Case Letter

To the Editor:

Unilateral nevoid telangiectasia (UNT) is a rare cutaneous disease characterized by superficial telangiectases arranged in a unilateral linear pattern. First described by Alfred Blaschko in 1899, this rare disease has been reported in higher frequency in recent years, with approximately 100 cases published in the literature according to a PubMed search of articles indexed for MEDLINE using the term unilateral nevoid telangiectasia.¹ Unilateral nevoid telangiectasia can be congenital or acquired; occurs more commonly in women; and typically involves the dermatomal distributions of the trigeminal, cervical, and upper thoracic nerves. Although the pathogenesis of the disease remains unknown, the currently proposed etiology involves hyperestrogenic states, including puberty, pregnancy, and chronic liver disease.² We report a case of progressively worsening, pruritic, unilateral telangiectases of unknown etiology.

A 55-year-old woman presented to our dermatology clinic with progressive red spots involving the right side of the upper body of 3 years’ duration. She noted pruritus, and the rash was otherwise asymptomatic. Her medical history was notable for hypertension, dyspepsia, sciatica, uterine fibroids, and a hysterectomy. Her medications included lisinopril, hydrochlorothiazide, tramadol, aspirin, and a multivitamin. The patient did not report the use of oral contraceptive pills or hormone replacement therapy. She also denied the use of cigarettes or illicit drugs but reported occasional alcohol consumption. A review of systems was negative for any constitutional symptoms or symptoms of liver disease. Her family history also was noncontributory.

Physical examination revealed multiple, 1- to 3-mm, telangiectatic macules and patches in a blaschkoid distribution on the right side of the upper chest, back, shoulder, and arm (Figure, A–C). Darier sign was negative. There was no evidence of palmar erythema, hepatosplenomegaly, ascites, thyromegaly, or thyroid nodules. Dermoscopy confirmed the presence of telangiectasia (Figure, D). More specifically, dermoscopy revealed plump telangiectasia with faint pigment in the background, consistent with UNT. Additionally, there was no pink-white, shiny, scarlike background, and vessels were not thin or arborized, further supporting our diagnosis vs other entities included in the differential diagnosis.

Laboratory testing for estrogen levels was within normal postmenopausal limits. A complete blood cell count, basic metabolic panel, hepatic panel, and thyroid stimulating hormone levels all were within reference range. Hepatitis B and C virus testing was nonreactive. The diagnosis of UNT was made based on clinical characteristics. The patient then was referred for pulsed dye laser treatment.

Since the first reports of UNT in 1899, it has been described in multiple individually reported cases. The typical description of UNT involves linearly arranged telangiectasia of one side of the body, following either dermatomal or blaschkoid distribution, most commonly along the C3 and C4 dermatome. In 1970, Selmanowitz³ divided the diagnosis into 2 categories: congenital and acquired. The congenital form is less common overall, seen more frequently in males, and occurs in direct relation to the neonatal period.⁴ The acquired form that is more common overall and seen more frequently in females is suggested to be due to hyperestrogenic states. Most reports of the acquired form involve some underlying pathology that may lead to higher estrogen states. In a review article published in 2011, Wenson et al¹ summarized the reported cases to date. The authors found that out of close to 100 cases reported, 26 acquired cases were associated with pregnancy and 23 with puberty. They further found 10 cases associated with hepatic disease, 2 associated with hormonal contraceptive pills, 1 associated with hyperthyroidism, and 1 associated with carcinoid syndrome.¹Interestingly, a more varied presentation of disease has been reported, as cases are now being reported in healthy patients with no comorbidities or reasons for hyperestrogenism.⁵ In fact, presentations in healthy adult men have led some authors to believe that estrogen may not play a major role in the pathogenesis of the disease.^5-8 Reports of 16 cases of UNT have indicated no association with hyperestrogenic states.¹ Because the etiology remains unknown, individual cases both supporting and refuting the hypothesis of estrogen-driven vessel inflammation may drive the investigation of further explanations.

Because UNT usually is asymptomatic, treatment options are largely based on improvement in appearance of the lesions. The pulsed dye laser (PDL) has shown success in treatment of lesions, as Sharma et al,⁹ reported resolution of lesions in 9 cases. These cases were not without side effects, as some patients did experience reversible pigmentary changes. Other studies have validated the use of PDL for cosmetic improvement of UNT; however, some studies have noted the recurrence of lesions after treatment.¹⁰

Our case provides another unique presentation of UNT. Our patient was a healthy adult woman with no hyperestrogen-based etiology for disease. Importantly, our patient also represented a rare instance of UNT presenting with symptoms such as pruritus, though UNT classically is described as an asymptomatic phenomenon. In our patient, treatment with PDL was suggested and believed to be warranted not only for cosmetic improvement but also in light of the fact that her lesions were symptomatic.

To the Editor:

Unilateral nevoid telangiectasia (UNT) is a rare cutaneous disease characterized by superficial telangiectases arranged in a unilateral linear pattern. First described by Alfred Blaschko in 1899, this rare disease has been reported in higher frequency in recent years, with approximately 100 cases published in the literature according to a PubMed search of articles indexed for MEDLINE using the term unilateral nevoid telangiectasia.¹ Unilateral nevoid telangiectasia can be congenital or acquired; occurs more commonly in women; and typically involves the dermatomal distributions of the trigeminal, cervical, and upper thoracic nerves. Although the pathogenesis of the disease remains unknown, the currently proposed etiology involves hyperestrogenic states, including puberty, pregnancy, and chronic liver disease.² We report a case of progressively worsening, pruritic, unilateral telangiectases of unknown etiology.

A 55-year-old woman presented to our dermatology clinic with progressive red spots involving the right side of the upper body of 3 years’ duration. She noted pruritus, and the rash was otherwise asymptomatic. Her medical history was notable for hypertension, dyspepsia, sciatica, uterine fibroids, and a hysterectomy. Her medications included lisinopril, hydrochlorothiazide, tramadol, aspirin, and a multivitamin. The patient did not report the use of oral contraceptive pills or hormone replacement therapy. She also denied the use of cigarettes or illicit drugs but reported occasional alcohol consumption. A review of systems was negative for any constitutional symptoms or symptoms of liver disease. Her family history also was noncontributory.

Physical examination revealed multiple, 1- to 3-mm, telangiectatic macules and patches in a blaschkoid distribution on the right side of the upper chest, back, shoulder, and arm (Figure, A–C). Darier sign was negative. There was no evidence of palmar erythema, hepatosplenomegaly, ascites, thyromegaly, or thyroid nodules. Dermoscopy confirmed the presence of telangiectasia (Figure, D). More specifically, dermoscopy revealed plump telangiectasia with faint pigment in the background, consistent with UNT. Additionally, there was no pink-white, shiny, scarlike background, and vessels were not thin or arborized, further supporting our diagnosis vs other entities included in the differential diagnosis.

Laboratory testing for estrogen levels was within normal postmenopausal limits. A complete blood cell count, basic metabolic panel, hepatic panel, and thyroid stimulating hormone levels all were within reference range. Hepatitis B and C virus testing was nonreactive. The diagnosis of UNT was made based on clinical characteristics. The patient then was referred for pulsed dye laser treatment.

Since the first reports of UNT in 1899, it has been described in multiple individually reported cases. The typical description of UNT involves linearly arranged telangiectasia of one side of the body, following either dermatomal or blaschkoid distribution, most commonly along the C3 and C4 dermatome. In 1970, Selmanowitz³ divided the diagnosis into 2 categories: congenital and acquired. The congenital form is less common overall, seen more frequently in males, and occurs in direct relation to the neonatal period.⁴ The acquired form that is more common overall and seen more frequently in females is suggested to be due to hyperestrogenic states. Most reports of the acquired form involve some underlying pathology that may lead to higher estrogen states. In a review article published in 2011, Wenson et al¹ summarized the reported cases to date. The authors found that out of close to 100 cases reported, 26 acquired cases were associated with pregnancy and 23 with puberty. They further found 10 cases associated with hepatic disease, 2 associated with hormonal contraceptive pills, 1 associated with hyperthyroidism, and 1 associated with carcinoid syndrome.¹Interestingly, a more varied presentation of disease has been reported, as cases are now being reported in healthy patients with no comorbidities or reasons for hyperestrogenism.⁵ In fact, presentations in healthy adult men have led some authors to believe that estrogen may not play a major role in the pathogenesis of the disease.^5-8 Reports of 16 cases of UNT have indicated no association with hyperestrogenic states.¹ Because the etiology remains unknown, individual cases both supporting and refuting the hypothesis of estrogen-driven vessel inflammation may drive the investigation of further explanations.

Because UNT usually is asymptomatic, treatment options are largely based on improvement in appearance of the lesions. The pulsed dye laser (PDL) has shown success in treatment of lesions, as Sharma et al,⁹ reported resolution of lesions in 9 cases. These cases were not without side effects, as some patients did experience reversible pigmentary changes. Other studies have validated the use of PDL for cosmetic improvement of UNT; however, some studies have noted the recurrence of lesions after treatment.¹⁰

Our case provides another unique presentation of UNT. Our patient was a healthy adult woman with no hyperestrogen-based etiology for disease. Importantly, our patient also represented a rare instance of UNT presenting with symptoms such as pruritus, though UNT classically is described as an asymptomatic phenomenon. In our patient, treatment with PDL was suggested and believed to be warranted not only for cosmetic improvement but also in light of the fact that her lesions were symptomatic.

To the Editor:

Unilateral nevoid telangiectasia (UNT) is a rare cutaneous disease characterized by superficial telangiectases arranged in a unilateral linear pattern. First described by Alfred Blaschko in 1899, this rare disease has been reported in higher frequency in recent years, with approximately 100 cases published in the literature according to a PubMed search of articles indexed for MEDLINE using the term unilateral nevoid telangiectasia.¹ Unilateral nevoid telangiectasia can be congenital or acquired; occurs more commonly in women; and typically involves the dermatomal distributions of the trigeminal, cervical, and upper thoracic nerves. Although the pathogenesis of the disease remains unknown, the currently proposed etiology involves hyperestrogenic states, including puberty, pregnancy, and chronic liver disease.² We report a case of progressively worsening, pruritic, unilateral telangiectases of unknown etiology.

A 55-year-old woman presented to our dermatology clinic with progressive red spots involving the right side of the upper body of 3 years’ duration. She noted pruritus, and the rash was otherwise asymptomatic. Her medical history was notable for hypertension, dyspepsia, sciatica, uterine fibroids, and a hysterectomy. Her medications included lisinopril, hydrochlorothiazide, tramadol, aspirin, and a multivitamin. The patient did not report the use of oral contraceptive pills or hormone replacement therapy. She also denied the use of cigarettes or illicit drugs but reported occasional alcohol consumption. A review of systems was negative for any constitutional symptoms or symptoms of liver disease. Her family history also was noncontributory.

Physical examination revealed multiple, 1- to 3-mm, telangiectatic macules and patches in a blaschkoid distribution on the right side of the upper chest, back, shoulder, and arm (Figure, A–C). Darier sign was negative. There was no evidence of palmar erythema, hepatosplenomegaly, ascites, thyromegaly, or thyroid nodules. Dermoscopy confirmed the presence of telangiectasia (Figure, D). More specifically, dermoscopy revealed plump telangiectasia with faint pigment in the background, consistent with UNT. Additionally, there was no pink-white, shiny, scarlike background, and vessels were not thin or arborized, further supporting our diagnosis vs other entities included in the differential diagnosis.

Laboratory testing for estrogen levels was within normal postmenopausal limits. A complete blood cell count, basic metabolic panel, hepatic panel, and thyroid stimulating hormone levels all were within reference range. Hepatitis B and C virus testing was nonreactive. The diagnosis of UNT was made based on clinical characteristics. The patient then was referred for pulsed dye laser treatment.

