Wounds

Cardiac implantable electronic devices (CIEDs) – cardiac pacemakers and implantable cardioverter defibrillators –are an established treatment for the management of cardiac dysrhythmias in millions of patients. Complications occur in up to 15%, some of which may present first to the dermatologist.

The differential diagnosis of dermatoses overlying pacemakers includes infection, irritant or allergic contact dermatitis, reticular telangiectatic erythema (caused by local venous obstruction and pressure dermatitis), and impending skin erosion/device extrusion.

Erosion and extrusion is a major complication with significant morbidity and mortality. The two main causes are pressure necrosis and infection. Pressure necrosis is influenced by the size of the device, complexity of the connections, and technical skill with which the pacemaker chest wall pocket is created.

After extrusion, the pacemaker should be considered contaminated and removed, and the necrotic tissue debrided. If infected, a prolonged course of appropriate antibiotic therapy is indicated. A bacterial culture in the patient presented here was negative.

Pocket infection of CIEDs is rare and may manifest as erythema, tenderness, drainage, erosion, or pruritus above the site of the pacemaker, along with systemic symptoms and signs, including fever, chills, or malaise. Some may have just the systemic symptoms. Fewer than half of patients with CIED infection present within 1 year of their last procedure.

Ruptured epidermal cysts usually manifest as acute swelling, inflammation, and tenderness of previously long-standing asymptomatic epidermal cysts. There may be drainage of malodorous keratinous and purulent debris. They are typically not infected. Treatment includes incision and drainage for fluctuant lesions or intralesional corticosteroid injection for early, nonfluctuant cases.

Allergic contact dermatitis to metal may be seen with implantable devices. Patch testing to various metal allergens can be helpful in determining if any allergy is present.

This case and photo were submitted by Michael Stierstorfer, MD, East Penn Dermatology, North Wales, Pa.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

Cardiac implantable electronic devices (CIEDs) – cardiac pacemakers and implantable cardioverter defibrillators –are an established treatment for the management of cardiac dysrhythmias in millions of patients. Complications occur in up to 15%, some of which may present first to the dermatologist.

The differential diagnosis of dermatoses overlying pacemakers includes infection, irritant or allergic contact dermatitis, reticular telangiectatic erythema (caused by local venous obstruction and pressure dermatitis), and impending skin erosion/device extrusion.

Erosion and extrusion is a major complication with significant morbidity and mortality. The two main causes are pressure necrosis and infection. Pressure necrosis is influenced by the size of the device, complexity of the connections, and technical skill with which the pacemaker chest wall pocket is created.

After extrusion, the pacemaker should be considered contaminated and removed, and the necrotic tissue debrided. If infected, a prolonged course of appropriate antibiotic therapy is indicated. A bacterial culture in the patient presented here was negative.

Pocket infection of CIEDs is rare and may manifest as erythema, tenderness, drainage, erosion, or pruritus above the site of the pacemaker, along with systemic symptoms and signs, including fever, chills, or malaise. Some may have just the systemic symptoms. Fewer than half of patients with CIED infection present within 1 year of their last procedure.

Ruptured epidermal cysts usually manifest as acute swelling, inflammation, and tenderness of previously long-standing asymptomatic epidermal cysts. There may be drainage of malodorous keratinous and purulent debris. They are typically not infected. Treatment includes incision and drainage for fluctuant lesions or intralesional corticosteroid injection for early, nonfluctuant cases.

Allergic contact dermatitis to metal may be seen with implantable devices. Patch testing to various metal allergens can be helpful in determining if any allergy is present.

This case and photo were submitted by Michael Stierstorfer, MD, East Penn Dermatology, North Wales, Pa.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

Cardiac implantable electronic devices (CIEDs) – cardiac pacemakers and implantable cardioverter defibrillators –are an established treatment for the management of cardiac dysrhythmias in millions of patients. Complications occur in up to 15%, some of which may present first to the dermatologist.

The differential diagnosis of dermatoses overlying pacemakers includes infection, irritant or allergic contact dermatitis, reticular telangiectatic erythema (caused by local venous obstruction and pressure dermatitis), and impending skin erosion/device extrusion.

Erosion and extrusion is a major complication with significant morbidity and mortality. The two main causes are pressure necrosis and infection. Pressure necrosis is influenced by the size of the device, complexity of the connections, and technical skill with which the pacemaker chest wall pocket is created.

After extrusion, the pacemaker should be considered contaminated and removed, and the necrotic tissue debrided. If infected, a prolonged course of appropriate antibiotic therapy is indicated. A bacterial culture in the patient presented here was negative.

Pocket infection of CIEDs is rare and may manifest as erythema, tenderness, drainage, erosion, or pruritus above the site of the pacemaker, along with systemic symptoms and signs, including fever, chills, or malaise. Some may have just the systemic symptoms. Fewer than half of patients with CIED infection present within 1 year of their last procedure.

Ruptured epidermal cysts usually manifest as acute swelling, inflammation, and tenderness of previously long-standing asymptomatic epidermal cysts. There may be drainage of malodorous keratinous and purulent debris. They are typically not infected. Treatment includes incision and drainage for fluctuant lesions or intralesional corticosteroid injection for early, nonfluctuant cases.

Allergic contact dermatitis to metal may be seen with implantable devices. Patch testing to various metal allergens can be helpful in determining if any allergy is present.

This case and photo were submitted by Michael Stierstorfer, MD, East Penn Dermatology, North Wales, Pa.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

Danish researchers have linked multiple factors to higher risk of first-time diabetic foot ulcers (DFUs) in patients with type 1 and type 2 diabetes, although some of the factors – older age, smoking, history of cardiovascular disease, and longer duration of diabetes – seem to indicate increased risk only in type 1 disease, according to the new study findings.

The authors suggest that since clinical information gathered from patients during routine follow-up visits often includes mention of the risk factors for first-time DFU, it could form the basis of a risk stratification process for first-time DFU that can be integrated into the electronic record system and easily incorporated into routine care.

DFU is a significant complication for both type 1 and type 2 diabetes, but no previous research has stratified the risk factors for first-time DFUs by type of diabetes, emphasized the study authors, led by Sine Hangaard, MSc, of Steno Diabetes Center Copenhagen.

For the new study, the researchers tracked 5,588 patients with type 1 diabetes and 7,113 with type 2, all of whom were treated at a hospital clinic in Denmark between 2001 and 2015. The authors noted that the patients with type 2 disease who were treated at the center were clinically more complicated and had a longer disease duration than average type 2 patients, whereas the patients with type 1 diabetes did not differ from average type 1 patients.

Several factors boosted the risk of first-time DFU in both types of disease, including high or low levels of albumin excretion, advanced diabetic retinopathy, limited or nonexistent vibration sense, symptoms of neuropathy, and absence of foot pulses per univariable regression (all P less than .01). The researchers linked the neuropathy and absences of foot pulses to especially high spikes in risk.

Female gender was protective for type 1 and type 2 disease (hazard ratios, 0.7 and 0.5, respectively; P = .0000). Various body mass index levels seemed to have no impact on risk.

Three factors that posed a higher risk for first-time DFU in type 1 disease, but not type 2, were: smoking (HR, 1.4 vs. no smoking, P = .0220), age of 60-79 years (HR, 1.7 vs. age 40-59; P = .0000), cardiovascular disease (HR, 2.2 vs. no cardiovascular disease; P = .0000), and diabetes duration of between 5 and 20 years (HR, 2.2 vs. less than 5 years; P = .0027) or 20 years or more (HR, 5.2 vs. less than 5 years; P = .0000).

The authors noted that “25% of all patients with diabetes develop DFU during their lifetime, and DFUs precede 80% of all lower leg amputations in patients with diabetes.” In addition, DFU often occurs in feet already compromised by neuropathy or peripheral vascular disease, and is therefore associated with greater risk for infection, poorer outcomes, recurrent ulceration, amputation, and increased mortality. These risks underscore the need for the earliest-possible identification of first-time DFU and timely adoption of effective, preventative strategies, they wrote.

The study was not funded. Several of the authors reported that they own shares in Novo Nordisk.

SOURCE: Hangaard S et al. Diabetes Res Clin Pract. 2019 Apr 18;151:177-86.

Danish researchers have linked multiple factors to higher risk of first-time diabetic foot ulcers (DFUs) in patients with type 1 and type 2 diabetes, although some of the factors – older age, smoking, history of cardiovascular disease, and longer duration of diabetes – seem to indicate increased risk only in type 1 disease, according to the new study findings.

The authors suggest that since clinical information gathered from patients during routine follow-up visits often includes mention of the risk factors for first-time DFU, it could form the basis of a risk stratification process for first-time DFU that can be integrated into the electronic record system and easily incorporated into routine care.

DFU is a significant complication for both type 1 and type 2 diabetes, but no previous research has stratified the risk factors for first-time DFUs by type of diabetes, emphasized the study authors, led by Sine Hangaard, MSc, of Steno Diabetes Center Copenhagen.

For the new study, the researchers tracked 5,588 patients with type 1 diabetes and 7,113 with type 2, all of whom were treated at a hospital clinic in Denmark between 2001 and 2015. The authors noted that the patients with type 2 disease who were treated at the center were clinically more complicated and had a longer disease duration than average type 2 patients, whereas the patients with type 1 diabetes did not differ from average type 1 patients.

