient’s cutaneous lesions responded to oral doxycycline. 

The Diagnosis: Disseminated Erythema Chronicum Migrans 

Empiric treatment with doxycycline 100 mg twice daily for 14 days was initiated for suspected early disseminated Lyme disease manifesting as disseminated multifocal erythema chronicum migrans (Figure). Lyme screening immunoassay and confirmatory IgM Western blot testing subsequently were found to be positive. The clinical history of recent travel to an endemic area and tick bite combined with the recent onset of multifocal erythema migrans lesions, systemic symptoms, elevated erythrocyte sedimentation rate, and positive Lyme serology supported the diagnosis of Lyme disease.

The appropriate clinical context and cutaneous morphology are key when considering the differential diagnosis for multifocal annular lesions. Several entities comprised the differential diagnosis considered in our patient. Sweet syndrome is a neutrophilic dermatosis that can present with fever and varying painful cutaneous lesions. It often is associated with certain medications, underlying illnesses, and infections.¹ Our patient’s lesions were not painful, and she had no notable medical history, recent infections, or new medication use, making Sweet syndrome unlikely. A fixed drug eruption was low on the differential, as the patient denied starting any new medications within the 3 months prior to presentation. Erythema multiforme is an acute-onset immunemediated condition of the skin and mucous membranes that typically affects young adults and often is associated with infection (eg, herpes simplex virus, Mycoplasma pneumoniae) or medication use. Cutaneous lesions typically are self-limited, less than 3 cm targets with 3 concentric distinct color zones, often with central bullae or erosions. Although erythema multiforme was higher on the differential, it was less likely, as the patient lacked mucosal lesions and did not have symptoms of underlying herpetic or mycoplasma infection, and the clinical picture was more consistent with Lyme disease. Lastly, the failure for individual skin lesions to resolve within 
 24 hours excluded the diagnosis of urticaria.

Lyme disease is a tick-borne illness caused by 3 species of the Borrelia spirochete: Borrelia burgdorferi, Borrelia afzelii, and Borrelia garinii.² In the United States, the disease predominantly is caused by B burgdorferi that is endemic in the upper Midwest and Northeast regions.3 There are 3 stages of Lyme disease: early localized, early disseminated, and late disseminated disease. Early localized disease typically presents with a characteristic single erythema migrans (EM) lesion 3 to 30 days following a bite by the tick Ixodes scapularis.² The EM lesion gradually can enlarge over a period of several days, reaching up to 12 inches in diameter.² Early disseminated disease can occur weeks to months following a tick bite and may present with systemic symptoms, multiple widespread 
EM lesions, neurologic features such as meningitis or facial nerve palsy, and/or cardiac manifestations such as atrioventricular block or myocarditis. Late disseminated disease can present with chronic arthritis or encephalopathy after months to years if the disease is left untreated.⁴

Early localized Lyme disease can be diagnosed clinically if the characteristic EM lesion is present in a patient who visited an endemic area. Laboratory testing and Lyme serology are neither required nor recommended in these cases, as the lesion often appears before adequate time has lapsed to develop an adaptive immune response to the organism.5 In contrast, Lyme serology should be ordered in any patient who meets all of the following criteria: (1) patient lives in or has recently traveled to an area endemic for Lyme disease, (2) presence of a risk factor for tick exposure, and (3) symptoms consistent with early disseminated or late Lyme disease. Patients with signs of early or late disseminated disease typically are seropositive, as IgM antibodies can be detected within 2 weeks of onset of the EM lesion and IgG antibodies within 2 to 6 weeks.⁶ The Centers for Disease Control and Prevention recommends a 2-tiered approach when testing for Lyme disease.⁷ A screening test with high sensitivity such as an enzyme-linked immunosorbent assay or an immunofluorescence assay initially should be performed.⁷ If results of the screening test are equivocal or positive, secondary confirmatory testing should be performed via IgM, with or without IgG Western immunoblot assay.⁷ Biopsy with histologic evaluation can reveal nonspecific findings of vascular endothelial injury and increased mucin deposition. Patients with suspected Lyme disease should immediately be started on empiric treatment with doxycycline 100 mg twice daily for a minimum of 10 days (14–28 days if there is concern for dissemination) to prevent post-Lyme sequelae.⁵ Our patient’s cutaneous lesions responded to oral doxycycline. 

To the Editor:

The transient and generic appearance of exercise-induced vasculitis (EIV) makes it a commonly misdiagnosed condition. The lesion often is only encountered through photographs brought by the patient or by taking a thorough history. The lack of findings on clinical inspection and the generic appearance of EIV may lead to misdiagnosis as stasis dermatitis due to its presentation as erythematous lesions on the medial lower legs.