Since the first reports of UNT in 1899, it has been described in multiple individually reported cases. The typical description of UNT involves linearly arranged telangiectasia of one side of the body, following either dermatomal or blaschkoid distribution, most commonly along the C3 and C4 dermatome. In 1970, Selmanowitz³ divided the diagnosis into 2 categories: congenital and acquired. The congenital form is less common overall, seen more frequently in males, and occurs in direct relation to the neonatal period.⁴ The acquired form that is more common overall and seen more frequently in females is suggested to be due to hyperestrogenic states. Most reports of the acquired form involve some underlying pathology that may lead to higher estrogen states. In a review article published in 2011, Wenson et al¹ summarized the reported cases to date. The authors found that out of close to 100 cases reported, 26 acquired cases were associated with pregnancy and 23 with puberty. They further found 10 cases associated with hepatic disease, 2 associated with hormonal contraceptive pills, 1 associated with hyperthyroidism, and 1 associated with carcinoid syndrome.¹Interestingly, a more varied presentation of disease has been reported, as cases are now being reported in healthy patients with no comorbidities or reasons for hyperestrogenism.⁵ In fact, presentations in healthy adult men have led some authors to believe that estrogen may not play a major role in the pathogenesis of the disease.^5-8 Reports of 16 cases of UNT have indicated no association with hyperestrogenic states.¹ Because the etiology remains unknown, individual cases both supporting and refuting the hypothesis of estrogen-driven vessel inflammation may drive the investigation of further explanations.

Because UNT usually is asymptomatic, treatment options are largely based on improvement in appearance of the lesions. The pulsed dye laser (PDL) has shown success in treatment of lesions, as Sharma et al,⁹ reported resolution of lesions in 9 cases. These cases were not without side effects, as some patients did experience reversible pigmentary changes. Other studies have validated the use of PDL for cosmetic improvement of UNT; however, some studies have noted the recurrence of lesions after treatment.¹⁰

Our case provides another unique presentation of UNT. Our patient was a healthy adult woman with no hyperestrogen-based etiology for disease. Importantly, our patient also represented a rare instance of UNT presenting with symptoms such as pruritus, though UNT classically is described as an asymptomatic phenomenon. In our patient, treatment with PDL was suggested and believed to be warranted not only for cosmetic improvement but also in light of the fact that her lesions were symptomatic.

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

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.

Our patient stated that her 64-year-old sister had reported the same presentation over the last 8 years. Her physical activity was limited strictly to walking, and the lesions occurred after walking for many hours during the day in the heat, involving the medial aspects of the lower legs extending from the ankles to the full length of the calves. Her eruption was warm but was not painful or pruritic. It resolved spontaneously after 5 days with no therapy.

Our patient was advised to wear compression stockings as a preventative measure, but she did not adhere to these recommendations, stating it was impractical to wear compression garments while playing tennis.

Exercise-induced vasculitis most commonly is seen in the medial aspects of the lower extremities as an erythematous urticarial eruption or pigmented purpuric plaque rapidly occurring after a period of exercise.^1,2 Lesions often are symmetric and can be pruritic and painful with a lack of systemic symptoms.³ These generic clinical manifestations may lead to a misdiagnosis of stasis dermatitis. One case report included initial treatment of presumptive cellulitis.⁴ Important clinical findings include a sparing of skin compressed by tight clothing such as socks, a lack of systemic symptoms, rapid appearance after exercise, and spontaneous resolution within a few days. No correlation with chronic venous disease has been demonstrated, as EIV can occur in patients with or without chronic venous insufficiency.⁵ Duplex ultrasound evaluation showed no venous reflux in our patient.

The pathophysiology of EIV remains unknown, but the concept of exercise-altered microcirculation has been proposed. Heat generated from exercise is normally dissipated by thermoregulatory mechanisms such as cutaneous vasodilation and sweat.^1,6 When exercise is extended, done concomitantly in the heat, or performed in legs with preexisting edema or substantial adipose tissue that limit heat attenuation, the thermoregulatory capacity is overloaded and heat-induced muscle fiber breakdown occurs.^1,7 Atrophy impairs the skeletal muscle’s ability to pump the increased venous return demanded by exercise to the heart, leading to backflow of venous return and eventual venous stasis.¹ Reduction of venous return together with cutaneous vasodilation is thought to induce erythrocyte extravasation.

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.

Our patient stated that her 64-year-old sister had reported the same presentation over the last 8 years. Her physical activity was limited strictly to walking, and the lesions occurred after walking for many hours during the day in the heat, involving the medial aspects of the lower legs extending from the ankles to the full length of the calves. Her eruption was warm but was not painful or pruritic. It resolved spontaneously after 5 days with no therapy.

Our patient was advised to wear compression stockings as a preventative measure, but she did not adhere to these recommendations, stating it was impractical to wear compression garments while playing tennis.

Exercise-induced vasculitis most commonly is seen in the medial aspects of the lower extremities as an erythematous urticarial eruption or pigmented purpuric plaque rapidly occurring after a period of exercise.^1,2 Lesions often are symmetric and can be pruritic and painful with a lack of systemic symptoms.³ These generic clinical manifestations may lead to a misdiagnosis of stasis dermatitis. One case report included initial treatment of presumptive cellulitis.⁴ Important clinical findings include a sparing of skin compressed by tight clothing such as socks, a lack of systemic symptoms, rapid appearance after exercise, and spontaneous resolution within a few days. No correlation with chronic venous disease has been demonstrated, as EIV can occur in patients with or without chronic venous insufficiency.⁵ Duplex ultrasound evaluation showed no venous reflux in our patient.

The pathophysiology of EIV remains unknown, but the concept of exercise-altered microcirculation has been proposed. Heat generated from exercise is normally dissipated by thermoregulatory mechanisms such as cutaneous vasodilation and sweat.^1,6 When exercise is extended, done concomitantly in the heat, or performed in legs with preexisting edema or substantial adipose tissue that limit heat attenuation, the thermoregulatory capacity is overloaded and heat-induced muscle fiber breakdown occurs.^1,7 Atrophy impairs the skeletal muscle’s ability to pump the increased venous return demanded by exercise to the heart, leading to backflow of venous return and eventual venous stasis.¹ Reduction of venous return together with cutaneous vasodilation is thought to induce erythrocyte extravasation.

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.

Our patient stated that her 64-year-old sister had reported the same presentation over the last 8 years. Her physical activity was limited strictly to walking, and the lesions occurred after walking for many hours during the day in the heat, involving the medial aspects of the lower legs extending from the ankles to the full length of the calves. Her eruption was warm but was not painful or pruritic. It resolved spontaneously after 5 days with no therapy.

Our patient was advised to wear compression stockings as a preventative measure, but she did not adhere to these recommendations, stating it was impractical to wear compression garments while playing tennis.

Exercise-induced vasculitis most commonly is seen in the medial aspects of the lower extremities as an erythematous urticarial eruption or pigmented purpuric plaque rapidly occurring after a period of exercise.^1,2 Lesions often are symmetric and can be pruritic and painful with a lack of systemic symptoms.³ These generic clinical manifestations may lead to a misdiagnosis of stasis dermatitis. One case report included initial treatment of presumptive cellulitis.⁴ Important clinical findings include a sparing of skin compressed by tight clothing such as socks, a lack of systemic symptoms, rapid appearance after exercise, and spontaneous resolution within a few days. No correlation with chronic venous disease has been demonstrated, as EIV can occur in patients with or without chronic venous insufficiency.⁵ Duplex ultrasound evaluation showed no venous reflux in our patient.

The pathophysiology of EIV remains unknown, but the concept of exercise-altered microcirculation has been proposed. Heat generated from exercise is normally dissipated by thermoregulatory mechanisms such as cutaneous vasodilation and sweat.^1,6 When exercise is extended, done concomitantly in the heat, or performed in legs with preexisting edema or substantial adipose tissue that limit heat attenuation, the thermoregulatory capacity is overloaded and heat-induced muscle fiber breakdown occurs.^1,7 Atrophy impairs the skeletal muscle’s ability to pump the increased venous return demanded by exercise to the heart, leading to backflow of venous return and eventual venous stasis.¹ Reduction of venous return together with cutaneous vasodilation is thought to induce erythrocyte extravasation.

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:

Few cases of unilateral nail changes affecting only the hemiplegic side after a stroke have been reported. We present a case of acquired unilateral nail clubbing and longitudinal melanonychia in a hemiparetic patient.

A 79-year-old Black man with a history of smoking and stroke presented with concerns of discoloration of the fingernails. His medical history was notable for congestive heart failure; hypertension; diabetes mellitus; hypercholesterolemia; and stroke 11 years prior, which resulted in right-sided hemiparesis. Physical examination revealed longitudinal, even hyperpigmentation of several fingernails on the hands, in addition to whitening of the nail beds, sparing the tips (Terry nails). Clubbing was noted only on the fingernails of the right hand; the fingernails of the left hand exhibited normal curvature (Figure). Pulse oximetry was conducted and demonstrated the following readings: unaffected left index finger, 98%; unaffected left middle finger, 100%; affected right index finger, 95%; and affected right middle finger, 97%. The patient was diagnosed with benign longitudinal melanonychia secondary to ethnic variation, Terry nails without underlying anemia or hypoalbuminemic state, and unilateral right-sided clubbing of the fingernails in the setting of right-sided hemiparesis.

Prior reports have documented the occurrence of nail pathologies after stroke and affecting hemiplegic limbs. Unilateral digital nail clubbing following a stroke was first reported in 1975¹; 2 reports concluded clubbing developed in all digits affected by the stroke, and the severity of clubbing was associated with the duration of the stroke.^1,2 One study noted longitudinal reddish striation, Neapolitan nails, and unilateral clubbing more commonly in hemiplegic patients.³ Longitudinal reddish striation was the most frequent condition observed in this population, always affecting the entire thumbnail of the hemiplegic limb.³ A similar report observed clubbing only on the fingernails of the hemiplegic side.⁴

Digital clubbing describes an exaggerated nail curvature and bulbous overgrowth of the fingertips due to an expansion of connective tissue between the nail plate and the nail bed.^3,5 Clubbed fingers are found in various chronic conditions affecting the heart, lungs, and liver. Although the pathogenesis of clubbing remains unknown, many hypothesize that it is a state of proliferation in response to digital hypoxia.⁵ Fittingly, our patient exhibited a relative hypoperfusion of the clubbed fingers in comparison to the unaffected side.

This case provides additional support for the phenomenon of unilateral nail changes limited to hemiplegic or hemiparetic limbs. The unique presentation of longitudinal melanonychia, clubbing, and a lowered pulse oximetry reading only affecting the hemiparetic side demonstrates the possible connection between hypoxia and nail clubbing in this patient population.

To the Editor:

Few cases of unilateral nail changes affecting only the hemiplegic side after a stroke have been reported. We present a case of acquired unilateral nail clubbing and longitudinal melanonychia in a hemiparetic patient.

A 79-year-old Black man with a history of smoking and stroke presented with concerns of discoloration of the fingernails. His medical history was notable for congestive heart failure; hypertension; diabetes mellitus; hypercholesterolemia; and stroke 11 years prior, which resulted in right-sided hemiparesis. Physical examination revealed longitudinal, even hyperpigmentation of several fingernails on the hands, in addition to whitening of the nail beds, sparing the tips (Terry nails). Clubbing was noted only on the fingernails of the right hand; the fingernails of the left hand exhibited normal curvature (Figure). Pulse oximetry was conducted and demonstrated the following readings: unaffected left index finger, 98%; unaffected left middle finger, 100%; affected right index finger, 95%; and affected right middle finger, 97%. The patient was diagnosed with benign longitudinal melanonychia secondary to ethnic variation, Terry nails without underlying anemia or hypoalbuminemic state, and unilateral right-sided clubbing of the fingernails in the setting of right-sided hemiparesis.

Prior reports have documented the occurrence of nail pathologies after stroke and affecting hemiplegic limbs. Unilateral digital nail clubbing following a stroke was first reported in 1975¹; 2 reports concluded clubbing developed in all digits affected by the stroke, and the severity of clubbing was associated with the duration of the stroke.^1,2 One study noted longitudinal reddish striation, Neapolitan nails, and unilateral clubbing more commonly in hemiplegic patients.³ Longitudinal reddish striation was the most frequent condition observed in this population, always affecting the entire thumbnail of the hemiplegic limb.³ A similar report observed clubbing only on the fingernails of the hemiplegic side.⁴

Digital clubbing describes an exaggerated nail curvature and bulbous overgrowth of the fingertips due to an expansion of connective tissue between the nail plate and the nail bed.^3,5 Clubbed fingers are found in various chronic conditions affecting the heart, lungs, and liver. Although the pathogenesis of clubbing remains unknown, many hypothesize that it is a state of proliferation in response to digital hypoxia.⁵ Fittingly, our patient exhibited a relative hypoperfusion of the clubbed fingers in comparison to the unaffected side.