Several factors boosted the risk of first-time DFU in both types of disease, including high or low levels of albumin excretion, advanced diabetic retinopathy, limited or nonexistent vibration sense, symptoms of neuropathy, and absence of foot pulses per univariable regression (all P less than .01). The researchers linked the neuropathy and absences of foot pulses to especially high spikes in risk.

Female gender was protective for type 1 and type 2 disease (hazard ratios, 0.7 and 0.5, respectively; P = .0000). Various body mass index levels seemed to have no impact on risk.

Three factors that posed a higher risk for first-time DFU in type 1 disease, but not type 2, were: smoking (HR, 1.4 vs. no smoking, P = .0220), age of 60-79 years (HR, 1.7 vs. age 40-59; P = .0000), cardiovascular disease (HR, 2.2 vs. no cardiovascular disease; P = .0000), and diabetes duration of between 5 and 20 years (HR, 2.2 vs. less than 5 years; P = .0027) or 20 years or more (HR, 5.2 vs. less than 5 years; P = .0000).

The authors noted that “25% of all patients with diabetes develop DFU during their lifetime, and DFUs precede 80% of all lower leg amputations in patients with diabetes.” In addition, DFU often occurs in feet already compromised by neuropathy or peripheral vascular disease, and is therefore associated with greater risk for infection, poorer outcomes, recurrent ulceration, amputation, and increased mortality. These risks underscore the need for the earliest-possible identification of first-time DFU and timely adoption of effective, preventative strategies, they wrote.

The study was not funded. Several of the authors reported that they own shares in Novo Nordisk.

SOURCE: Hangaard S et al. Diabetes Res Clin Pract. 2019 Apr 18;151:177-86.

Danish researchers have linked multiple factors to higher risk of first-time diabetic foot ulcers (DFUs) in patients with type 1 and type 2 diabetes, although some of the factors – older age, smoking, history of cardiovascular disease, and longer duration of diabetes – seem to indicate increased risk only in type 1 disease, according to the new study findings.

The authors suggest that since clinical information gathered from patients during routine follow-up visits often includes mention of the risk factors for first-time DFU, it could form the basis of a risk stratification process for first-time DFU that can be integrated into the electronic record system and easily incorporated into routine care.

DFU is a significant complication for both type 1 and type 2 diabetes, but no previous research has stratified the risk factors for first-time DFUs by type of diabetes, emphasized the study authors, led by Sine Hangaard, MSc, of Steno Diabetes Center Copenhagen.

For the new study, the researchers tracked 5,588 patients with type 1 diabetes and 7,113 with type 2, all of whom were treated at a hospital clinic in Denmark between 2001 and 2015. The authors noted that the patients with type 2 disease who were treated at the center were clinically more complicated and had a longer disease duration than average type 2 patients, whereas the patients with type 1 diabetes did not differ from average type 1 patients.

Several factors boosted the risk of first-time DFU in both types of disease, including high or low levels of albumin excretion, advanced diabetic retinopathy, limited or nonexistent vibration sense, symptoms of neuropathy, and absence of foot pulses per univariable regression (all P less than .01). The researchers linked the neuropathy and absences of foot pulses to especially high spikes in risk.

Female gender was protective for type 1 and type 2 disease (hazard ratios, 0.7 and 0.5, respectively; P = .0000). Various body mass index levels seemed to have no impact on risk.

Three factors that posed a higher risk for first-time DFU in type 1 disease, but not type 2, were: smoking (HR, 1.4 vs. no smoking, P = .0220), age of 60-79 years (HR, 1.7 vs. age 40-59; P = .0000), cardiovascular disease (HR, 2.2 vs. no cardiovascular disease; P = .0000), and diabetes duration of between 5 and 20 years (HR, 2.2 vs. less than 5 years; P = .0027) or 20 years or more (HR, 5.2 vs. less than 5 years; P = .0000).

The authors noted that “25% of all patients with diabetes develop DFU during their lifetime, and DFUs precede 80% of all lower leg amputations in patients with diabetes.” In addition, DFU often occurs in feet already compromised by neuropathy or peripheral vascular disease, and is therefore associated with greater risk for infection, poorer outcomes, recurrent ulceration, amputation, and increased mortality. These risks underscore the need for the earliest-possible identification of first-time DFU and timely adoption of effective, preventative strategies, they wrote.

The study was not funded. Several of the authors reported that they own shares in Novo Nordisk.

SOURCE: Hangaard S et al. Diabetes Res Clin Pract. 2019 Apr 18;151:177-86.

To the Editor:

A 25-year-old woman with no notable medical history was admitted to the hospital for suspected Stevens-Johnson syndrome (SJS). The patient was started on amoxicillin 7 days prior to the skin eruption for prophylaxis before removal of an intrauterine device. On the day of admission, she reported ocular discomfort, dysphagia, and dysuria. She developed erythema of the conjunctivae, face, chest, and proximal upper extremities, as well as erosions of the vermilion lips. She presented to the local emergency department and was transferred to our institution for urgent dermatologic consultation. On physical examination by the dermatology service, the patient had erythematous macules coalescing into patches with overlying flaccid bullae, some denuded, involving the face, chest, abdomen, back (Figure 1), bilateral upper extremities, bilateral thighs, and labia majora and minora. Additionally, she had conjunctivitis, superficial erosions of the vermilion lips, and tense bullae of the palms and soles. On palpation of the flaccid bullae, the Asboe-Hansen sign was elicited (Figure 2 and video). A shave biopsy of the newly elicited bullae was performed. Pathology showed a subepidermal bulla with confluent necrosis of the epidermis and minimal inflammatory infiltrate. An additional shave biopsy of perilesional skin was obtained for direct immunofluorescence, which was negative for IgG, C3, IgM, and IgA. Based on the clinical presentation involving more than 30% of the patient’s body surface area (BSA) and the pathology findings, a diagnosis of toxic epidermal necrolysis (TEN) was made. The patient remained in the intensive care unit with a multidisciplinary team consisting of dermatology, ophthalmology, gynecology, gastroenterology, and the general surgery burn group. Following treatment with intravenous immunoglobulin, systemic corticosteroids, and aggressive wound care, the patient made a full recovery.

Vidyard Video

Toxic epidermal necrolysis is a rare, acute, life-threatening mucocutaneous disease within a spectrum of adverse cutaneous drug reactions. The estimated worldwide incidence of TEN is 0.4 to 1.9 per million individuals annually.¹ Toxic epidermal necrolysis is clinically characterized by diffuse exfoliation of the skin and mucosae with flaccid bullae. These clinical features are a consequence of extensive keratinocyte death, leading to dermoepidermal junction dissociation. Commonly, there is a prodrome of fever, pharyngitis, and painful skin preceding the diffuse erythema and sloughing of skin and mucous membranes. Lesions typically first appear on the trunk and then follow a centrifugal spread, often sparing the distal aspects of the arms and legs.

Toxic epidermal necrolysis is part of a continuous spectrum with SJS. Less than 10% BSA involvement is considered SJS, 10% to 30% BSA involvement is SJS/TEN overlap, and more than 30% BSA detachment is TEN. Stevens-Johnson syndrome can progress to TEN. In TEN, the distribution of cutaneous lesions is more confluent, and mucosal involvement is more severe.² The differential diagnosis may include staphylococcal scalded skin syndrome, drug-induced linear IgA bullous dermatosis, severe acute graft-vs-host disease, drug reaction with eosinophilia and systemic symptoms, and invasive fungal dermatitis. An accurate diagnosis of TEN is imperative, as the management and morbidity of these diseases are vastly different. Toxic epidermal necrolysis has an estimated mortality rate of 25% to 30%, with sepsis leading to multiorgan failure being the most common cause of death.³

Although the pathophysiology of TEN has yet to be fully elucidated, it is thought to be a T cell–mediated process with CD8⁺ cells acting as the primary means of keratinocyte death. An estimated 80% to 95% of cases are due to drug reactions.³ The medications that are most commonly associated with TEN include allopurinol, antibiotics, nonsteroidal anti-inflammatory drugs, and anticonvulsants. Symptoms typically begin 7 to 21 days after starting the drug. Less commonly, Mycoplasma pneumoniae, dengue virus, cytomegalovirus, and contrast medium have been reported as inciting factors for TEN.²

The diagnosis of TEN is established by correlating clinical features with a histopathologic examination obtained from a lesional skin biopsy. The classic cutaneous features of TEN begin as erythematous, flesh-colored, dusky to violaceous macules and/or morbilliform or targetoid lesions. These early lesions have the tendency to coalesce. The cutaneous findings will eventually progress into flaccid bullae, diffuse epidermal sloughing, and full-thickness skin necrosis.^2,3 The evolution of skin lesions may be rapid or may take several days to develop. On palpation, the Nikolsky (lateral shearing of epidermis with minimal pressure) and Asboe-Hansen sign will be positive in patients with SJS/TEN, demonstrating that the associated blisters are flaccid and may be displaced peripherally.⁴ For an accurate diagnosis, the biopsy must contain full-thickness epidermis. It is imperative to choose a biopsy site from an acute blister, as old lesions of other diseases, such as erythema multiforme, will eventually become necrotic and mimic the histopathologic appearance of SJS/TEN, potentially leading to an incorrect diagnosis.⁴ Full-thickness epidermal necrosis has a high sensitivity but low specificity for TEN.³ The histologic features of TEN vary depending on the stage of the disease. Classic histologic findings include satellite necrosis of keratinocytes followed by full-thickness necrosis of keratinocytes and perivascular lymphoid infiltrates. The stratum corneum retains its original structure.⁴