A 68-year-old woman with no notable medical history was referred to our clinic for suspected stasis dermatitis. At presentation, no lesions were identified on the legs, but she brought photographs of an erythematous urticarial eruption on the medial lower legs, extending from just above the sock line to the mid-calves (Figure). The eruptions had occurred over the last 16 years, typically presenting suddenly after playing tennis or an extended period of walking and spontaneously resolving in 4 days. The lesions were painless, restricted to the calves, and were not pruritic, though the initial presentation 16 years prior included pruritic pigmented patches on the anterior thighs. Because the condition spontaneously improved within days, no treatment was attempted. An ultrasound venous reflux study ruled out venous reflux and stasis dermatitis.

Histologic examination demonstrates features of leukocytoclastic vasculitis with perivascular lymphocytic and neutrophilic infiltrates.² Erythrocyte extravasation, IgM deposits, and identification of C3 also have been reported.^8,9 The spontaneous resolution of EIV has led to treatment efforts being focused on preventative measures. Several cases have reported some degree of success in preventing EIV with compression therapy, venoactive drugs, systemic steroids, and application of topical steroids before exercise.³

The clinical morphology and lower leg location of EIV leads to a common misdiagnosis of stasis dermatitis. Clinical history of a transient nature is the mainstay in the diagnosis of EIV, and ultrasound venous reflux study may be required in some cases. Preventative measures are superior to treatment and mainly include compression therapy.

To the Editor:

The transient and generic appearance of exercise-induced vasculitis (EIV) makes it a commonly misdiagnosed condition. The lesion often is only encountered through photographs brought by the patient or by taking a thorough history. The lack of findings on clinical inspection and the generic appearance of EIV may lead to misdiagnosis as stasis dermatitis due to its presentation as erythematous lesions on the medial lower legs.

A 68-year-old woman with no notable medical history was referred to our clinic for suspected stasis dermatitis. At presentation, no lesions were identified on the legs, but she brought photographs of an erythematous urticarial eruption on the medial lower legs, extending from just above the sock line to the mid-calves (Figure). The eruptions had occurred over the last 16 years, typically presenting suddenly after playing tennis or an extended period of walking and spontaneously resolving in 4 days. The lesions were painless, restricted to the calves, and were not pruritic, though the initial presentation 16 years prior included pruritic pigmented patches on the anterior thighs. Because the condition spontaneously improved within days, no treatment was attempted. An ultrasound venous reflux study ruled out venous reflux and stasis dermatitis.

Histologic examination demonstrates features of leukocytoclastic vasculitis with perivascular lymphocytic and neutrophilic infiltrates.² Erythrocyte extravasation, IgM deposits, and identification of C3 also have been reported.^8,9 The spontaneous resolution of EIV has led to treatment efforts being focused on preventative measures. Several cases have reported some degree of success in preventing EIV with compression therapy, venoactive drugs, systemic steroids, and application of topical steroids before exercise.³

The clinical morphology and lower leg location of EIV leads to a common misdiagnosis of stasis dermatitis. Clinical history of a transient nature is the mainstay in the diagnosis of EIV, and ultrasound venous reflux study may be required in some cases. Preventative measures are superior to treatment and mainly include compression therapy.

To the Editor:

The transient and generic appearance of exercise-induced vasculitis (EIV) makes it a commonly misdiagnosed condition. The lesion often is only encountered through photographs brought by the patient or by taking a thorough history. The lack of findings on clinical inspection and the generic appearance of EIV may lead to misdiagnosis as stasis dermatitis due to its presentation as erythematous lesions on the medial lower legs.

A 68-year-old woman with no notable medical history was referred to our clinic for suspected stasis dermatitis. At presentation, no lesions were identified on the legs, but she brought photographs of an erythematous urticarial eruption on the medial lower legs, extending from just above the sock line to the mid-calves (Figure). The eruptions had occurred over the last 16 years, typically presenting suddenly after playing tennis or an extended period of walking and spontaneously resolving in 4 days. The lesions were painless, restricted to the calves, and were not pruritic, though the initial presentation 16 years prior included pruritic pigmented patches on the anterior thighs. Because the condition spontaneously improved within days, no treatment was attempted. An ultrasound venous reflux study ruled out venous reflux and stasis dermatitis.

Histologic examination demonstrates features of leukocytoclastic vasculitis with perivascular lymphocytic and neutrophilic infiltrates.² Erythrocyte extravasation, IgM deposits, and identification of C3 also have been reported.^8,9 The spontaneous resolution of EIV has led to treatment efforts being focused on preventative measures. Several cases have reported some degree of success in preventing EIV with compression therapy, venoactive drugs, systemic steroids, and application of topical steroids before exercise.³

The clinical morphology and lower leg location of EIV leads to a common misdiagnosis of stasis dermatitis. Clinical history of a transient nature is the mainstay in the diagnosis of EIV, and ultrasound venous reflux study may be required in some cases. Preventative measures are superior to treatment and mainly include compression therapy.