This case provides additional support for the phenomenon of unilateral nail changes limited to hemiplegic or hemiparetic limbs. The unique presentation of longitudinal melanonychia, clubbing, and a lowered pulse oximetry reading only affecting the hemiparetic side demonstrates the possible connection between hypoxia and nail clubbing in this patient population.

To the Editor:

Few cases of unilateral nail changes affecting only the hemiplegic side after a stroke have been reported. We present a case of acquired unilateral nail clubbing and longitudinal melanonychia in a hemiparetic patient.

A 79-year-old Black man with a history of smoking and stroke presented with concerns of discoloration of the fingernails. His medical history was notable for congestive heart failure; hypertension; diabetes mellitus; hypercholesterolemia; and stroke 11 years prior, which resulted in right-sided hemiparesis. Physical examination revealed longitudinal, even hyperpigmentation of several fingernails on the hands, in addition to whitening of the nail beds, sparing the tips (Terry nails). Clubbing was noted only on the fingernails of the right hand; the fingernails of the left hand exhibited normal curvature (Figure). Pulse oximetry was conducted and demonstrated the following readings: unaffected left index finger, 98%; unaffected left middle finger, 100%; affected right index finger, 95%; and affected right middle finger, 97%. The patient was diagnosed with benign longitudinal melanonychia secondary to ethnic variation, Terry nails without underlying anemia or hypoalbuminemic state, and unilateral right-sided clubbing of the fingernails in the setting of right-sided hemiparesis.

Prior reports have documented the occurrence of nail pathologies after stroke and affecting hemiplegic limbs. Unilateral digital nail clubbing following a stroke was first reported in 1975¹; 2 reports concluded clubbing developed in all digits affected by the stroke, and the severity of clubbing was associated with the duration of the stroke.^1,2 One study noted longitudinal reddish striation, Neapolitan nails, and unilateral clubbing more commonly in hemiplegic patients.³ Longitudinal reddish striation was the most frequent condition observed in this population, always affecting the entire thumbnail of the hemiplegic limb.³ A similar report observed clubbing only on the fingernails of the hemiplegic side.⁴

Digital clubbing describes an exaggerated nail curvature and bulbous overgrowth of the fingertips due to an expansion of connective tissue between the nail plate and the nail bed.^3,5 Clubbed fingers are found in various chronic conditions affecting the heart, lungs, and liver. Although the pathogenesis of clubbing remains unknown, many hypothesize that it is a state of proliferation in response to digital hypoxia.⁵ Fittingly, our patient exhibited a relative hypoperfusion of the clubbed fingers in comparison to the unaffected side.

This case provides additional support for the phenomenon of unilateral nail changes limited to hemiplegic or hemiparetic limbs. The unique presentation of longitudinal melanonychia, clubbing, and a lowered pulse oximetry reading only affecting the hemiparetic side demonstrates the possible connection between hypoxia and nail clubbing in this patient population.

To the Editor:

Bullous pemphigoid (BP) is a rare complication of lower limb amputation. Termed stump pemphigoid, it previously was described as a late complication arising on the stumps of leg amputees and tends to remain localized. We describe a case of stump pemphigoid presenting with an urticarial prodromal phase without generalized progression, confirmed by serum assay for circulating anti–basement membrane antibodies.

A 62-year-old man with a history of a right above-knee amputation initially presented with erythema as well as coalescing erosions and ulcers with fluid-filled vesicles and bullae on the amputation stump (Figure 1). The amputation was performed 15 years prior after a motorcycle accident. A skin biopsy of a vesicle on the amputation stump revealed subepidermal and focal intraepidermal clefting with hemorrhage and rare inflammatory cells composed of neutrophils and eosinophils (Figure 2). A tissue direct immunofluorescence test demonstrated linear C3 and IgG deposition along the dermoepidermal junction. Serum enzyme-linked immunosorbent assay (ELISA) demonstrated an anti-BP180 IgG of 50.90 U/mL and anti-BP230 IgG of 129.40 U/mL (reference range, <9.00 U/mL [for both]).

Topical clobetasol led to only modest improvement of blistering on the stump. Minor frictional trauma related to his leg prosthesis continued to trigger new vesicles and bullae on the stump. Oral prednisone 0.5 mg/kg daily was administered and tapered slowly over the course of 6 months. He also received oral niacinamide and doxycycline. He was completely clear after 3 weeks of initiating treatment and remained clear while prednisone was slowly tapered. One month after stopping prednisone he had recurrence of blisters on the stump only after he resumed wearing his prosthesis. Mycophenolate mofetil was started at a dosage of 1 g twice daily while he refrained from wearing the prosthesis. After 3 months he was able to wear the prosthesis without developing blisters. Two years after the initial presentation, repeat serum ELISA demonstrated normalization of the anti-BP180 IgG and anti-BP230 IgG titers. Thirty months after the initial presentation, mycophenolate mofetil was tapered and discontinued. The patient remained blisterfree and continued to wear his leg prosthesis without further blistering.

Amputees experience a high rate of skin complications on their stump,¹ including friction blisters, shear injury, contact dermatitis, infections, and autoimmune blistering disorders (ie, BP, epidermolysis bullosa acquisita). The etiology of stump pemphigoid is not entirely understood but could be related to exposure of structural components of the hemidesmosome (eg, BP230, BP180), leading to autoantibody production as a consequence of either the underlying limb injury or from recurrent trauma related to limb prosthetics.²

Two previously reported cases of stump pemphigoid demonstrated a positive direct immunofluorescence antibody test.^3,4 Another case demonstrated the presence of circulating IgG antibodies on indirect immunofluorescence to salt-split skin.⁵ We report a case of stump pemphigoid confirmed by presence of circulating anti–basement membrane antibodies on ELISA, supporting its use in the diagnostic workup and monitoring treatment response.

To the Editor:

Bullous pemphigoid (BP) is a rare complication of lower limb amputation. Termed stump pemphigoid, it previously was described as a late complication arising on the stumps of leg amputees and tends to remain localized. We describe a case of stump pemphigoid presenting with an urticarial prodromal phase without generalized progression, confirmed by serum assay for circulating anti–basement membrane antibodies.

A 62-year-old man with a history of a right above-knee amputation initially presented with erythema as well as coalescing erosions and ulcers with fluid-filled vesicles and bullae on the amputation stump (Figure 1). The amputation was performed 15 years prior after a motorcycle accident. A skin biopsy of a vesicle on the amputation stump revealed subepidermal and focal intraepidermal clefting with hemorrhage and rare inflammatory cells composed of neutrophils and eosinophils (Figure 2). A tissue direct immunofluorescence test demonstrated linear C3 and IgG deposition along the dermoepidermal junction. Serum enzyme-linked immunosorbent assay (ELISA) demonstrated an anti-BP180 IgG of 50.90 U/mL and anti-BP230 IgG of 129.40 U/mL (reference range, <9.00 U/mL [for both]).

Topical clobetasol led to only modest improvement of blistering on the stump. Minor frictional trauma related to his leg prosthesis continued to trigger new vesicles and bullae on the stump. Oral prednisone 0.5 mg/kg daily was administered and tapered slowly over the course of 6 months. He also received oral niacinamide and doxycycline. He was completely clear after 3 weeks of initiating treatment and remained clear while prednisone was slowly tapered. One month after stopping prednisone he had recurrence of blisters on the stump only after he resumed wearing his prosthesis. Mycophenolate mofetil was started at a dosage of 1 g twice daily while he refrained from wearing the prosthesis. After 3 months he was able to wear the prosthesis without developing blisters. Two years after the initial presentation, repeat serum ELISA demonstrated normalization of the anti-BP180 IgG and anti-BP230 IgG titers. Thirty months after the initial presentation, mycophenolate mofetil was tapered and discontinued. The patient remained blisterfree and continued to wear his leg prosthesis without further blistering.

Amputees experience a high rate of skin complications on their stump,¹ including friction blisters, shear injury, contact dermatitis, infections, and autoimmune blistering disorders (ie, BP, epidermolysis bullosa acquisita). The etiology of stump pemphigoid is not entirely understood but could be related to exposure of structural components of the hemidesmosome (eg, BP230, BP180), leading to autoantibody production as a consequence of either the underlying limb injury or from recurrent trauma related to limb prosthetics.²

Two previously reported cases of stump pemphigoid demonstrated a positive direct immunofluorescence antibody test.^3,4 Another case demonstrated the presence of circulating IgG antibodies on indirect immunofluorescence to salt-split skin.⁵ We report a case of stump pemphigoid confirmed by presence of circulating anti–basement membrane antibodies on ELISA, supporting its use in the diagnostic workup and monitoring treatment response.

To the Editor:

Bullous pemphigoid (BP) is a rare complication of lower limb amputation. Termed stump pemphigoid, it previously was described as a late complication arising on the stumps of leg amputees and tends to remain localized. We describe a case of stump pemphigoid presenting with an urticarial prodromal phase without generalized progression, confirmed by serum assay for circulating anti–basement membrane antibodies.

A 62-year-old man with a history of a right above-knee amputation initially presented with erythema as well as coalescing erosions and ulcers with fluid-filled vesicles and bullae on the amputation stump (Figure 1). The amputation was performed 15 years prior after a motorcycle accident. A skin biopsy of a vesicle on the amputation stump revealed subepidermal and focal intraepidermal clefting with hemorrhage and rare inflammatory cells composed of neutrophils and eosinophils (Figure 2). A tissue direct immunofluorescence test demonstrated linear C3 and IgG deposition along the dermoepidermal junction. Serum enzyme-linked immunosorbent assay (ELISA) demonstrated an anti-BP180 IgG of 50.90 U/mL and anti-BP230 IgG of 129.40 U/mL (reference range, <9.00 U/mL [for both]).

Topical clobetasol led to only modest improvement of blistering on the stump. Minor frictional trauma related to his leg prosthesis continued to trigger new vesicles and bullae on the stump. Oral prednisone 0.5 mg/kg daily was administered and tapered slowly over the course of 6 months. He also received oral niacinamide and doxycycline. He was completely clear after 3 weeks of initiating treatment and remained clear while prednisone was slowly tapered. One month after stopping prednisone he had recurrence of blisters on the stump only after he resumed wearing his prosthesis. Mycophenolate mofetil was started at a dosage of 1 g twice daily while he refrained from wearing the prosthesis. After 3 months he was able to wear the prosthesis without developing blisters. Two years after the initial presentation, repeat serum ELISA demonstrated normalization of the anti-BP180 IgG and anti-BP230 IgG titers. Thirty months after the initial presentation, mycophenolate mofetil was tapered and discontinued. The patient remained blisterfree and continued to wear his leg prosthesis without further blistering.

Amputees experience a high rate of skin complications on their stump,¹ including friction blisters, shear injury, contact dermatitis, infections, and autoimmune blistering disorders (ie, BP, epidermolysis bullosa acquisita). The etiology of stump pemphigoid is not entirely understood but could be related to exposure of structural components of the hemidesmosome (eg, BP230, BP180), leading to autoantibody production as a consequence of either the underlying limb injury or from recurrent trauma related to limb prosthetics.²

Two previously reported cases of stump pemphigoid demonstrated a positive direct immunofluorescence antibody test.^3,4 Another case demonstrated the presence of circulating IgG antibodies on indirect immunofluorescence to salt-split skin.⁵ We report a case of stump pemphigoid confirmed by presence of circulating anti–basement membrane antibodies on ELISA, supporting its use in the diagnostic workup and monitoring treatment response.

To the Editor:

Scrub typhus (ST) is an infection caused by Orientia tsutsugamushi (genus Rickettsia), which is transmitted by the larvae of trombiculid mites, commonly called chiggers. The disease mainly has been described in Asia in an area known as the Tsutsugamushi Triangle, delineated by Pakistan, eastern Russia, and northern Australia. Although this classic distribution remains, recent reports have documented 1 case in the Arabian Peninsula¹ and more than 16 cases in southern Chile.^2-4 The first case in Chile was published in 2011 from Chiloé Island.² To date, no other cases have been reported in the Americas.^1-6

We describe a new case of ST from Chiloé Island and compare it to the first case reported in Chile in 2011.² Both patients showed the typical clinical manifestation, but because ST has become an increasingly suspected disease in southern regions of Chile, new cases are now easily diagnosed. This infection is diagnosed mainly by skin lesions; therefore, dermatologists should be aware of this diagnosis when presented with a febrile rash.