The Asboe-Hansen sign, also known as the bulla spread sign, was originally described in 1960 as a diagnostic sign for pemphigus vulgaris.⁵ A positive Asboe-Hansen sign demonstrates the ability to enlarge a bulla in the lateral direction by applying perpendicular mechanical pressure to the roof of an intact bulla. The bulla is extended to adjacent nonblistered skin.⁶ A positive sign demonstrates decreased adhesion between keratinocytes or between the basal epidermal cells and the dermal connective tissue.⁵ In addition to pemphigus vulgaris, the Asboe-Hansen sign may be positive in TEN and SJS, as well as other diseases affecting the dermoepidermal junction including pemphigus foliaceus, pemphigus vegetans, and bullous pemphigoid. Asboe-Hansen⁵ made the argument that a fresh bulla should be biopsied if histopathologic diagnosis is necessary, as older bullae may exhibit epithelial cell regeneration and disturb an accurate diagnosis.

Accurate and early diagnosis of TEN is imperative, as prognosis is strongly correlated with the speed at which the offending drug is discontinued and appropriate medical treatment is initiated. Prompt withdrawal of the offending drug has been reported to reduce the risk for morbidity by 30% per day.⁷ Although classically associated with the pemphigus group of diseases, the Asboe-Hansen sign is of diagnostic value to the pathologist in diagnosing TEN by reproducing the same microscopic appearance of a fresh spontaneous blister. Due to the notable morbidity and mortality in SJS and TEN, the Asboe-Hansen sign should be attempted for the site of a lesional biopsy, as an accurate diagnosis relies on clinicopathologic correlation.

To the Editor:

A 25-year-old woman with no notable medical history was admitted to the hospital for suspected Stevens-Johnson syndrome (SJS). The patient was started on amoxicillin 7 days prior to the skin eruption for prophylaxis before removal of an intrauterine device. On the day of admission, she reported ocular discomfort, dysphagia, and dysuria. She developed erythema of the conjunctivae, face, chest, and proximal upper extremities, as well as erosions of the vermilion lips. She presented to the local emergency department and was transferred to our institution for urgent dermatologic consultation. On physical examination by the dermatology service, the patient had erythematous macules coalescing into patches with overlying flaccid bullae, some denuded, involving the face, chest, abdomen, back (Figure 1), bilateral upper extremities, bilateral thighs, and labia majora and minora. Additionally, she had conjunctivitis, superficial erosions of the vermilion lips, and tense bullae of the palms and soles. On palpation of the flaccid bullae, the Asboe-Hansen sign was elicited (Figure 2 and video). A shave biopsy of the newly elicited bullae was performed. Pathology showed a subepidermal bulla with confluent necrosis of the epidermis and minimal inflammatory infiltrate. An additional shave biopsy of perilesional skin was obtained for direct immunofluorescence, which was negative for IgG, C3, IgM, and IgA. Based on the clinical presentation involving more than 30% of the patient’s body surface area (BSA) and the pathology findings, a diagnosis of toxic epidermal necrolysis (TEN) was made. The patient remained in the intensive care unit with a multidisciplinary team consisting of dermatology, ophthalmology, gynecology, gastroenterology, and the general surgery burn group. Following treatment with intravenous immunoglobulin, systemic corticosteroids, and aggressive wound care, the patient made a full recovery.

Vidyard Video

Toxic epidermal necrolysis is a rare, acute, life-threatening mucocutaneous disease within a spectrum of adverse cutaneous drug reactions. The estimated worldwide incidence of TEN is 0.4 to 1.9 per million individuals annually.¹ Toxic epidermal necrolysis is clinically characterized by diffuse exfoliation of the skin and mucosae with flaccid bullae. These clinical features are a consequence of extensive keratinocyte death, leading to dermoepidermal junction dissociation. Commonly, there is a prodrome of fever, pharyngitis, and painful skin preceding the diffuse erythema and sloughing of skin and mucous membranes. Lesions typically first appear on the trunk and then follow a centrifugal spread, often sparing the distal aspects of the arms and legs.

Toxic epidermal necrolysis is part of a continuous spectrum with SJS. Less than 10% BSA involvement is considered SJS, 10% to 30% BSA involvement is SJS/TEN overlap, and more than 30% BSA detachment is TEN. Stevens-Johnson syndrome can progress to TEN. In TEN, the distribution of cutaneous lesions is more confluent, and mucosal involvement is more severe.² The differential diagnosis may include staphylococcal scalded skin syndrome, drug-induced linear IgA bullous dermatosis, severe acute graft-vs-host disease, drug reaction with eosinophilia and systemic symptoms, and invasive fungal dermatitis. An accurate diagnosis of TEN is imperative, as the management and morbidity of these diseases are vastly different. Toxic epidermal necrolysis has an estimated mortality rate of 25% to 30%, with sepsis leading to multiorgan failure being the most common cause of death.³

Although the pathophysiology of TEN has yet to be fully elucidated, it is thought to be a T cell–mediated process with CD8⁺ cells acting as the primary means of keratinocyte death. An estimated 80% to 95% of cases are due to drug reactions.³ The medications that are most commonly associated with TEN include allopurinol, antibiotics, nonsteroidal anti-inflammatory drugs, and anticonvulsants. Symptoms typically begin 7 to 21 days after starting the drug. Less commonly, Mycoplasma pneumoniae, dengue virus, cytomegalovirus, and contrast medium have been reported as inciting factors for TEN.²

The diagnosis of TEN is established by correlating clinical features with a histopathologic examination obtained from a lesional skin biopsy. The classic cutaneous features of TEN begin as erythematous, flesh-colored, dusky to violaceous macules and/or morbilliform or targetoid lesions. These early lesions have the tendency to coalesce. The cutaneous findings will eventually progress into flaccid bullae, diffuse epidermal sloughing, and full-thickness skin necrosis.^2,3 The evolution of skin lesions may be rapid or may take several days to develop. On palpation, the Nikolsky (lateral shearing of epidermis with minimal pressure) and Asboe-Hansen sign will be positive in patients with SJS/TEN, demonstrating that the associated blisters are flaccid and may be displaced peripherally.⁴ For an accurate diagnosis, the biopsy must contain full-thickness epidermis. It is imperative to choose a biopsy site from an acute blister, as old lesions of other diseases, such as erythema multiforme, will eventually become necrotic and mimic the histopathologic appearance of SJS/TEN, potentially leading to an incorrect diagnosis.⁴ Full-thickness epidermal necrosis has a high sensitivity but low specificity for TEN.³ The histologic features of TEN vary depending on the stage of the disease. Classic histologic findings include satellite necrosis of keratinocytes followed by full-thickness necrosis of keratinocytes and perivascular lymphoid infiltrates. The stratum corneum retains its original structure.⁴

The Asboe-Hansen sign, also known as the bulla spread sign, was originally described in 1960 as a diagnostic sign for pemphigus vulgaris.⁵ A positive Asboe-Hansen sign demonstrates the ability to enlarge a bulla in the lateral direction by applying perpendicular mechanical pressure to the roof of an intact bulla. The bulla is extended to adjacent nonblistered skin.⁶ A positive sign demonstrates decreased adhesion between keratinocytes or between the basal epidermal cells and the dermal connective tissue.⁵ In addition to pemphigus vulgaris, the Asboe-Hansen sign may be positive in TEN and SJS, as well as other diseases affecting the dermoepidermal junction including pemphigus foliaceus, pemphigus vegetans, and bullous pemphigoid. Asboe-Hansen⁵ made the argument that a fresh bulla should be biopsied if histopathologic diagnosis is necessary, as older bullae may exhibit epithelial cell regeneration and disturb an accurate diagnosis.

Accurate and early diagnosis of TEN is imperative, as prognosis is strongly correlated with the speed at which the offending drug is discontinued and appropriate medical treatment is initiated. Prompt withdrawal of the offending drug has been reported to reduce the risk for morbidity by 30% per day.⁷ Although classically associated with the pemphigus group of diseases, the Asboe-Hansen sign is of diagnostic value to the pathologist in diagnosing TEN by reproducing the same microscopic appearance of a fresh spontaneous blister. Due to the notable morbidity and mortality in SJS and TEN, the Asboe-Hansen sign should be attempted for the site of a lesional biopsy, as an accurate diagnosis relies on clinicopathologic correlation.

To the Editor:

A 25-year-old woman with no notable medical history was admitted to the hospital for suspected Stevens-Johnson syndrome (SJS). The patient was started on amoxicillin 7 days prior to the skin eruption for prophylaxis before removal of an intrauterine device. On the day of admission, she reported ocular discomfort, dysphagia, and dysuria. She developed erythema of the conjunctivae, face, chest, and proximal upper extremities, as well as erosions of the vermilion lips. She presented to the local emergency department and was transferred to our institution for urgent dermatologic consultation. On physical examination by the dermatology service, the patient had erythematous macules coalescing into patches with overlying flaccid bullae, some denuded, involving the face, chest, abdomen, back (Figure 1), bilateral upper extremities, bilateral thighs, and labia majora and minora. Additionally, she had conjunctivitis, superficial erosions of the vermilion lips, and tense bullae of the palms and soles. On palpation of the flaccid bullae, the Asboe-Hansen sign was elicited (Figure 2 and video). A shave biopsy of the newly elicited bullae was performed. Pathology showed a subepidermal bulla with confluent necrosis of the epidermis and minimal inflammatory infiltrate. An additional shave biopsy of perilesional skin was obtained for direct immunofluorescence, which was negative for IgG, C3, IgM, and IgA. Based on the clinical presentation involving more than 30% of the patient’s body surface area (BSA) and the pathology findings, a diagnosis of toxic epidermal necrolysis (TEN) was made. The patient remained in the intensive care unit with a multidisciplinary team consisting of dermatology, ophthalmology, gynecology, gastroenterology, and the general surgery burn group. Following treatment with intravenous immunoglobulin, systemic corticosteroids, and aggressive wound care, the patient made a full recovery.

Vidyard Video

Toxic epidermal necrolysis is a rare, acute, life-threatening mucocutaneous disease within a spectrum of adverse cutaneous drug reactions. The estimated worldwide incidence of TEN is 0.4 to 1.9 per million individuals annually.¹ Toxic epidermal necrolysis is clinically characterized by diffuse exfoliation of the skin and mucosae with flaccid bullae. These clinical features are a consequence of extensive keratinocyte death, leading to dermoepidermal junction dissociation. Commonly, there is a prodrome of fever, pharyngitis, and painful skin preceding the diffuse erythema and sloughing of skin and mucous membranes. Lesions typically first appear on the trunk and then follow a centrifugal spread, often sparing the distal aspects of the arms and legs.

Toxic epidermal necrolysis is part of a continuous spectrum with SJS. Less than 10% BSA involvement is considered SJS, 10% to 30% BSA involvement is SJS/TEN overlap, and more than 30% BSA detachment is TEN. Stevens-Johnson syndrome can progress to TEN. In TEN, the distribution of cutaneous lesions is more confluent, and mucosal involvement is more severe.² The differential diagnosis may include staphylococcal scalded skin syndrome, drug-induced linear IgA bullous dermatosis, severe acute graft-vs-host disease, drug reaction with eosinophilia and systemic symptoms, and invasive fungal dermatitis. An accurate diagnosis of TEN is imperative, as the management and morbidity of these diseases are vastly different. Toxic epidermal necrolysis has an estimated mortality rate of 25% to 30%, with sepsis leading to multiorgan failure being the most common cause of death.³

Although the pathophysiology of TEN has yet to be fully elucidated, it is thought to be a T cell–mediated process with CD8⁺ cells acting as the primary means of keratinocyte death. An estimated 80% to 95% of cases are due to drug reactions.³ The medications that are most commonly associated with TEN include allopurinol, antibiotics, nonsteroidal anti-inflammatory drugs, and anticonvulsants. Symptoms typically begin 7 to 21 days after starting the drug. Less commonly, Mycoplasma pneumoniae, dengue virus, cytomegalovirus, and contrast medium have been reported as inciting factors for TEN.²

The diagnosis of TEN is established by correlating clinical features with a histopathologic examination obtained from a lesional skin biopsy. The classic cutaneous features of TEN begin as erythematous, flesh-colored, dusky to violaceous macules and/or morbilliform or targetoid lesions. These early lesions have the tendency to coalesce. The cutaneous findings will eventually progress into flaccid bullae, diffuse epidermal sloughing, and full-thickness skin necrosis.^2,3 The evolution of skin lesions may be rapid or may take several days to develop. On palpation, the Nikolsky (lateral shearing of epidermis with minimal pressure) and Asboe-Hansen sign will be positive in patients with SJS/TEN, demonstrating that the associated blisters are flaccid and may be displaced peripherally.⁴ For an accurate diagnosis, the biopsy must contain full-thickness epidermis. It is imperative to choose a biopsy site from an acute blister, as old lesions of other diseases, such as erythema multiforme, will eventually become necrotic and mimic the histopathologic appearance of SJS/TEN, potentially leading to an incorrect diagnosis.⁴ Full-thickness epidermal necrosis has a high sensitivity but low specificity for TEN.³ The histologic features of TEN vary depending on the stage of the disease. Classic histologic findings include satellite necrosis of keratinocytes followed by full-thickness necrosis of keratinocytes and perivascular lymphoid infiltrates. The stratum corneum retains its original structure.⁴

The Asboe-Hansen sign, also known as the bulla spread sign, was originally described in 1960 as a diagnostic sign for pemphigus vulgaris.⁵ A positive Asboe-Hansen sign demonstrates the ability to enlarge a bulla in the lateral direction by applying perpendicular mechanical pressure to the roof of an intact bulla. The bulla is extended to adjacent nonblistered skin.⁶ A positive sign demonstrates decreased adhesion between keratinocytes or between the basal epidermal cells and the dermal connective tissue.⁵ In addition to pemphigus vulgaris, the Asboe-Hansen sign may be positive in TEN and SJS, as well as other diseases affecting the dermoepidermal junction including pemphigus foliaceus, pemphigus vegetans, and bullous pemphigoid. Asboe-Hansen⁵ made the argument that a fresh bulla should be biopsied if histopathologic diagnosis is necessary, as older bullae may exhibit epithelial cell regeneration and disturb an accurate diagnosis.

Accurate and early diagnosis of TEN is imperative, as prognosis is strongly correlated with the speed at which the offending drug is discontinued and appropriate medical treatment is initiated. Prompt withdrawal of the offending drug has been reported to reduce the risk for morbidity by 30% per day.⁷ Although classically associated with the pemphigus group of diseases, the Asboe-Hansen sign is of diagnostic value to the pathologist in diagnosing TEN by reproducing the same microscopic appearance of a fresh spontaneous blister. Due to the notable morbidity and mortality in SJS and TEN, the Asboe-Hansen sign should be attempted for the site of a lesional biopsy, as an accurate diagnosis relies on clinicopathologic correlation.

Patients seek healthy skin that conveys overall health and well-being. Cosmeceuticals claim to therapeutically affect the structure and function of the skin, and it is rational to hold them to scientific standards that substantiate efficacy claims.¹ Notably, it is increasingly important to consider nature-based products in helping patients and consumers to achieve healthier skin. Despite the availability of sophisticated efficacy testing, explanations of the underlying physiologic and pharmacologic principles of nature-based products lag behind those of conventional formulations. In many instances, simple form and function information cannot adequately support their desired use and expected benefits. In addition, cosmetic regulations do not even permit structure-function claims that are allowed for dietary supplements.

Physicians whose patients want recommendations for nature-based products often do not know where to turn for definitive product and use information. Unlike prescription medications or even beauty-from-within dietary supplement products, natural cosmetics and cosmeceuticals are barred from communicating scientific evidence and experience of use to form proper opinions for recommendations. Without the benefit of full product labeling, physicians are left to mine sparse, confusing, and often contradictory literature in an effort to self-educate. Here, we share our experiences with patients, our operating knowledge base, and our recommendations for investigation to improve the available information and ensure practicing physicians have the information they need to appropriately recommend nature-based products.

General Observations Pertaining to Patients and Nature-Based Products

Ethnic and cultural customs and traditions have accepted and employed nature-based products for skin health for millennia (eTables 1–3).^2-20 African and the derived Caribbean cultures frequently use shea butter, black soap, or coconut oil. East Asian ethnobotanical practices include the use of ginseng, green tea, almond, and angelica root in skin care. Indian culture employs Ayurvedic medicine principles that include herbal remedies comprised of ground chickpeas, rice, turmeric, neem, ashwagandha, moringa, and kutki. These cultural traditions continue into modern times, and patients regularly use these products. Modern social trends that focus on a healthy lifestyle also create demand for nature-based products for skin health. In our opinion, the current growing interest in nature-based products implies continued growth in their use as patients become more familiar and comfortable with them.

For beauty and skin health, a new trend has evolved in which the first source of advice is rarely a dermatologist. Social media, nonphysician influencers, and pseudoscience have created an authority previously reserved for dermatologists among patients and consumers. Bloggers and social media influencers, posting their individual real-world experiences, shape the perceptions of consumers and patients.^21,22 Nonphysician influencers leverage their celebrity to provide guidance and advice on beauty and cosmetic tips.²³ Much of the evidence supporting cosmetic and especially nature-based products for skin care and health often is believed to be less rigorous and of lower quality than that typically supporting physician recommendations.^24-26

Nature-Based Products in Skin Health and Dermatologic Conditions

Patients turn to nature-based products for skin care and health for many reasons. The simplest reason is that they grew up with such products and continue their use. Many patients find nature-based products themselves, have favorable experiences, and seek advice on their efficacy and safety for continued use. Patients also use these products as part of a holistic approach to health in which diet and exercise coincide with the idea of ministering to the whole self instead of preventing or treating an illness. These nature-based treatment options fit their natural lifestyles. Patients sometimes express concerns about synthetic products that lead them to seek out nature-based products. Chemicals and preservatives (eg, parabens, sunscreens, nanoparticles) may evoke concerns about negative health consequences, which can be a cause of great anxiety to patients.