A 67-year-old man from the city of Punta Arenas presented to the emergency department with a dark necrotic lesion on the right foot of 1 week’s duration. The patient later developed a generalized pruritic rash and fever. He also reported muscle pain, headache, cough, night sweats, and odynophagia. He reported recent travel to a rural area in the northern part of Chiloé Island, where he came into contact with firewood and participated in outdoor activities. He had no other relevant medical history.

Physical examination revealed a temperature of 38 °C and a macular rash, with some papules distributed mainly on the face, trunk, and proximal extremities (Figure 1). He had a necrotic eschar on the dorsum of the right foot, with an erythematous halo (tache noire)(Figure 2).

A complete blood cell count, urinalysis, and tests of hepatic and renal function were normal. C-reactive protein was elevated 18 times the normal value. Because of high awareness of ST in the region, eschar samples were taken and submitted for serologic testing and polymerase chain reaction (PCR) targeting the 16S rRNA Orientia gene. Empirical treatment with oral doxycycline 100 mg twice daily was started. Polymerase chain reaction analysis showed the presence of Orientia species, confirming the diagnosis of ST. The rash and eschar diminished considerably after 7 days of antibiotic treatment.

Scrub typhus is a high-impact disease in Asia, described mainly in an area known as the Tsutsugamushi Triangle. Recent reports show important epidemiologic changes in the distribution of the disease, with new published reports of cases outside this endemic area—1 in the Arabian peninsula¹ and more than 16 in southern Chile.^2-4

The disease begins with a painless, erythematous, and usually unnoticed papule at the site of the bite. After 48 to 72 hours, the papule changes to a necrotic form (tache noire), surrounded by a red halo that often is small, similar to a cigarette burn. This lesion is described in 20% to 90% of infected patients in different series.⁷ Two or 3 days later (1 to 3 weeks after exposure), high fever suddenly develops. Along with fever, a maculopapular rash distributed centrifugally develops, without compromise of the palms or soles. Patients frequently report headache and night sweating. Sometimes, ST is accompanied by muscle or joint pain, red eye, cough, and abdominal pain. Hearing loss and altered mental status less frequently have been reported.^5,8

 

Common laboratory tests can be of use in diagnosis. An elevated C-reactive protein level and a slight to moderate increase in hepatic transaminases should be expected. Thrombocytopenia, leukopenia, and elevation of the lactate dehydrogenase level less frequently are present.^5,9

Our case de1monstrated a typical presentation. The patient developed a febrile syndrome with a generalized rash and a tache noire–type eschar associated with muscle pain, headache, cough, night sweats, and odynophagia. Because of epidemiologic changes in the area, the familiar clinical findings, and laboratory confirmation, histologic studies were unnecessary. In cases in which the diagnosis is not evident, skin biopsy could be useful, as in the first case reported in Chile.²

In that first case, the patient initially was hospitalized because of a febrile syndrome; eventually, a necrotic eschar was noticed on his leg. He had been staying on Chiloé Island and reported being bitten by leeches on multiple occasions. Laboratory findings revealed only slightly raised levels of hepatic transaminases and alkaline phosphatase. After a more precise dermatologic evaluation, the eschar of a tache noire, combined with other clinical and laboratory findings, raised suspicion of ST. Because this entity had never been described in Chile, biopsy of the eschar was taken to consider other entities in the differential diagnosis. Biopsy showed necrotizing leukocytoclastic vasculitis in the dermis and subcutaneous tissue, perivascular inflammatory infiltrates comprising lymphocytes and macrophages, and rickettsial microorganisms inside endothelial cells under electron microscopic examination. The specimen was tested for the 16S ribosomal RNA Orientia gene; its presence confirmed the diagnosis.²

Classically, histology from the eschar shows signs of vasculitis and rickettsial microorganisms inside endothelial cells on electron microscopy.^2,10 More recent publications describe important necrotic changes within keratinocytes as well as an inflammatory infiltrate comprising antigen-presenting cells, monocytes, macrophages, and dendritic cells. Using high-resolution thin sections with confocal laser scanning microscopy and staining of specific monoclonal antibodies against 56 kDa type-specific surface antigens, the bacteria were found inside antigen-presenting cells, many of them located perivascularly or passing through the endothelium.¹¹

The causal agent in Asia is O tsutsugamushi, an obligate intracellular bacterium (genus Rickettsia). Orientia species are transmitted by larvae of trombiculid mites, commonly called chiggers. The reservoir is believed to be the same as with chiggers, in which some vertebrates become infected and trombiculid mites feed on them.¹² Recent studies of Chilean cases have revealed the presence of a novel Orientia species, Candidatus Orientia chiloensis and its vector, trombiculid mites from the Herpetacarus species, Quadraseta species, and Paratrombicula species genera.^13,14

A high seroprevalence of Orientia species in dogs was reported in the main cities of Chiloé Island. Rates were higher in rural settings and older dogs. Of 202 specimens, 21.3% were positive for IgG against Orientia species.¹⁵

In Chile, most cases of ST came from Chiloé Island; some reports of cases from continental Chilean regions have been published.⁶ Most cases have occurred in the context of activities that brought the patients in contact with plants and firewood in rural areas during the summer.^3-6

 

The diagnosis of ST is eminently clinical, based on the triad of fever, macular or papular rash, and an inoculation necrotic eschar. The diagnosis is supported by epidemiologic facts and fast recovery after treatment is initiated.¹⁶ Although the diagnosis can be established based on a quick recovery in endemic countries, in areas such as Chile where incidence and distribution are not completely known, it is better to confirm the diagnosis with laboratory tests without delaying treatment. Several testing options exist, including serologic techniques (immunofluorescence or enzyme-linked immunosorbent assay), culture, and detection of the genetic material of Orientia species by PCR. Usually, IgM titers initially are negative, and IgG testing requires paired samples (acute and convalescent) to demonstrate seroconversion and therefore acute infection.¹⁷ Because culture requires a highly specialized laboratory, it is not frequently used. Polymerase chain reaction is recognized as the best confirmation method due to its high sensitivity and because it remains positive for a few days after treatment has been initiated. The specimen of choice is the eschar because of its high bacterial load. The base of the scar and the buffy coat are useful specimens when the eschar is unavailable.^5,17-19

Due to potential complications of ST, empirical treatment with an antibiotic should be started based on clinical facts and never delayed because of diagnostic tests.¹⁸ Classically, ST is treated with a member of the tetracycline family, such as doxycycline, which provides a cure rate of 63% to 100% in ST.⁵

A 2017 systematic review of treatment options for this infection examined 11 studies from Southeast Asia, China, and South Korea (N=957).¹⁶ The review mainly compared doxycycline with azithromycin, chloramphenicol, and tetracycline. No significant difference in cure rate was noted in comparing doxycycline with any of the other 3 antibiotics; most of the studies examined were characterized by a moderate level of evidence. Regarding adverse effects, doxycycline showed a few more cases of gastrointestinal intolerance, and in 2 of 4 studies with chloramphenicol, patients presented with leukopenia.¹⁶ Several studies compared standard treatment (doxycycline) with rifampicin, telithromycin, erythromycin, and levofloxacin individually; similar cure rates were noted between doxycycline and each of those 4 agents.

Therapeutic failure in ST has been reported in several cases with the use of levofloxacin.²⁰ Evidence for this novel antibiotic is still insufficient. Further studies are needed before rifampicin, telithromycin, erythromycin, or levofloxacin can be considered as options.Scrub typhus usually resolves within a few weeks. Left untreated, the disease can cause complications such as pneumonia, meningoencephalitis, renal failure, and even multiorgan failure and death. Without treatment, mortality is variable. A 2015 systematic review of mortality from untreated ST showed, on average, mortality of 6% (range, 0%–70%).²¹ When ST is treated, mortality falls to 0% to 30%.²² Cases reported in Chile have neither been lethal nor presented with severe complications.^4,5

Scrub typhus is an infectious disease common in Asia, caused by O tsutsugamushi and transmitted by chiggers. It should be suspected when a febrile macular or papular rash and a tache noire appear. The diagnosis can be supported by laboratory findings, such as an elevated C-reactive protein level or a slight increase in the levels of hepatic transaminases, and response to treatment. The diagnosis is confirmed by serology or PCR of a specimen of the eschar. Empiric therapy with antibiotics is mandatory; doxycycline is the first option.

First described in Chile in 2011,² ST was seen in a patient in whom disease was suspected because of clinical characteristics, laboratory and histologic findings, absence of prior reporting in South America, and confirmation with PCR targeting the 16S ribosomal RNA Orientia gene from specimens of the eschar. By 2020, 60 cases have been confirmed in Chile, not all of them published; there are no other reported cases in South America.

When comparing the first case in Chile² with our case, we noted that both described classic clinical findings; however, the management approach and diagnostic challenges have evolved over time. Nowadays, ST is highly suspected, so it can be largely recognized and treated, which also provides better understanding of the nature of this disease in Chile. Because this infection is diagnosed mainly by characteristic cutaneous lesions, dermatologists should be aware of its epidemiology, clinical features, and transmission, and they should stay open to the possibility of this (until now) unusual diagnosis in South America.

Acknowledgments
The authors would like to thank the Chilean Rickettsia & Zoonosis Research Group (Thomas Weitzel, MD [Santiago, Chile]; Constanza Martínez-Valdebenito [Santiago, Chile]; and Gerardo Acosta-Jammet, DSc [Valdivia, Chile]), whose study in execution in the country allowed the detection of the case and confirmation by PCR. The authors also thank Juan Carlos Román, MD (Chiloé, Chile) who was part of the team that detected this case.

To the Editor:

Scrub typhus (ST) is an infection caused by Orientia tsutsugamushi (genus Rickettsia), which is transmitted by the larvae of trombiculid mites, commonly called chiggers. The disease mainly has been described in Asia in an area known as the Tsutsugamushi Triangle, delineated by Pakistan, eastern Russia, and northern Australia. Although this classic distribution remains, recent reports have documented 1 case in the Arabian Peninsula¹ and more than 16 cases in southern Chile.^2-4 The first case in Chile was published in 2011 from Chiloé Island.² To date, no other cases have been reported in the Americas.^1-6

We describe a new case of ST from Chiloé Island and compare it to the first case reported in Chile in 2011.² Both patients showed the typical clinical manifestation, but because ST has become an increasingly suspected disease in southern regions of Chile, new cases are now easily diagnosed. This infection is diagnosed mainly by skin lesions; therefore, dermatologists should be aware of this diagnosis when presented with a febrile rash.

A 67-year-old man from the city of Punta Arenas presented to the emergency department with a dark necrotic lesion on the right foot of 1 week’s duration. The patient later developed a generalized pruritic rash and fever. He also reported muscle pain, headache, cough, night sweats, and odynophagia. He reported recent travel to a rural area in the northern part of Chiloé Island, where he came into contact with firewood and participated in outdoor activities. He had no other relevant medical history.

Physical examination revealed a temperature of 38 °C and a macular rash, with some papules distributed mainly on the face, trunk, and proximal extremities (Figure 1). He had a necrotic eschar on the dorsum of the right foot, with an erythematous halo (tache noire)(Figure 2).

A complete blood cell count, urinalysis, and tests of hepatic and renal function were normal. C-reactive protein was elevated 18 times the normal value. Because of high awareness of ST in the region, eschar samples were taken and submitted for serologic testing and polymerase chain reaction (PCR) targeting the 16S rRNA Orientia gene. Empirical treatment with oral doxycycline 100 mg twice daily was started. Polymerase chain reaction analysis showed the presence of Orientia species, confirming the diagnosis of ST. The rash and eschar diminished considerably after 7 days of antibiotic treatment.