Nature-based products, when recommended by physicians, can fulfill important roles. As healthier alternatives, they can address health concerns in the belief that plant-based ingredients may be more compatible with overall health than synthetic ingredients. This compatibility may have resulted from the human species coevolving with plant species containing therapeutic utility, leading to the development of specific receptors for many natural products, such as digoxin from foxglove (Digitalis purpurea), opioids from poppies (Papaver somniferum), and cannabinoids (Cannabis sativa and hybrids). Natural products can become alternatives to synthetic products or adjuncts to prescription medications. Often, inclusion of nature-based products into a treatment plan enables patients to feel that they are a more integral part of the care team treating their conditions. By virtue of physician recommendations, patients may have expectations on product efficacy being as robust as prescription products with the safety profile of plant-based products. Patients should be advised to accept a realistic view of the efficacy and tolerability profiles. In the end, patients consider physician recommendations based on the assumption that they are credible and derived from experience and knowledge.

Physician Perceptions of Nature-Based Products

Physicians recommend nature-based products based on several factors. Central to the recommendation is an understanding, through appropriate documentation, that the product will be reasonably efficacious. Critical to this point, physicians must understand what ingredients are in nature-based products, their concentrations or amounts, and why they are present. However, our experience with nature-based products suggests that many of these factors are not met. Limited or unclear information on the efficacy of nature-based products fails to satisfy a physician’s need for adequate information to support recommendations. Although natural ingredients are listed on product labels, their intended benefit and efficacy characteristics often are unclear or poorly stated, in some cases resulting from improper labeling and in other cases due to claim restrictions imposed on cosmetics. In addition, insufficient details on formulation, such as type and percentages of oils, antioxidants, and vitamins, hinder the physician’s ability to identify and explain mechanisms that bring benefit to the patient. Universal benchmarks do not exist for amounts or concentrations of ingredients that are required for a stated benefit.²⁷ Currently, no standards exist for assurances that product quality, control, and efficacy are consistently reproducible. For example, angel dusting is a practice that discloses that an active ingredient is present, yet these ingredients may be present in quantities that are insufficient to provide measurable benefit. Sourcing of ingredients also can be concerning, as they may not always meet manufacturer, physician, or patient expectations for characterization or efficacy.^28,29 Dry testing, which is when a manufacturer contracts a laboratory to certify their ingredients without performing assays, has been increasingly reported in lay and botanical literature over the last few years.³⁰

It is unknown if many nature-based products clinically exhibit their stated efficacy. Empirical evidence or well-conducted clinical studies on which to base recommendations of these products are limited. Individual natural ingredients, however, do have some supporting evidence of efficacy: shea butter moisturizes³¹; coconut oil exhibits anti-inflammatory properties^32,33; and vinegar, yogurt, and diluted tea tree oil exhibit antibacterial properties in postprocedure care and fungal infections, and as adjuvants to prescription antibiotics in atopic dermatitis, acne, and rosacea.^34-41 Honey also has been shown to improve wound healing and is even available as a medical device for wounds.^42,43 Although nature-based products are an interesting alternative to synthetic products, they require a fulsome understanding of characteristics and efficacy properties to support physician recommendations.

Physician Recommendations

Physicians must be educated to understand when and how to recommend nature-based products. Although we recommend increased product information to guide physicians, current laws, including the Federal Food, Drug, and Cosmetic Act and the Fair Packaging and Labeling Act, are satisfactory from a regulatory standpoint.⁴⁴ Here, we discuss the information physicians could use to support an informed recommendation of nature-based products.

A clear specific explanation of natural ingredient sources, their intended efficacy, and rigorous scientific clinical evidence supporting their use should be given. Manufacturers are needed to document and report the structure and function of natural ingredients, leading to a common understanding by practicing dermatologists.⁴⁵ For this reason, manufacturers must provide nonambiguous and standardized methods and measures to demonstrate the mechanism of ingredient efficacy and the limits of safety and tolerability.

We recommend that manufacturers provide standardized transparency into the composition of nature-based formulations, including amounts and concentrations of ingredients; geographic sources; parts of plants used; and if extracted, what agent(s) this standard is based on (eg, hypericin in Saint-John’s-wort or kavalactones in kava kava). Most natural products contain an aqueous phase and therefore will likely require preservatives such as synthetic parabens or alcohols to avoid degradation. Unnecessary ingredients, including fragrances, fillers, and support chemicals, should be absent since inert agents may exhibit biologic effects, obscuring the boundary between active and inert. A clear explanation of the origins of these nature-based ingredients and the concentration, purity, and activity assessment should be provided. In the context of an authoritative review with standardized measures, labels that provide the common name, plant name, part used, how it was obtained, concentrations and/or amounts, and standardized activity measures can be helpful to the recommending physician, who will then know the efficacy patients should expect from the ingredients. They also can assess the expected tolerability based on the concentrations and their own experience managing a particular disorder, tempered by the patient’s experiences with prior therapies. Transparent and standardized labeling describing the formulation, quantities of ingredients, and intended activity will help inform expectations of efficacy.

We recommend clear preclinical and clinical demonstrations of the efficacy and benefits that are claimed by nature-based formulations. Properly designed placebo- or active-controlled, blinded, randomized studies with standardized measures and end points are recommended to determine efficacy and safety. These demonstrations of efficacy can provide physicians with credible evidence on which to base their recommendations and guide the use of products for the patient’s best experience. Given sufficient involvement from manufacturers and publication of the information in peer-reviewed journals, the relative benefits for each nature-based product can be cataloged as a resource for physicians.

Conclusion

Patients turn to nature-based products for many reasons. They have high expectations but also harbor concerns as to the efficacy of these products for skin and health care. Physicians seek to recommend nature-based products for these patients but often find themselves disadvantaged by limited published evidence and insufficient labeling information on composition and efficacy, which should support recommendations for use. To remedy this situation, we suggest research to allow a clear explanation of the activity of natural ingredients, clear demonstrations of the efficacy of nature-based formulas using clinical standardized measures and end points, and clear education and disclosure of ingredients contained within nature-based products.



Acknowledgments—Burt’s Bees (Durham, North Carolina) provided funding for editorial support by Medical Dynamics, Inc (New York, New York).

Patients seek healthy skin that conveys overall health and well-being. Cosmeceuticals claim to therapeutically affect the structure and function of the skin, and it is rational to hold them to scientific standards that substantiate efficacy claims.¹ Notably, it is increasingly important to consider nature-based products in helping patients and consumers to achieve healthier skin. Despite the availability of sophisticated efficacy testing, explanations of the underlying physiologic and pharmacologic principles of nature-based products lag behind those of conventional formulations. In many instances, simple form and function information cannot adequately support their desired use and expected benefits. In addition, cosmetic regulations do not even permit structure-function claims that are allowed for dietary supplements.

Physicians whose patients want recommendations for nature-based products often do not know where to turn for definitive product and use information. Unlike prescription medications or even beauty-from-within dietary supplement products, natural cosmetics and cosmeceuticals are barred from communicating scientific evidence and experience of use to form proper opinions for recommendations. Without the benefit of full product labeling, physicians are left to mine sparse, confusing, and often contradictory literature in an effort to self-educate. Here, we share our experiences with patients, our operating knowledge base, and our recommendations for investigation to improve the available information and ensure practicing physicians have the information they need to appropriately recommend nature-based products.

General Observations Pertaining to Patients and Nature-Based Products

Ethnic and cultural customs and traditions have accepted and employed nature-based products for skin health for millennia (eTables 1–3).^2-20 African and the derived Caribbean cultures frequently use shea butter, black soap, or coconut oil. East Asian ethnobotanical practices include the use of ginseng, green tea, almond, and angelica root in skin care. Indian culture employs Ayurvedic medicine principles that include herbal remedies comprised of ground chickpeas, rice, turmeric, neem, ashwagandha, moringa, and kutki. These cultural traditions continue into modern times, and patients regularly use these products. Modern social trends that focus on a healthy lifestyle also create demand for nature-based products for skin health. In our opinion, the current growing interest in nature-based products implies continued growth in their use as patients become more familiar and comfortable with them.

For beauty and skin health, a new trend has evolved in which the first source of advice is rarely a dermatologist. Social media, nonphysician influencers, and pseudoscience have created an authority previously reserved for dermatologists among patients and consumers. Bloggers and social media influencers, posting their individual real-world experiences, shape the perceptions of consumers and patients.^21,22 Nonphysician influencers leverage their celebrity to provide guidance and advice on beauty and cosmetic tips.²³ Much of the evidence supporting cosmetic and especially nature-based products for skin care and health often is believed to be less rigorous and of lower quality than that typically supporting physician recommendations.^24-26

Nature-Based Products in Skin Health and Dermatologic Conditions

Patients turn to nature-based products for skin care and health for many reasons. The simplest reason is that they grew up with such products and continue their use. Many patients find nature-based products themselves, have favorable experiences, and seek advice on their efficacy and safety for continued use. Patients also use these products as part of a holistic approach to health in which diet and exercise coincide with the idea of ministering to the whole self instead of preventing or treating an illness. These nature-based treatment options fit their natural lifestyles. Patients sometimes express concerns about synthetic products that lead them to seek out nature-based products. Chemicals and preservatives (eg, parabens, sunscreens, nanoparticles) may evoke concerns about negative health consequences, which can be a cause of great anxiety to patients.

Nature-based products, when recommended by physicians, can fulfill important roles. As healthier alternatives, they can address health concerns in the belief that plant-based ingredients may be more compatible with overall health than synthetic ingredients. This compatibility may have resulted from the human species coevolving with plant species containing therapeutic utility, leading to the development of specific receptors for many natural products, such as digoxin from foxglove (Digitalis purpurea), opioids from poppies (Papaver somniferum), and cannabinoids (Cannabis sativa and hybrids). Natural products can become alternatives to synthetic products or adjuncts to prescription medications. Often, inclusion of nature-based products into a treatment plan enables patients to feel that they are a more integral part of the care team treating their conditions. By virtue of physician recommendations, patients may have expectations on product efficacy being as robust as prescription products with the safety profile of plant-based products. Patients should be advised to accept a realistic view of the efficacy and tolerability profiles. In the end, patients consider physician recommendations based on the assumption that they are credible and derived from experience and knowledge.

Physician Perceptions of Nature-Based Products

Physicians recommend nature-based products based on several factors. Central to the recommendation is an understanding, through appropriate documentation, that the product will be reasonably efficacious. Critical to this point, physicians must understand what ingredients are in nature-based products, their concentrations or amounts, and why they are present. However, our experience with nature-based products suggests that many of these factors are not met. Limited or unclear information on the efficacy of nature-based products fails to satisfy a physician’s need for adequate information to support recommendations. Although natural ingredients are listed on product labels, their intended benefit and efficacy characteristics often are unclear or poorly stated, in some cases resulting from improper labeling and in other cases due to claim restrictions imposed on cosmetics. In addition, insufficient details on formulation, such as type and percentages of oils, antioxidants, and vitamins, hinder the physician’s ability to identify and explain mechanisms that bring benefit to the patient. Universal benchmarks do not exist for amounts or concentrations of ingredients that are required for a stated benefit.²⁷ Currently, no standards exist for assurances that product quality, control, and efficacy are consistently reproducible. For example, angel dusting is a practice that discloses that an active ingredient is present, yet these ingredients may be present in quantities that are insufficient to provide measurable benefit. Sourcing of ingredients also can be concerning, as they may not always meet manufacturer, physician, or patient expectations for characterization or efficacy.^28,29 Dry testing, which is when a manufacturer contracts a laboratory to certify their ingredients without performing assays, has been increasingly reported in lay and botanical literature over the last few years.³⁰

It is unknown if many nature-based products clinically exhibit their stated efficacy. Empirical evidence or well-conducted clinical studies on which to base recommendations of these products are limited. Individual natural ingredients, however, do have some supporting evidence of efficacy: shea butter moisturizes³¹; coconut oil exhibits anti-inflammatory properties^32,33; and vinegar, yogurt, and diluted tea tree oil exhibit antibacterial properties in postprocedure care and fungal infections, and as adjuvants to prescription antibiotics in atopic dermatitis, acne, and rosacea.^34-41 Honey also has been shown to improve wound healing and is even available as a medical device for wounds.^42,43 Although nature-based products are an interesting alternative to synthetic products, they require a fulsome understanding of characteristics and efficacy properties to support physician recommendations.

Physician Recommendations

Physicians must be educated to understand when and how to recommend nature-based products. Although we recommend increased product information to guide physicians, current laws, including the Federal Food, Drug, and Cosmetic Act and the Fair Packaging and Labeling Act, are satisfactory from a regulatory standpoint.⁴⁴ Here, we discuss the information physicians could use to support an informed recommendation of nature-based products.

A clear specific explanation of natural ingredient sources, their intended efficacy, and rigorous scientific clinical evidence supporting their use should be given. Manufacturers are needed to document and report the structure and function of natural ingredients, leading to a common understanding by practicing dermatologists.⁴⁵ For this reason, manufacturers must provide nonambiguous and standardized methods and measures to demonstrate the mechanism of ingredient efficacy and the limits of safety and tolerability.

We recommend that manufacturers provide standardized transparency into the composition of nature-based formulations, including amounts and concentrations of ingredients; geographic sources; parts of plants used; and if extracted, what agent(s) this standard is based on (eg, hypericin in Saint-John’s-wort or kavalactones in kava kava). Most natural products contain an aqueous phase and therefore will likely require preservatives such as synthetic parabens or alcohols to avoid degradation. Unnecessary ingredients, including fragrances, fillers, and support chemicals, should be absent since inert agents may exhibit biologic effects, obscuring the boundary between active and inert. A clear explanation of the origins of these nature-based ingredients and the concentration, purity, and activity assessment should be provided. In the context of an authoritative review with standardized measures, labels that provide the common name, plant name, part used, how it was obtained, concentrations and/or amounts, and standardized activity measures can be helpful to the recommending physician, who will then know the efficacy patients should expect from the ingredients. They also can assess the expected tolerability based on the concentrations and their own experience managing a particular disorder, tempered by the patient’s experiences with prior therapies. Transparent and standardized labeling describing the formulation, quantities of ingredients, and intended activity will help inform expectations of efficacy.

We recommend clear preclinical and clinical demonstrations of the efficacy and benefits that are claimed by nature-based formulations. Properly designed placebo- or active-controlled, blinded, randomized studies with standardized measures and end points are recommended to determine efficacy and safety. These demonstrations of efficacy can provide physicians with credible evidence on which to base their recommendations and guide the use of products for the patient’s best experience. Given sufficient involvement from manufacturers and publication of the information in peer-reviewed journals, the relative benefits for each nature-based product can be cataloged as a resource for physicians.

Conclusion

Patients turn to nature-based products for many reasons. They have high expectations but also harbor concerns as to the efficacy of these products for skin and health care. Physicians seek to recommend nature-based products for these patients but often find themselves disadvantaged by limited published evidence and insufficient labeling information on composition and efficacy, which should support recommendations for use. To remedy this situation, we suggest research to allow a clear explanation of the activity of natural ingredients, clear demonstrations of the efficacy of nature-based formulas using clinical standardized measures and end points, and clear education and disclosure of ingredients contained within nature-based products.



Acknowledgments—Burt’s Bees (Durham, North Carolina) provided funding for editorial support by Medical Dynamics, Inc (New York, New York).

Patients seek healthy skin that conveys overall health and well-being. Cosmeceuticals claim to therapeutically affect the structure and function of the skin, and it is rational to hold them to scientific standards that substantiate efficacy claims.¹ Notably, it is increasingly important to consider nature-based products in helping patients and consumers to achieve healthier skin. Despite the availability of sophisticated efficacy testing, explanations of the underlying physiologic and pharmacologic principles of nature-based products lag behind those of conventional formulations. In many instances, simple form and function information cannot adequately support their desired use and expected benefits. In addition, cosmetic regulations do not even permit structure-function claims that are allowed for dietary supplements.

Physicians whose patients want recommendations for nature-based products often do not know where to turn for definitive product and use information. Unlike prescription medications or even beauty-from-within dietary supplement products, natural cosmetics and cosmeceuticals are barred from communicating scientific evidence and experience of use to form proper opinions for recommendations. Without the benefit of full product labeling, physicians are left to mine sparse, confusing, and often contradictory literature in an effort to self-educate. Here, we share our experiences with patients, our operating knowledge base, and our recommendations for investigation to improve the available information and ensure practicing physicians have the information they need to appropriately recommend nature-based products.

General Observations Pertaining to Patients and Nature-Based Products

Ethnic and cultural customs and traditions have accepted and employed nature-based products for skin health for millennia (eTables 1–3).^2-20 African and the derived Caribbean cultures frequently use shea butter, black soap, or coconut oil. East Asian ethnobotanical practices include the use of ginseng, green tea, almond, and angelica root in skin care. Indian culture employs Ayurvedic medicine principles that include herbal remedies comprised of ground chickpeas, rice, turmeric, neem, ashwagandha, moringa, and kutki. These cultural traditions continue into modern times, and patients regularly use these products. Modern social trends that focus on a healthy lifestyle also create demand for nature-based products for skin health. In our opinion, the current growing interest in nature-based products implies continued growth in their use as patients become more familiar and comfortable with them.