Scrub typhus is a high-impact disease in Asia, described mainly in an area known as the Tsutsugamushi Triangle. Recent reports show important epidemiologic changes in the distribution of the disease, with new published reports of cases outside this endemic area—1 in the Arabian peninsula¹ and more than 16 in southern Chile.^2-4

The disease begins with a painless, erythematous, and usually unnoticed papule at the site of the bite. After 48 to 72 hours, the papule changes to a necrotic form (tache noire), surrounded by a red halo that often is small, similar to a cigarette burn. This lesion is described in 20% to 90% of infected patients in different series.⁷ Two or 3 days later (1 to 3 weeks after exposure), high fever suddenly develops. Along with fever, a maculopapular rash distributed centrifugally develops, without compromise of the palms or soles. Patients frequently report headache and night sweating. Sometimes, ST is accompanied by muscle or joint pain, red eye, cough, and abdominal pain. Hearing loss and altered mental status less frequently have been reported.^5,8

 

Common laboratory tests can be of use in diagnosis. An elevated C-reactive protein level and a slight to moderate increase in hepatic transaminases should be expected. Thrombocytopenia, leukopenia, and elevation of the lactate dehydrogenase level less frequently are present.^5,9

Our case de1monstrated a typical presentation. The patient developed a febrile syndrome with a generalized rash and a tache noire–type eschar associated with muscle pain, headache, cough, night sweats, and odynophagia. Because of epidemiologic changes in the area, the familiar clinical findings, and laboratory confirmation, histologic studies were unnecessary. In cases in which the diagnosis is not evident, skin biopsy could be useful, as in the first case reported in Chile.²

In that first case, the patient initially was hospitalized because of a febrile syndrome; eventually, a necrotic eschar was noticed on his leg. He had been staying on Chiloé Island and reported being bitten by leeches on multiple occasions. Laboratory findings revealed only slightly raised levels of hepatic transaminases and alkaline phosphatase. After a more precise dermatologic evaluation, the eschar of a tache noire, combined with other clinical and laboratory findings, raised suspicion of ST. Because this entity had never been described in Chile, biopsy of the eschar was taken to consider other entities in the differential diagnosis. Biopsy showed necrotizing leukocytoclastic vasculitis in the dermis and subcutaneous tissue, perivascular inflammatory infiltrates comprising lymphocytes and macrophages, and rickettsial microorganisms inside endothelial cells under electron microscopic examination. The specimen was tested for the 16S ribosomal RNA Orientia gene; its presence confirmed the diagnosis.²

Classically, histology from the eschar shows signs of vasculitis and rickettsial microorganisms inside endothelial cells on electron microscopy.^2,10 More recent publications describe important necrotic changes within keratinocytes as well as an inflammatory infiltrate comprising antigen-presenting cells, monocytes, macrophages, and dendritic cells. Using high-resolution thin sections with confocal laser scanning microscopy and staining of specific monoclonal antibodies against 56 kDa type-specific surface antigens, the bacteria were found inside antigen-presenting cells, many of them located perivascularly or passing through the endothelium.¹¹

The causal agent in Asia is O tsutsugamushi, an obligate intracellular bacterium (genus Rickettsia). Orientia species are transmitted by larvae of trombiculid mites, commonly called chiggers. The reservoir is believed to be the same as with chiggers, in which some vertebrates become infected and trombiculid mites feed on them.¹² Recent studies of Chilean cases have revealed the presence of a novel Orientia species, Candidatus Orientia chiloensis and its vector, trombiculid mites from the Herpetacarus species, Quadraseta species, and Paratrombicula species genera.^13,14

A high seroprevalence of Orientia species in dogs was reported in the main cities of Chiloé Island. Rates were higher in rural settings and older dogs. Of 202 specimens, 21.3% were positive for IgG against Orientia species.¹⁵

In Chile, most cases of ST came from Chiloé Island; some reports of cases from continental Chilean regions have been published.⁶ Most cases have occurred in the context of activities that brought the patients in contact with plants and firewood in rural areas during the summer.^3-6

 

The diagnosis of ST is eminently clinical, based on the triad of fever, macular or papular rash, and an inoculation necrotic eschar. The diagnosis is supported by epidemiologic facts and fast recovery after treatment is initiated.¹⁶ Although the diagnosis can be established based on a quick recovery in endemic countries, in areas such as Chile where incidence and distribution are not completely known, it is better to confirm the diagnosis with laboratory tests without delaying treatment. Several testing options exist, including serologic techniques (immunofluorescence or enzyme-linked immunosorbent assay), culture, and detection of the genetic material of Orientia species by PCR. Usually, IgM titers initially are negative, and IgG testing requires paired samples (acute and convalescent) to demonstrate seroconversion and therefore acute infection.¹⁷ Because culture requires a highly specialized laboratory, it is not frequently used. Polymerase chain reaction is recognized as the best confirmation method due to its high sensitivity and because it remains positive for a few days after treatment has been initiated. The specimen of choice is the eschar because of its high bacterial load. The base of the scar and the buffy coat are useful specimens when the eschar is unavailable.^5,17-19

Due to potential complications of ST, empirical treatment with an antibiotic should be started based on clinical facts and never delayed because of diagnostic tests.¹⁸ Classically, ST is treated with a member of the tetracycline family, such as doxycycline, which provides a cure rate of 63% to 100% in ST.⁵

A 2017 systematic review of treatment options for this infection examined 11 studies from Southeast Asia, China, and South Korea (N=957).¹⁶ The review mainly compared doxycycline with azithromycin, chloramphenicol, and tetracycline. No significant difference in cure rate was noted in comparing doxycycline with any of the other 3 antibiotics; most of the studies examined were characterized by a moderate level of evidence. Regarding adverse effects, doxycycline showed a few more cases of gastrointestinal intolerance, and in 2 of 4 studies with chloramphenicol, patients presented with leukopenia.¹⁶ Several studies compared standard treatment (doxycycline) with rifampicin, telithromycin, erythromycin, and levofloxacin individually; similar cure rates were noted between doxycycline and each of those 4 agents.

Therapeutic failure in ST has been reported in several cases with the use of levofloxacin.²⁰ Evidence for this novel antibiotic is still insufficient. Further studies are needed before rifampicin, telithromycin, erythromycin, or levofloxacin can be considered as options.Scrub typhus usually resolves within a few weeks. Left untreated, the disease can cause complications such as pneumonia, meningoencephalitis, renal failure, and even multiorgan failure and death. Without treatment, mortality is variable. A 2015 systematic review of mortality from untreated ST showed, on average, mortality of 6% (range, 0%–70%).²¹ When ST is treated, mortality falls to 0% to 30%.²² Cases reported in Chile have neither been lethal nor presented with severe complications.^4,5

Scrub typhus is an infectious disease common in Asia, caused by O tsutsugamushi and transmitted by chiggers. It should be suspected when a febrile macular or papular rash and a tache noire appear. The diagnosis can be supported by laboratory findings, such as an elevated C-reactive protein level or a slight increase in the levels of hepatic transaminases, and response to treatment. The diagnosis is confirmed by serology or PCR of a specimen of the eschar. Empiric therapy with antibiotics is mandatory; doxycycline is the first option.

First described in Chile in 2011,² ST was seen in a patient in whom disease was suspected because of clinical characteristics, laboratory and histologic findings, absence of prior reporting in South America, and confirmation with PCR targeting the 16S ribosomal RNA Orientia gene from specimens of the eschar. By 2020, 60 cases have been confirmed in Chile, not all of them published; there are no other reported cases in South America.

When comparing the first case in Chile² with our case, we noted that both described classic clinical findings; however, the management approach and diagnostic challenges have evolved over time. Nowadays, ST is highly suspected, so it can be largely recognized and treated, which also provides better understanding of the nature of this disease in Chile. Because this infection is diagnosed mainly by characteristic cutaneous lesions, dermatologists should be aware of its epidemiology, clinical features, and transmission, and they should stay open to the possibility of this (until now) unusual diagnosis in South America.

Acknowledgments
The authors would like to thank the Chilean Rickettsia & Zoonosis Research Group (Thomas Weitzel, MD [Santiago, Chile]; Constanza Martínez-Valdebenito [Santiago, Chile]; and Gerardo Acosta-Jammet, DSc [Valdivia, Chile]), whose study in execution in the country allowed the detection of the case and confirmation by PCR. The authors also thank Juan Carlos Román, MD (Chiloé, Chile) who was part of the team that detected this case.

To the Editor:

Scrub typhus (ST) is an infection caused by Orientia tsutsugamushi (genus Rickettsia), which is transmitted by the larvae of trombiculid mites, commonly called chiggers. The disease mainly has been described in Asia in an area known as the Tsutsugamushi Triangle, delineated by Pakistan, eastern Russia, and northern Australia. Although this classic distribution remains, recent reports have documented 1 case in the Arabian Peninsula¹ and more than 16 cases in southern Chile.^2-4 The first case in Chile was published in 2011 from Chiloé Island.² To date, no other cases have been reported in the Americas.^1-6

We describe a new case of ST from Chiloé Island and compare it to the first case reported in Chile in 2011.² Both patients showed the typical clinical manifestation, but because ST has become an increasingly suspected disease in southern regions of Chile, new cases are now easily diagnosed. This infection is diagnosed mainly by skin lesions; therefore, dermatologists should be aware of this diagnosis when presented with a febrile rash.

A 67-year-old man from the city of Punta Arenas presented to the emergency department with a dark necrotic lesion on the right foot of 1 week’s duration. The patient later developed a generalized pruritic rash and fever. He also reported muscle pain, headache, cough, night sweats, and odynophagia. He reported recent travel to a rural area in the northern part of Chiloé Island, where he came into contact with firewood and participated in outdoor activities. He had no other relevant medical history.

Physical examination revealed a temperature of 38 °C and a macular rash, with some papules distributed mainly on the face, trunk, and proximal extremities (Figure 1). He had a necrotic eschar on the dorsum of the right foot, with an erythematous halo (tache noire)(Figure 2).

A complete blood cell count, urinalysis, and tests of hepatic and renal function were normal. C-reactive protein was elevated 18 times the normal value. Because of high awareness of ST in the region, eschar samples were taken and submitted for serologic testing and polymerase chain reaction (PCR) targeting the 16S rRNA Orientia gene. Empirical treatment with oral doxycycline 100 mg twice daily was started. Polymerase chain reaction analysis showed the presence of Orientia species, confirming the diagnosis of ST. The rash and eschar diminished considerably after 7 days of antibiotic treatment.

Scrub typhus is a high-impact disease in Asia, described mainly in an area known as the Tsutsugamushi Triangle. Recent reports show important epidemiologic changes in the distribution of the disease, with new published reports of cases outside this endemic area—1 in the Arabian peninsula¹ and more than 16 in southern Chile.^2-4

The disease begins with a painless, erythematous, and usually unnoticed papule at the site of the bite. After 48 to 72 hours, the papule changes to a necrotic form (tache noire), surrounded by a red halo that often is small, similar to a cigarette burn. This lesion is described in 20% to 90% of infected patients in different series.⁷ Two or 3 days later (1 to 3 weeks after exposure), high fever suddenly develops. Along with fever, a maculopapular rash distributed centrifugally develops, without compromise of the palms or soles. Patients frequently report headache and night sweating. Sometimes, ST is accompanied by muscle or joint pain, red eye, cough, and abdominal pain. Hearing loss and altered mental status less frequently have been reported.^5,8

 

Common laboratory tests can be of use in diagnosis. An elevated C-reactive protein level and a slight to moderate increase in hepatic transaminases should be expected. Thrombocytopenia, leukopenia, and elevation of the lactate dehydrogenase level less frequently are present.^5,9

Our case de1monstrated a typical presentation. The patient developed a febrile syndrome with a generalized rash and a tache noire–type eschar associated with muscle pain, headache, cough, night sweats, and odynophagia. Because of epidemiologic changes in the area, the familiar clinical findings, and laboratory confirmation, histologic studies were unnecessary. In cases in which the diagnosis is not evident, skin biopsy could be useful, as in the first case reported in Chile.²

In that first case, the patient initially was hospitalized because of a febrile syndrome; eventually, a necrotic eschar was noticed on his leg. He had been staying on Chiloé Island and reported being bitten by leeches on multiple occasions. Laboratory findings revealed only slightly raised levels of hepatic transaminases and alkaline phosphatase. After a more precise dermatologic evaluation, the eschar of a tache noire, combined with other clinical and laboratory findings, raised suspicion of ST. Because this entity had never been described in Chile, biopsy of the eschar was taken to consider other entities in the differential diagnosis. Biopsy showed necrotizing leukocytoclastic vasculitis in the dermis and subcutaneous tissue, perivascular inflammatory infiltrates comprising lymphocytes and macrophages, and rickettsial microorganisms inside endothelial cells under electron microscopic examination. The specimen was tested for the 16S ribosomal RNA Orientia gene; its presence confirmed the diagnosis.²