For beauty and skin health, a new trend has evolved in which the first source of advice is rarely a dermatologist. Social media, nonphysician influencers, and pseudoscience have created an authority previously reserved for dermatologists among patients and consumers. Bloggers and social media influencers, posting their individual real-world experiences, shape the perceptions of consumers and patients.^21,22 Nonphysician influencers leverage their celebrity to provide guidance and advice on beauty and cosmetic tips.²³ Much of the evidence supporting cosmetic and especially nature-based products for skin care and health often is believed to be less rigorous and of lower quality than that typically supporting physician recommendations.^24-26

Nature-Based Products in Skin Health and Dermatologic Conditions

Patients turn to nature-based products for skin care and health for many reasons. The simplest reason is that they grew up with such products and continue their use. Many patients find nature-based products themselves, have favorable experiences, and seek advice on their efficacy and safety for continued use. Patients also use these products as part of a holistic approach to health in which diet and exercise coincide with the idea of ministering to the whole self instead of preventing or treating an illness. These nature-based treatment options fit their natural lifestyles. Patients sometimes express concerns about synthetic products that lead them to seek out nature-based products. Chemicals and preservatives (eg, parabens, sunscreens, nanoparticles) may evoke concerns about negative health consequences, which can be a cause of great anxiety to patients.

Nature-based products, when recommended by physicians, can fulfill important roles. As healthier alternatives, they can address health concerns in the belief that plant-based ingredients may be more compatible with overall health than synthetic ingredients. This compatibility may have resulted from the human species coevolving with plant species containing therapeutic utility, leading to the development of specific receptors for many natural products, such as digoxin from foxglove (Digitalis purpurea), opioids from poppies (Papaver somniferum), and cannabinoids (Cannabis sativa and hybrids). Natural products can become alternatives to synthetic products or adjuncts to prescription medications. Often, inclusion of nature-based products into a treatment plan enables patients to feel that they are a more integral part of the care team treating their conditions. By virtue of physician recommendations, patients may have expectations on product efficacy being as robust as prescription products with the safety profile of plant-based products. Patients should be advised to accept a realistic view of the efficacy and tolerability profiles. In the end, patients consider physician recommendations based on the assumption that they are credible and derived from experience and knowledge.

Physician Perceptions of Nature-Based Products

Physicians recommend nature-based products based on several factors. Central to the recommendation is an understanding, through appropriate documentation, that the product will be reasonably efficacious. Critical to this point, physicians must understand what ingredients are in nature-based products, their concentrations or amounts, and why they are present. However, our experience with nature-based products suggests that many of these factors are not met. Limited or unclear information on the efficacy of nature-based products fails to satisfy a physician’s need for adequate information to support recommendations. Although natural ingredients are listed on product labels, their intended benefit and efficacy characteristics often are unclear or poorly stated, in some cases resulting from improper labeling and in other cases due to claim restrictions imposed on cosmetics. In addition, insufficient details on formulation, such as type and percentages of oils, antioxidants, and vitamins, hinder the physician’s ability to identify and explain mechanisms that bring benefit to the patient. Universal benchmarks do not exist for amounts or concentrations of ingredients that are required for a stated benefit.²⁷ Currently, no standards exist for assurances that product quality, control, and efficacy are consistently reproducible. For example, angel dusting is a practice that discloses that an active ingredient is present, yet these ingredients may be present in quantities that are insufficient to provide measurable benefit. Sourcing of ingredients also can be concerning, as they may not always meet manufacturer, physician, or patient expectations for characterization or efficacy.^28,29 Dry testing, which is when a manufacturer contracts a laboratory to certify their ingredients without performing assays, has been increasingly reported in lay and botanical literature over the last few years.³⁰

It is unknown if many nature-based products clinically exhibit their stated efficacy. Empirical evidence or well-conducted clinical studies on which to base recommendations of these products are limited. Individual natural ingredients, however, do have some supporting evidence of efficacy: shea butter moisturizes³¹; coconut oil exhibits anti-inflammatory properties^32,33; and vinegar, yogurt, and diluted tea tree oil exhibit antibacterial properties in postprocedure care and fungal infections, and as adjuvants to prescription antibiotics in atopic dermatitis, acne, and rosacea.^34-41 Honey also has been shown to improve wound healing and is even available as a medical device for wounds.^42,43 Although nature-based products are an interesting alternative to synthetic products, they require a fulsome understanding of characteristics and efficacy properties to support physician recommendations.

Physician Recommendations

Physicians must be educated to understand when and how to recommend nature-based products. Although we recommend increased product information to guide physicians, current laws, including the Federal Food, Drug, and Cosmetic Act and the Fair Packaging and Labeling Act, are satisfactory from a regulatory standpoint.⁴⁴ Here, we discuss the information physicians could use to support an informed recommendation of nature-based products.

A clear specific explanation of natural ingredient sources, their intended efficacy, and rigorous scientific clinical evidence supporting their use should be given. Manufacturers are needed to document and report the structure and function of natural ingredients, leading to a common understanding by practicing dermatologists.⁴⁵ For this reason, manufacturers must provide nonambiguous and standardized methods and measures to demonstrate the mechanism of ingredient efficacy and the limits of safety and tolerability.

We recommend that manufacturers provide standardized transparency into the composition of nature-based formulations, including amounts and concentrations of ingredients; geographic sources; parts of plants used; and if extracted, what agent(s) this standard is based on (eg, hypericin in Saint-John’s-wort or kavalactones in kava kava). Most natural products contain an aqueous phase and therefore will likely require preservatives such as synthetic parabens or alcohols to avoid degradation. Unnecessary ingredients, including fragrances, fillers, and support chemicals, should be absent since inert agents may exhibit biologic effects, obscuring the boundary between active and inert. A clear explanation of the origins of these nature-based ingredients and the concentration, purity, and activity assessment should be provided. In the context of an authoritative review with standardized measures, labels that provide the common name, plant name, part used, how it was obtained, concentrations and/or amounts, and standardized activity measures can be helpful to the recommending physician, who will then know the efficacy patients should expect from the ingredients. They also can assess the expected tolerability based on the concentrations and their own experience managing a particular disorder, tempered by the patient’s experiences with prior therapies. Transparent and standardized labeling describing the formulation, quantities of ingredients, and intended activity will help inform expectations of efficacy.

We recommend clear preclinical and clinical demonstrations of the efficacy and benefits that are claimed by nature-based formulations. Properly designed placebo- or active-controlled, blinded, randomized studies with standardized measures and end points are recommended to determine efficacy and safety. These demonstrations of efficacy can provide physicians with credible evidence on which to base their recommendations and guide the use of products for the patient’s best experience. Given sufficient involvement from manufacturers and publication of the information in peer-reviewed journals, the relative benefits for each nature-based product can be cataloged as a resource for physicians.

Conclusion

Patients turn to nature-based products for many reasons. They have high expectations but also harbor concerns as to the efficacy of these products for skin and health care. Physicians seek to recommend nature-based products for these patients but often find themselves disadvantaged by limited published evidence and insufficient labeling information on composition and efficacy, which should support recommendations for use. To remedy this situation, we suggest research to allow a clear explanation of the activity of natural ingredients, clear demonstrations of the efficacy of nature-based formulas using clinical standardized measures and end points, and clear education and disclosure of ingredients contained within nature-based products.



Acknowledgments—Burt’s Bees (Durham, North Carolina) provided funding for editorial support by Medical Dynamics, Inc (New York, New York).

Clinical Presentation

Millipedes secrete a noxious toxin implicated in millipede burns. The toxic substance is benzoquinone, a strong irritant secreted from the repugnatorial glands contained in each segment of the arthropod (Figure 1). This compound serves as a natural insect repellant, acting as the millipede’s defense mechanism from potential predators.¹ On human skin, benzoquinone causes localized pigmentary changes most commonly presenting on the feet and toes. Local lesions may be associated with pain or burning, but there are no known reports of adverse systemic effects.² Affected patients experience cutaneous pigmentary changes, which may be dark red, blue, or black, and spontaneously resolve over time.² The degree of pigment change may be associated with duration of skin contact with the toxin. The affected areas may resemble burns, dermatitis, or skin necrosis. More distal lesions may present similarly to blue toe syndrome or acute arterial occlusion but can be differentiated by the presence of intact peripheral pulses and lack of temperature discrepancy between the feet.^3,4 Histologic evaluation of the lesions generally reveals nonspecific full-thickness epidermal necrosis, making clinical suspicion and physical examination paramount to the diagnosis of millipede burns.⁵

Diagnostic Difficulties

Accurate diagnosis of millipede burns is more difficult when the burn involves an unusual site. The most common site of involvement is the foot (Figure 2), followed by other commonly exposed areas such as the arms, face, and eyes.^2,3,6,7 Covered parts of the body are much less commonly affected, requiring the arthropod to gain access via infiltration of clothing, often when hanging on a clothesline. In these cases, burns may be mistaken for child abuse, especially if certain areas of the body are involved, such as the groin and genitals.² The well-defined arcuate lesions of the burns may resemble injuries from a wire or belt to the unsuspecting observer.

Conclusion

Although millipedes often are regarded as harmless, they are capable of causing adverse reactions through the secretion of toxic chemicals. Millipede burns cause localized pigmentary changes that may be associated with pain or burning in some patients. Because these burns may resemble child abuse in pediatric patients, physicians should be aware of this diagnosis when unusual parts of the body are involved.