Classically, histology from the eschar shows signs of vasculitis and rickettsial microorganisms inside endothelial cells on electron microscopy.^2,10 More recent publications describe important necrotic changes within keratinocytes as well as an inflammatory infiltrate comprising antigen-presenting cells, monocytes, macrophages, and dendritic cells. Using high-resolution thin sections with confocal laser scanning microscopy and staining of specific monoclonal antibodies against 56 kDa type-specific surface antigens, the bacteria were found inside antigen-presenting cells, many of them located perivascularly or passing through the endothelium.¹¹

The causal agent in Asia is O tsutsugamushi, an obligate intracellular bacterium (genus Rickettsia). Orientia species are transmitted by larvae of trombiculid mites, commonly called chiggers. The reservoir is believed to be the same as with chiggers, in which some vertebrates become infected and trombiculid mites feed on them.¹² Recent studies of Chilean cases have revealed the presence of a novel Orientia species, Candidatus Orientia chiloensis and its vector, trombiculid mites from the Herpetacarus species, Quadraseta species, and Paratrombicula species genera.^13,14

A high seroprevalence of Orientia species in dogs was reported in the main cities of Chiloé Island. Rates were higher in rural settings and older dogs. Of 202 specimens, 21.3% were positive for IgG against Orientia species.¹⁵

In Chile, most cases of ST came from Chiloé Island; some reports of cases from continental Chilean regions have been published.⁶ Most cases have occurred in the context of activities that brought the patients in contact with plants and firewood in rural areas during the summer.^3-6

 

The diagnosis of ST is eminently clinical, based on the triad of fever, macular or papular rash, and an inoculation necrotic eschar. The diagnosis is supported by epidemiologic facts and fast recovery after treatment is initiated.¹⁶ Although the diagnosis can be established based on a quick recovery in endemic countries, in areas such as Chile where incidence and distribution are not completely known, it is better to confirm the diagnosis with laboratory tests without delaying treatment. Several testing options exist, including serologic techniques (immunofluorescence or enzyme-linked immunosorbent assay), culture, and detection of the genetic material of Orientia species by PCR. Usually, IgM titers initially are negative, and IgG testing requires paired samples (acute and convalescent) to demonstrate seroconversion and therefore acute infection.¹⁷ Because culture requires a highly specialized laboratory, it is not frequently used. Polymerase chain reaction is recognized as the best confirmation method due to its high sensitivity and because it remains positive for a few days after treatment has been initiated. The specimen of choice is the eschar because of its high bacterial load. The base of the scar and the buffy coat are useful specimens when the eschar is unavailable.^5,17-19

Due to potential complications of ST, empirical treatment with an antibiotic should be started based on clinical facts and never delayed because of diagnostic tests.¹⁸ Classically, ST is treated with a member of the tetracycline family, such as doxycycline, which provides a cure rate of 63% to 100% in ST.⁵

A 2017 systematic review of treatment options for this infection examined 11 studies from Southeast Asia, China, and South Korea (N=957).¹⁶ The review mainly compared doxycycline with azithromycin, chloramphenicol, and tetracycline. No significant difference in cure rate was noted in comparing doxycycline with any of the other 3 antibiotics; most of the studies examined were characterized by a moderate level of evidence. Regarding adverse effects, doxycycline showed a few more cases of gastrointestinal intolerance, and in 2 of 4 studies with chloramphenicol, patients presented with leukopenia.¹⁶ Several studies compared standard treatment (doxycycline) with rifampicin, telithromycin, erythromycin, and levofloxacin individually; similar cure rates were noted between doxycycline and each of those 4 agents.

Therapeutic failure in ST has been reported in several cases with the use of levofloxacin.²⁰ Evidence for this novel antibiotic is still insufficient. Further studies are needed before rifampicin, telithromycin, erythromycin, or levofloxacin can be considered as options.Scrub typhus usually resolves within a few weeks. Left untreated, the disease can cause complications such as pneumonia, meningoencephalitis, renal failure, and even multiorgan failure and death. Without treatment, mortality is variable. A 2015 systematic review of mortality from untreated ST showed, on average, mortality of 6% (range, 0%–70%).²¹ When ST is treated, mortality falls to 0% to 30%.²² Cases reported in Chile have neither been lethal nor presented with severe complications.^4,5

Scrub typhus is an infectious disease common in Asia, caused by O tsutsugamushi and transmitted by chiggers. It should be suspected when a febrile macular or papular rash and a tache noire appear. The diagnosis can be supported by laboratory findings, such as an elevated C-reactive protein level or a slight increase in the levels of hepatic transaminases, and response to treatment. The diagnosis is confirmed by serology or PCR of a specimen of the eschar. Empiric therapy with antibiotics is mandatory; doxycycline is the first option.

First described in Chile in 2011,² ST was seen in a patient in whom disease was suspected because of clinical characteristics, laboratory and histologic findings, absence of prior reporting in South America, and confirmation with PCR targeting the 16S ribosomal RNA Orientia gene from specimens of the eschar. By 2020, 60 cases have been confirmed in Chile, not all of them published; there are no other reported cases in South America.

When comparing the first case in Chile² with our case, we noted that both described classic clinical findings; however, the management approach and diagnostic challenges have evolved over time. Nowadays, ST is highly suspected, so it can be largely recognized and treated, which also provides better understanding of the nature of this disease in Chile. Because this infection is diagnosed mainly by characteristic cutaneous lesions, dermatologists should be aware of its epidemiology, clinical features, and transmission, and they should stay open to the possibility of this (until now) unusual diagnosis in South America.

Acknowledgments
The authors would like to thank the Chilean Rickettsia & Zoonosis Research Group (Thomas Weitzel, MD [Santiago, Chile]; Constanza Martínez-Valdebenito [Santiago, Chile]; and Gerardo Acosta-Jammet, DSc [Valdivia, Chile]), whose study in execution in the country allowed the detection of the case and confirmation by PCR. The authors also thank Juan Carlos Román, MD (Chiloé, Chile) who was part of the team that detected this case.

To the Editor:

Hailey-Hailey disease (HHD), or familial benign chronic pemphigus, is a genetic disorder caused by an autosomal-dominant mutation in ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1, which disrupts intracellular calcium signaling and blocks synthesis of junctional proteins required for cell-cell adhesion.^1,2 As a result, patients develop acantholysis of the suprabasilar epidermis resulting in chronic flaccid blisters and erosions, particularly in intertriginous areas.³ Patients often report associated itching, pain, and burning, and they frequently present with secondary polymicrobial infections.⁴ Although HHD is genetic, patients may present without a family history due to variable expressivity and sporadic germline mutations.⁵ Therapeutic options are numerous, and patients may attempt many treatments before a benefit is observed.⁴ Local disease improvement was noted in a case series of 3 patients treated with electron beam radiotherapy with no disease recurrence in treated sites at 38, 33, and 9 months’ follow-up.⁶ Herein, we present a case of HHD refractory to numerous prior therapies that was successfully treated with electron beam radiotherapy, highlighting the potential role for palliative radiotherapy in select refractory cases of HHD.

A 35-year-old woman with a 7-year of history of HHD presented with severe recalcitrant disease including extensive erosive patches and plaques in the intertriginous areas of the bilateral axillae, groin, and inframammary folds (Figure 1). The skin eruptions first appeared at 28 years of age after her last pregnancy and continued as painful blistering that worsened with each menstrual cycle. Initially the affected desquamated skin would heal between menstrual cycles, but large areas of desquamation remained unhealed in the groin and inframammary regions throughout her full menstrual cycles by the time of referral. Family history included 4 family members with HHD: 2 aunts, an uncle, and a cousin on the paternal side of her family. Over a 7-year period, treatment with clobetasol cream, clindamycin gel, tacrolimus ointment, doxycycline, dapsone, cyclosporine, methotrexate, etanercept, isotretinoin, and prednisone (15 mg every other day) all failed. Most recently, axillary abobotulinumtoxinA injections were attempted but failed. She had been prednisone dependent for more than 1 year. Due to the ongoing refractory disease, she was referred to radiation oncology to discuss radiotherapy treatment options.

At the time of presentation to the radiation oncology clinic, she continued to have extensive involvement of the intertriginous areas as well as involvement of the right neck at sites of skin chafing from clothing. Consistent with the limited available evidence, a dose of 20 Gy in 10 fractions was first prescribed to the axillae to assess response in the event of radiosensitivity, resulting in brisk desquamation. The conventional fractionation of 2 Gy per fraction allowed for assessment of response/tolerance and the opportunity to stop the treatment in the unlikely event of a severe skin reaction. Her skin tolerated treatment well with slight dryness and mild irritation that was less severe than the typical HHD flares. Concurrently with the axillary radiotherapy, we delivered a trial of low-level laser therapy to areas of severe disease in both inguinal regions in the hope that it could be used instead of radiotherapy to avoid any associated risks of radiation. Low-level laser therapy was administered with a light-emitting diode cluster probe at 2.5 Hz for 1 minute to 2 sites in each inguinal area daily for a total of 10 treatments. Unfortunately, this therapy temporarily exacerbated exudation present in the skin before it resolved to its pretreatment state with no improvement.

One month after treatment she had total resolution of the erosive patches and plaques with mild residual hyperpigmentation in the axillae, establishing that radiation therapy was reasonably effective. To lower the total radiation dose and decrease the risk of radiation-induced malignancy, we treated the bilateral groin and the inframammary region with a treatment schedule of 8 Gy in 2 fractions at a higher dose of 4 Gy per fraction instead of 2 Gy. At 12 days posttreatment, she had a dramatic response in the groin and a mixed response in the inframammary region, with a focus that had not yet regressed. Given the dramatic response in the treated sites, the patient requested treatment to the right side of the neck. Thus, we treated this area with a similar 8 Gy in 2 fractions, and an additional 6 Gy in 2 fractions boost was added to the slow responding focus in the inframammary fold for a total of 14 Gy in 4 fractions. The patient tolerated all treatments well with mild grade 1 skin irritation that was unlike the blistering of the typical HHD flares. Two months following completion of the first course of radiotherapy to the axillae and 2 weeks from the most recent course, she tapered off her prednisone regimen (15 mg every other day) but had a relapse of disease with her subsequent menstrual cycles that presented as a blistering skin reaction in the inframammary region, which healed in response to restarting steroids. This flare was less severe than those prior to radiotherapy. At 10 months posttreatment, the patient was free of disease in the neck and axillae (Figure 2). She continued to have relapses in the inframammary region with menstrual cycles and noted new disease in the popliteal regions; however, the relapses were less severe, and her skin had improved more with radiation than any of the prior therapies.

Our experience with low-level laser therapy indicated that it should be completely avoided in HHD. Our patient’s treatment with radiotherapy demonstrated excellent short-term responses in areas of pemphigus but later proved to be a mixed response with further follow-up including a mild posttreatment flare of the inframammary region that responded to steroids and new popliteal region involvement. As summarized in the Table, earlier reports of radiotherapy for the treatment of HHD have yielded varied results.^6-8 The mixed response seen in our patient suggests that response to radiotherapy may be site specific, related to underlying inflammation from microbial overgrowth, or a function of the disease severity.

Although the number of reports on radiotherapy in HHD is small, there have been several reports of Darier disease, another acantholytic autosomal-dominant genodermatosis affecting the ATP2A2 gene, successfully treated incidentally with radiation.^9,10 Total skin electron beam therapy also has been employed in the treatment of Darier disease; this patient experienced a severe flare after a relatively low treatment dose that required intensive care monitoring, possibly highlighting the potential radiosensitivity of patients with underlying genodermatoses and cautioning against radiotherapy dose escalation.¹¹ In light of the mixed responses seen, radiation therapy should be used sparingly for severe relapsing cases that have failed a plethora of prior treatments. The risk of second cancer induction is especially of concern when using radiotherapy in a benign disease.¹² We observed excellent initial responses in our patient, both with conventionally fractionated radiotherapy and hypofractionation. The risk of second malignancy induction is a linear function of radiotherapy dose.¹² Thus, utilization of hypofractionated regimens such as 4 Gy times 2 fractions seems most prudent. It remains unclear if further dose de-escalation may yield a similar response, as seen in studies utilizing radiotherapy for other benign disease.^13,14 Overall, given our mixed results with short follow-up, we conclude that the consideration of radiotherapy should be limited to patients with severe recalcitrant HHD.

To the Editor:

Hailey-Hailey disease (HHD), or familial benign chronic pemphigus, is a genetic disorder caused by an autosomal-dominant mutation in ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1, which disrupts intracellular calcium signaling and blocks synthesis of junctional proteins required for cell-cell adhesion.^1,2 As a result, patients develop acantholysis of the suprabasilar epidermis resulting in chronic flaccid blisters and erosions, particularly in intertriginous areas.³ Patients often report associated itching, pain, and burning, and they frequently present with secondary polymicrobial infections.⁴ Although HHD is genetic, patients may present without a family history due to variable expressivity and sporadic germline mutations.⁵ Therapeutic options are numerous, and patients may attempt many treatments before a benefit is observed.⁴ Local disease improvement was noted in a case series of 3 patients treated with electron beam radiotherapy with no disease recurrence in treated sites at 38, 33, and 9 months’ follow-up.⁶ Herein, we present a case of HHD refractory to numerous prior therapies that was successfully treated with electron beam radiotherapy, highlighting the potential role for palliative radiotherapy in select refractory cases of HHD.

A 35-year-old woman with a 7-year of history of HHD presented with severe recalcitrant disease including extensive erosive patches and plaques in the intertriginous areas of the bilateral axillae, groin, and inframammary folds (Figure 1). The skin eruptions first appeared at 28 years of age after her last pregnancy and continued as painful blistering that worsened with each menstrual cycle. Initially the affected desquamated skin would heal between menstrual cycles, but large areas of desquamation remained unhealed in the groin and inframammary regions throughout her full menstrual cycles by the time of referral. Family history included 4 family members with HHD: 2 aunts, an uncle, and a cousin on the paternal side of her family. Over a 7-year period, treatment with clobetasol cream, clindamycin gel, tacrolimus ointment, doxycycline, dapsone, cyclosporine, methotrexate, etanercept, isotretinoin, and prednisone (15 mg every other day) all failed. Most recently, axillary abobotulinumtoxinA injections were attempted but failed. She had been prednisone dependent for more than 1 year. Due to the ongoing refractory disease, she was referred to radiation oncology to discuss radiotherapy treatment options.

At the time of presentation to the radiation oncology clinic, she continued to have extensive involvement of the intertriginous areas as well as involvement of the right neck at sites of skin chafing from clothing. Consistent with the limited available evidence, a dose of 20 Gy in 10 fractions was first prescribed to the axillae to assess response in the event of radiosensitivity, resulting in brisk desquamation. The conventional fractionation of 2 Gy per fraction allowed for assessment of response/tolerance and the opportunity to stop the treatment in the unlikely event of a severe skin reaction. Her skin tolerated treatment well with slight dryness and mild irritation that was less severe than the typical HHD flares. Concurrently with the axillary radiotherapy, we delivered a trial of low-level laser therapy to areas of severe disease in both inguinal regions in the hope that it could be used instead of radiotherapy to avoid any associated risks of radiation. Low-level laser therapy was administered with a light-emitting diode cluster probe at 2.5 Hz for 1 minute to 2 sites in each inguinal area daily for a total of 10 treatments. Unfortunately, this therapy temporarily exacerbated exudation present in the skin before it resolved to its pretreatment state with no improvement.

One month after treatment she had total resolution of the erosive patches and plaques with mild residual hyperpigmentation in the axillae, establishing that radiation therapy was reasonably effective. To lower the total radiation dose and decrease the risk of radiation-induced malignancy, we treated the bilateral groin and the inframammary region with a treatment schedule of 8 Gy in 2 fractions at a higher dose of 4 Gy per fraction instead of 2 Gy. At 12 days posttreatment, she had a dramatic response in the groin and a mixed response in the inframammary region, with a focus that had not yet regressed. Given the dramatic response in the treated sites, the patient requested treatment to the right side of the neck. Thus, we treated this area with a similar 8 Gy in 2 fractions, and an additional 6 Gy in 2 fractions boost was added to the slow responding focus in the inframammary fold for a total of 14 Gy in 4 fractions. The patient tolerated all treatments well with mild grade 1 skin irritation that was unlike the blistering of the typical HHD flares. Two months following completion of the first course of radiotherapy to the axillae and 2 weeks from the most recent course, she tapered off her prednisone regimen (15 mg every other day) but had a relapse of disease with her subsequent menstrual cycles that presented as a blistering skin reaction in the inframammary region, which healed in response to restarting steroids. This flare was less severe than those prior to radiotherapy. At 10 months posttreatment, the patient was free of disease in the neck and axillae (Figure 2). She continued to have relapses in the inframammary region with menstrual cycles and noted new disease in the popliteal regions; however, the relapses were less severe, and her skin had improved more with radiation than any of the prior therapies.

Our experience with low-level laser therapy indicated that it should be completely avoided in HHD. Our patient’s treatment with radiotherapy demonstrated excellent short-term responses in areas of pemphigus but later proved to be a mixed response with further follow-up including a mild posttreatment flare of the inframammary region that responded to steroids and new popliteal region involvement. As summarized in the Table, earlier reports of radiotherapy for the treatment of HHD have yielded varied results.^6-8 The mixed response seen in our patient suggests that response to radiotherapy may be site specific, related to underlying inflammation from microbial overgrowth, or a function of the disease severity.

Although the number of reports on radiotherapy in HHD is small, there have been several reports of Darier disease, another acantholytic autosomal-dominant genodermatosis affecting the ATP2A2 gene, successfully treated incidentally with radiation.^9,10 Total skin electron beam therapy also has been employed in the treatment of Darier disease; this patient experienced a severe flare after a relatively low treatment dose that required intensive care monitoring, possibly highlighting the potential radiosensitivity of patients with underlying genodermatoses and cautioning against radiotherapy dose escalation.¹¹ In light of the mixed responses seen, radiation therapy should be used sparingly for severe relapsing cases that have failed a plethora of prior treatments. The risk of second cancer induction is especially of concern when using radiotherapy in a benign disease.¹² We observed excellent initial responses in our patient, both with conventionally fractionated radiotherapy and hypofractionation. The risk of second malignancy induction is a linear function of radiotherapy dose.¹² Thus, utilization of hypofractionated regimens such as 4 Gy times 2 fractions seems most prudent. It remains unclear if further dose de-escalation may yield a similar response, as seen in studies utilizing radiotherapy for other benign disease.^13,14 Overall, given our mixed results with short follow-up, we conclude that the consideration of radiotherapy should be limited to patients with severe recalcitrant HHD.

To the Editor:

Hailey-Hailey disease (HHD), or familial benign chronic pemphigus, is a genetic disorder caused by an autosomal-dominant mutation in ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1, which disrupts intracellular calcium signaling and blocks synthesis of junctional proteins required for cell-cell adhesion.^1,2 As a result, patients develop acantholysis of the suprabasilar epidermis resulting in chronic flaccid blisters and erosions, particularly in intertriginous areas.³ Patients often report associated itching, pain, and burning, and they frequently present with secondary polymicrobial infections.⁴ Although HHD is genetic, patients may present without a family history due to variable expressivity and sporadic germline mutations.⁵ Therapeutic options are numerous, and patients may attempt many treatments before a benefit is observed.⁴ Local disease improvement was noted in a case series of 3 patients treated with electron beam radiotherapy with no disease recurrence in treated sites at 38, 33, and 9 months’ follow-up.⁶ Herein, we present a case of HHD refractory to numerous prior therapies that was successfully treated with electron beam radiotherapy, highlighting the potential role for palliative radiotherapy in select refractory cases of HHD.

A 35-year-old woman with a 7-year of history of HHD presented with severe recalcitrant disease including extensive erosive patches and plaques in the intertriginous areas of the bilateral axillae, groin, and inframammary folds (Figure 1). The skin eruptions first appeared at 28 years of age after her last pregnancy and continued as painful blistering that worsened with each menstrual cycle. Initially the affected desquamated skin would heal between menstrual cycles, but large areas of desquamation remained unhealed in the groin and inframammary regions throughout her full menstrual cycles by the time of referral. Family history included 4 family members with HHD: 2 aunts, an uncle, and a cousin on the paternal side of her family. Over a 7-year period, treatment with clobetasol cream, clindamycin gel, tacrolimus ointment, doxycycline, dapsone, cyclosporine, methotrexate, etanercept, isotretinoin, and prednisone (15 mg every other day) all failed. Most recently, axillary abobotulinumtoxinA injections were attempted but failed. She had been prednisone dependent for more than 1 year. Due to the ongoing refractory disease, she was referred to radiation oncology to discuss radiotherapy treatment options.

At the time of presentation to the radiation oncology clinic, she continued to have extensive involvement of the intertriginous areas as well as involvement of the right neck at sites of skin chafing from clothing. Consistent with the limited available evidence, a dose of 20 Gy in 10 fractions was first prescribed to the axillae to assess response in the event of radiosensitivity, resulting in brisk desquamation. The conventional fractionation of 2 Gy per fraction allowed for assessment of response/tolerance and the opportunity to stop the treatment in the unlikely event of a severe skin reaction. Her skin tolerated treatment well with slight dryness and mild irritation that was less severe than the typical HHD flares. Concurrently with the axillary radiotherapy, we delivered a trial of low-level laser therapy to areas of severe disease in both inguinal regions in the hope that it could be used instead of radiotherapy to avoid any associated risks of radiation. Low-level laser therapy was administered with a light-emitting diode cluster probe at 2.5 Hz for 1 minute to 2 sites in each inguinal area daily for a total of 10 treatments. Unfortunately, this therapy temporarily exacerbated exudation present in the skin before it resolved to its pretreatment state with no improvement.

One month after treatment she had total resolution of the erosive patches and plaques with mild residual hyperpigmentation in the axillae, establishing that radiation therapy was reasonably effective. To lower the total radiation dose and decrease the risk of radiation-induced malignancy, we treated the bilateral groin and the inframammary region with a treatment schedule of 8 Gy in 2 fractions at a higher dose of 4 Gy per fraction instead of 2 Gy. At 12 days posttreatment, she had a dramatic response in the groin and a mixed response in the inframammary region, with a focus that had not yet regressed. Given the dramatic response in the treated sites, the patient requested treatment to the right side of the neck. Thus, we treated this area with a similar 8 Gy in 2 fractions, and an additional 6 Gy in 2 fractions boost was added to the slow responding focus in the inframammary fold for a total of 14 Gy in 4 fractions. The patient tolerated all treatments well with mild grade 1 skin irritation that was unlike the blistering of the typical HHD flares. Two months following completion of the first course of radiotherapy to the axillae and 2 weeks from the most recent course, she tapered off her prednisone regimen (15 mg every other day) but had a relapse of disease with her subsequent menstrual cycles that presented as a blistering skin reaction in the inframammary region, which healed in response to restarting steroids. This flare was less severe than those prior to radiotherapy. At 10 months posttreatment, the patient was free of disease in the neck and axillae (Figure 2). She continued to have relapses in the inframammary region with menstrual cycles and noted new disease in the popliteal regions; however, the relapses were less severe, and her skin had improved more with radiation than any of the prior therapies.

Our experience with low-level laser therapy indicated that it should be completely avoided in HHD. Our patient’s treatment with radiotherapy demonstrated excellent short-term responses in areas of pemphigus but later proved to be a mixed response with further follow-up including a mild posttreatment flare of the inframammary region that responded to steroids and new popliteal region involvement. As summarized in the Table, earlier reports of radiotherapy for the treatment of HHD have yielded varied results.^6-8 The mixed response seen in our patient suggests that response to radiotherapy may be site specific, related to underlying inflammation from microbial overgrowth, or a function of the disease severity.

Although the number of reports on radiotherapy in HHD is small, there have been several reports of Darier disease, another acantholytic autosomal-dominant genodermatosis affecting the ATP2A2 gene, successfully treated incidentally with radiation.^9,10 Total skin electron beam therapy also has been employed in the treatment of Darier disease; this patient experienced a severe flare after a relatively low treatment dose that required intensive care monitoring, possibly highlighting the potential radiosensitivity of patients with underlying genodermatoses and cautioning against radiotherapy dose escalation.¹¹ In light of the mixed responses seen, radiation therapy should be used sparingly for severe relapsing cases that have failed a plethora of prior treatments. The risk of second cancer induction is especially of concern when using radiotherapy in a benign disease.¹² We observed excellent initial responses in our patient, both with conventionally fractionated radiotherapy and hypofractionation. The risk of second malignancy induction is a linear function of radiotherapy dose.¹² Thus, utilization of hypofractionated regimens such as 4 Gy times 2 fractions seems most prudent. It remains unclear if further dose de-escalation may yield a similar response, as seen in studies utilizing radiotherapy for other benign disease.^13,14 Overall, given our mixed results with short follow-up, we conclude that the consideration of radiotherapy should be limited to patients with severe recalcitrant HHD.

To the Editor:

Pembrolizumab, a humanized monoclonal anti–programmed cell death protein 1 (PD-1) antibody, acts by blocking negative immune regulators such as PD-1.¹ Since its approval by the US Food and Drug Administration in 2014, the use of PD-1 inhibitors such as pembrolizumab has dramatically increased, and they are now the standard of care for cancers such as melanoma, lung cancer, and renal cell carcinoma.^2,3 With increased use comes a better understanding of the cutaneous adverse effects that may occur. To date, almost 50% of patients treated with PD-1 inhibitors will develop an adverse cutaneous reaction.⁴ Thus far, cases of patients developing vitiligo, bullous pemphigoid, psoriasis, granulomatous skin reactions, severe cutaneous reactions (ie, toxic epidermal necrolysis), lupus erythematosus, and lichenoid reactions have been described.^3,5,6 There are fewer than 30 documented cases of lichenoid reactions due to anti–PD-1 treatment described in the literature, increasing the importance of case reports to demonstrate a full range of cutaneous findings.³ We present a case of a reaction to pembrolizumab with an eruption of lichenoid papules predominantly involving the hands and feet as well as nail changes.

A 60-year-old man with ocular melanoma metastatic to the right lung, transverse colon, and right axillary lymph nodes presented with a chief concern of growing skin lesions present for 6 weeks on the hands and feet. The lesions were tender to the touch and occasionally drained a clear fluid. He also reported nail fragility. Of note, the patient was being treated for metastatic melanoma with pembrolizumab infusions every 3 weeks, which started 6 weeks prior to the onset of the eruption. 

Physical examination demonstrated lichenoid papules on the dorsal and ventral aspects of the hands and feet (Figure 1), as well as longitudinal ridging on numerous fingernails and mild koilonychia. A punch biopsy revealed lichenoid interface dermatitis with irregular epidermal hyperplasia (Figure 2). A diagnosis of hypertrophic lichen planus–like drug eruption in response to pembrolizumab was made and clobetasol cream was prescribed.

 

At 1-month follow-up, the patient reported notable improvement with clobetasol, and he was transitioned to tacrolimus ointment 0.1%. He continued to improve until a month later when he reported new lesions arising a week after a pembrolizumab infusion. He continued to use clobetasol cream for flares and tacrolimus ointment for maintenance.

Almost 3 months after the initial visit, the patient presented with inflammation around his right third fingernail of 1 week’s duration, with more notable fragility than his other nails. No trauma was described, and the nail abnormality was attributed to pembrolizumab. Clobetasol cream and biotin 3 mg daily resulted in improvement, and no other nails were affected in a similar way.

Programmed cell death protein 1 blockers are associated with a variety of adverse events including hypothyroidism, gastrointestinal abnormalities, fatigue, and skin disorders.⁷ In one study (N=83), cutaneous adverse drug events were found to occur in 42% (35/83) of patients following pembrolizumab therapy, with the most common cutaneous lesions being maculopapular eruptions (29% [24/83]), pruritus (12% [10/83]), and hypopigmentation (8% [7/83]).⁵

A total of 29 cases of lichenoid dermatitis following anti–PD-1 therapy have been described in the literature.³ Cases range from an eruption of photodistributed hyperkeratotic papules and plaques to hypertrophic vesiculobullous lesions.^3,6 Suggested pathophysiology involves blocking the interaction of programmed death ligand 1 on keratinocytes with PD-1 on T cells.³ Management typically includes topical or systemic steroids. Cyclosporine and acitretin also have been successful in a small number of patients. Most patients continue anti–PD-1 treatment with systemic therapy.³

Our patient represents a similar lichenoid eruption; however, the distribution on the dorsal and ventral aspects of the hands and feet as well as nail dystrophy make the presentation unique. Anticancer drugs that increase the T-cell immune response by altering the complex signaling among T cells, antigen-presenting cells, and tumor cells have been associated with cutaneous eruptions. Although the exact mechanism is still not fully understood, clinical suspicion of a pembrolizumab reaction should remain high on the differential in the setting of hyperkeratotic papules in association with anti–PD-1 therapy.

To the Editor:

Pembrolizumab, a humanized monoclonal anti–programmed cell death protein 1 (PD-1) antibody, acts by blocking negative immune regulators such as PD-1.¹ Since its approval by the US Food and Drug Administration in 2014, the use of PD-1 inhibitors such as pembrolizumab has dramatically increased, and they are now the standard of care for cancers such as melanoma, lung cancer, and renal cell carcinoma.^2,3 With increased use comes a better understanding of the cutaneous adverse effects that may occur. To date, almost 50% of patients treated with PD-1 inhibitors will develop an adverse cutaneous reaction.⁴ Thus far, cases of patients developing vitiligo, bullous pemphigoid, psoriasis, granulomatous skin reactions, severe cutaneous reactions (ie, toxic epidermal necrolysis), lupus erythematosus, and lichenoid reactions have been described.^3,5,6 There are fewer than 30 documented cases of lichenoid reactions due to anti–PD-1 treatment described in the literature, increasing the importance of case reports to demonstrate a full range of cutaneous findings.³ We present a case of a reaction to pembrolizumab with an eruption of lichenoid papules predominantly involving the hands and feet as well as nail changes.

A 60-year-old man with ocular melanoma metastatic to the right lung, transverse colon, and right axillary lymph nodes presented with a chief concern of growing skin lesions present for 6 weeks on the hands and feet. The lesions were tender to the touch and occasionally drained a clear fluid. He also reported nail fragility. Of note, the patient was being treated for metastatic melanoma with pembrolizumab infusions every 3 weeks, which started 6 weeks prior to the onset of the eruption. 

Physical examination demonstrated lichenoid papules on the dorsal and ventral aspects of the hands and feet (Figure 1), as well as longitudinal ridging on numerous fingernails and mild koilonychia. A punch biopsy revealed lichenoid interface dermatitis with irregular epidermal hyperplasia (Figure 2). A diagnosis of hypertrophic lichen planus–like drug eruption in response to pembrolizumab was made and clobetasol cream was prescribed.

 

At 1-month follow-up, the patient reported notable improvement with clobetasol, and he was transitioned to tacrolimus ointment 0.1%. He continued to improve until a month later when he reported new lesions arising a week after a pembrolizumab infusion. He continued to use clobetasol cream for flares and tacrolimus ointment for maintenance.

Almost 3 months after the initial visit, the patient presented with inflammation around his right third fingernail of 1 week’s duration, with more notable fragility than his other nails. No trauma was described, and the nail abnormality was attributed to pembrolizumab. Clobetasol cream and biotin 3 mg daily resulted in improvement, and no other nails were affected in a similar way.

Programmed cell death protein 1 blockers are associated with a variety of adverse events including hypothyroidism, gastrointestinal abnormalities, fatigue, and skin disorders.⁷ In one study (N=83), cutaneous adverse drug events were found to occur in 42% (35/83) of patients following pembrolizumab therapy, with the most common cutaneous lesions being maculopapular eruptions (29% [24/83]), pruritus (12% [10/83]), and hypopigmentation (8% [7/83]).⁵

A total of 29 cases of lichenoid dermatitis following anti–PD-1 therapy have been described in the literature.³ Cases range from an eruption of photodistributed hyperkeratotic papules and plaques to hypertrophic vesiculobullous lesions.^3,6 Suggested pathophysiology involves blocking the interaction of programmed death ligand 1 on keratinocytes with PD-1 on T cells.³ Management typically includes topical or systemic steroids. Cyclosporine and acitretin also have been successful in a small number of patients. Most patients continue anti–PD-1 treatment with systemic therapy.³

Our patient represents a similar lichenoid eruption; however, the distribution on the dorsal and ventral aspects of the hands and feet as well as nail dystrophy make the presentation unique. Anticancer drugs that increase the T-cell immune response by altering the complex signaling among T cells, antigen-presenting cells, and tumor cells have been associated with cutaneous eruptions. Although the exact mechanism is still not fully understood, clinical suspicion of a pembrolizumab reaction should remain high on the differential in the setting of hyperkeratotic papules in association with anti–PD-1 therapy.

To the Editor:

Pembrolizumab, a humanized monoclonal anti–programmed cell death protein 1 (PD-1) antibody, acts by blocking negative immune regulators such as PD-1.¹ Since its approval by the US Food and Drug Administration in 2014, the use of PD-1 inhibitors such as pembrolizumab has dramatically increased, and they are now the standard of care for cancers such as melanoma, lung cancer, and renal cell carcinoma.^2,3 With increased use comes a better understanding of the cutaneous adverse effects that may occur. To date, almost 50% of patients treated with PD-1 inhibitors will develop an adverse cutaneous reaction.⁴ Thus far, cases of patients developing vitiligo, bullous pemphigoid, psoriasis, granulomatous skin reactions, severe cutaneous reactions (ie, toxic epidermal necrolysis), lupus erythematosus, and lichenoid reactions have been described.^3,5,6 There are fewer than 30 documented cases of lichenoid reactions due to anti–PD-1 treatment described in the literature, increasing the importance of case reports to demonstrate a full range of cutaneous findings.³ We present a case of a reaction to pembrolizumab with an eruption of lichenoid papules predominantly involving the hands and feet as well as nail changes.

A 60-year-old man with ocular melanoma metastatic to the right lung, transverse colon, and right axillary lymph nodes presented with a chief concern of growing skin lesions present for 6 weeks on the hands and feet. The lesions were tender to the touch and occasionally drained a clear fluid. He also reported nail fragility. Of note, the patient was being treated for metastatic melanoma with pembrolizumab infusions every 3 weeks, which started 6 weeks prior to the onset of the eruption. 

Physical examination demonstrated lichenoid papules on the dorsal and ventral aspects of the hands and feet (Figure 1), as well as longitudinal ridging on numerous fingernails and mild koilonychia. A punch biopsy revealed lichenoid interface dermatitis with irregular epidermal hyperplasia (Figure 2). A diagnosis of hypertrophic lichen planus–like drug eruption in response to pembrolizumab was made and clobetasol cream was prescribed.

 

At 1-month follow-up, the patient reported notable improvement with clobetasol, and he was transitioned to tacrolimus ointment 0.1%. He continued to improve until a month later when he reported new lesions arising a week after a pembrolizumab infusion. He continued to use clobetasol cream for flares and tacrolimus ointment for maintenance.

Almost 3 months after the initial visit, the patient presented with inflammation around his right third fingernail of 1 week’s duration, with more notable fragility than his other nails. No trauma was described, and the nail abnormality was attributed to pembrolizumab. Clobetasol cream and biotin 3 mg daily resulted in improvement, and no other nails were affected in a similar way.

Programmed cell death protein 1 blockers are associated with a variety of adverse events including hypothyroidism, gastrointestinal abnormalities, fatigue, and skin disorders.⁷ In one study (N=83), cutaneous adverse drug events were found to occur in 42% (35/83) of patients following pembrolizumab therapy, with the most common cutaneous lesions being maculopapular eruptions (29% [24/83]), pruritus (12% [10/83]), and hypopigmentation (8% [7/83]).⁵

A total of 29 cases of lichenoid dermatitis following anti–PD-1 therapy have been described in the literature.³ Cases range from an eruption of photodistributed hyperkeratotic papules and plaques to hypertrophic vesiculobullous lesions.^3,6 Suggested pathophysiology involves blocking the interaction of programmed death ligand 1 on keratinocytes with PD-1 on T cells.³ Management typically includes topical or systemic steroids. Cyclosporine and acitretin also have been successful in a small number of patients. Most patients continue anti–PD-1 treatment with systemic therapy.³

Our patient represents a similar lichenoid eruption; however, the distribution on the dorsal and ventral aspects of the hands and feet as well as nail dystrophy make the presentation unique. Anticancer drugs that increase the T-cell immune response by altering the complex signaling among T cells, antigen-presenting cells, and tumor cells have been associated with cutaneous eruptions. Although the exact mechanism is still not fully understood, clinical suspicion of a pembrolizumab reaction should remain high on the differential in the setting of hyperkeratotic papules in association with anti–PD-1 therapy.