Clinical Presentation

Millipedes secrete a noxious toxin implicated in millipede burns. The toxic substance is benzoquinone, a strong irritant secreted from the repugnatorial glands contained in each segment of the arthropod (Figure 1). This compound serves as a natural insect repellant, acting as the millipede’s defense mechanism from potential predators.¹ On human skin, benzoquinone causes localized pigmentary changes most commonly presenting on the feet and toes. Local lesions may be associated with pain or burning, but there are no known reports of adverse systemic effects.² Affected patients experience cutaneous pigmentary changes, which may be dark red, blue, or black, and spontaneously resolve over time.² The degree of pigment change may be associated with duration of skin contact with the toxin. The affected areas may resemble burns, dermatitis, or skin necrosis. More distal lesions may present similarly to blue toe syndrome or acute arterial occlusion but can be differentiated by the presence of intact peripheral pulses and lack of temperature discrepancy between the feet.^3,4 Histologic evaluation of the lesions generally reveals nonspecific full-thickness epidermal necrosis, making clinical suspicion and physical examination paramount to the diagnosis of millipede burns.⁵

Diagnostic Difficulties

Accurate diagnosis of millipede burns is more difficult when the burn involves an unusual site. The most common site of involvement is the foot (Figure 2), followed by other commonly exposed areas such as the arms, face, and eyes.^2,3,6,7 Covered parts of the body are much less commonly affected, requiring the arthropod to gain access via infiltration of clothing, often when hanging on a clothesline. In these cases, burns may be mistaken for child abuse, especially if certain areas of the body are involved, such as the groin and genitals.² The well-defined arcuate lesions of the burns may resemble injuries from a wire or belt to the unsuspecting observer.

Conclusion

Although millipedes often are regarded as harmless, they are capable of causing adverse reactions through the secretion of toxic chemicals. Millipede burns cause localized pigmentary changes that may be associated with pain or burning in some patients. Because these burns may resemble child abuse in pediatric patients, physicians should be aware of this diagnosis when unusual parts of the body are involved.

Clinical Presentation

Millipedes secrete a noxious toxin implicated in millipede burns. The toxic substance is benzoquinone, a strong irritant secreted from the repugnatorial glands contained in each segment of the arthropod (Figure 1). This compound serves as a natural insect repellant, acting as the millipede’s defense mechanism from potential predators.¹ On human skin, benzoquinone causes localized pigmentary changes most commonly presenting on the feet and toes. Local lesions may be associated with pain or burning, but there are no known reports of adverse systemic effects.² Affected patients experience cutaneous pigmentary changes, which may be dark red, blue, or black, and spontaneously resolve over time.² The degree of pigment change may be associated with duration of skin contact with the toxin. The affected areas may resemble burns, dermatitis, or skin necrosis. More distal lesions may present similarly to blue toe syndrome or acute arterial occlusion but can be differentiated by the presence of intact peripheral pulses and lack of temperature discrepancy between the feet.^3,4 Histologic evaluation of the lesions generally reveals nonspecific full-thickness epidermal necrosis, making clinical suspicion and physical examination paramount to the diagnosis of millipede burns.⁵

Diagnostic Difficulties

Accurate diagnosis of millipede burns is more difficult when the burn involves an unusual site. The most common site of involvement is the foot (Figure 2), followed by other commonly exposed areas such as the arms, face, and eyes.^2,3,6,7 Covered parts of the body are much less commonly affected, requiring the arthropod to gain access via infiltration of clothing, often when hanging on a clothesline. In these cases, burns may be mistaken for child abuse, especially if certain areas of the body are involved, such as the groin and genitals.² The well-defined arcuate lesions of the burns may resemble injuries from a wire or belt to the unsuspecting observer.

Conclusion

Although millipedes often are regarded as harmless, they are capable of causing adverse reactions through the secretion of toxic chemicals. Millipede burns cause localized pigmentary changes that may be associated with pain or burning in some patients. Because these burns may resemble child abuse in pediatric patients, physicians should be aware of this diagnosis when unusual parts of the body are involved.

DENVER – A clinically identifiable scar occurs after full-thickness skin wounds greater than 400-500 mcm in diameter, while wounds of smaller diameter heal with no clinically perceptible scar.

The findings come from a small pilot trial that set out to determine the biopsy size limit at which healing occurs without a scar, as well as demonstrate the safety of performing multiple skin microbiopsies. “The broader purpose of this work is to contribute to the development of techniques for harvesting skin tissue with less morbidity than conventional methods,” lead study author Amanda H. Champlain, MD, said in an interview in advance of the annual conference of the American Society for Laser Medicine and Surgery. “The size threshold at which a full-thickness skin wound can heal without scarring had not been determined prior to this study.”

Dr. Champlain, a fellow at Massachusetts General Hospital and The Wellman Center for Photomedicine, both in Boston, and her colleagues designed a way to evaluate healing responses and safety after collecting skin microbiopsies of different sizes from preabdominoplasty skin. According to the study abstract, the concept “is based on fractional photothermolysis in which a multitude of small, full-thickness thermal burns are produced by a laser on the skin with rapid healing and no scarring.” Measures included the Patient and Observer Scar Assessment Scale (POSAS), donor site pain scale, subject satisfaction survey, and an assessment of side effects, clinical photographs, and histology.

Preliminary data are available for five subjects. The POSAS-Observer scale ranges from 5 to 50 while the POSAS-Patient scale ranges from 6 to 60. The researchers observed that average final POSAS-Observer scores were 5.6 for scars 200 mcm in diameter, 5.2 for scars 400 mcm in diameter, 7.0 for scars 500 mcm in diameter, 6.8 for scars 600 mcm in diameter, 8.2 for scars 800 mcm in diameter, 9.6 for scars 1 mm in diameter, and 13.2 for those 2 mm in diameter. Meanwhile, the average final POSAS-Subject scores were 6.0 for scars 200 mcm in diameter, 6.0 for scars 400 mcm in diameter, 6.6 for scars 500 mcm in diameter, 6.4 for those 600 mcm in diameter, 7.2 for scars 800 mcm in diameter, 7.4 for scars 1 mm in diameter, and 10.0 for those 2 mm in diameter.

The maximum donor site pain reported was 4 out of 10 in one subject. “The procedure was very well tolerated by the subjects,” Dr. Champlain said. “They healed quickly, and the majority were happy with the cosmetic outcome regardless of the diameter of the microbiopsy used.”

The most common side effects of the study procedures included mild bleeding, scabbing, redness, and hyper/hypopigmentation. “The majority of study participants strongly agree that the study procedure was safe, tolerable, and cosmetically sound,” she said.

Dr. Champlain does not have any disclosures, but she said that the study was funded by the Department of Defense.

[email protected]

DENVER – A clinically identifiable scar occurs after full-thickness skin wounds greater than 400-500 mcm in diameter, while wounds of smaller diameter heal with no clinically perceptible scar.

The findings come from a small pilot trial that set out to determine the biopsy size limit at which healing occurs without a scar, as well as demonstrate the safety of performing multiple skin microbiopsies. “The broader purpose of this work is to contribute to the development of techniques for harvesting skin tissue with less morbidity than conventional methods,” lead study author Amanda H. Champlain, MD, said in an interview in advance of the annual conference of the American Society for Laser Medicine and Surgery. “The size threshold at which a full-thickness skin wound can heal without scarring had not been determined prior to this study.”

Dr. Champlain, a fellow at Massachusetts General Hospital and The Wellman Center for Photomedicine, both in Boston, and her colleagues designed a way to evaluate healing responses and safety after collecting skin microbiopsies of different sizes from preabdominoplasty skin. According to the study abstract, the concept “is based on fractional photothermolysis in which a multitude of small, full-thickness thermal burns are produced by a laser on the skin with rapid healing and no scarring.” Measures included the Patient and Observer Scar Assessment Scale (POSAS), donor site pain scale, subject satisfaction survey, and an assessment of side effects, clinical photographs, and histology.

Preliminary data are available for five subjects. The POSAS-Observer scale ranges from 5 to 50 while the POSAS-Patient scale ranges from 6 to 60. The researchers observed that average final POSAS-Observer scores were 5.6 for scars 200 mcm in diameter, 5.2 for scars 400 mcm in diameter, 7.0 for scars 500 mcm in diameter, 6.8 for scars 600 mcm in diameter, 8.2 for scars 800 mcm in diameter, 9.6 for scars 1 mm in diameter, and 13.2 for those 2 mm in diameter. Meanwhile, the average final POSAS-Subject scores were 6.0 for scars 200 mcm in diameter, 6.0 for scars 400 mcm in diameter, 6.6 for scars 500 mcm in diameter, 6.4 for those 600 mcm in diameter, 7.2 for scars 800 mcm in diameter, 7.4 for scars 1 mm in diameter, and 10.0 for those 2 mm in diameter.

The maximum donor site pain reported was 4 out of 10 in one subject. “The procedure was very well tolerated by the subjects,” Dr. Champlain said. “They healed quickly, and the majority were happy with the cosmetic outcome regardless of the diameter of the microbiopsy used.”

The most common side effects of the study procedures included mild bleeding, scabbing, redness, and hyper/hypopigmentation. “The majority of study participants strongly agree that the study procedure was safe, tolerable, and cosmetically sound,” she said.

Dr. Champlain does not have any disclosures, but she said that the study was funded by the Department of Defense.

[email protected]

DENVER – A clinically identifiable scar occurs after full-thickness skin wounds greater than 400-500 mcm in diameter, while wounds of smaller diameter heal with no clinically perceptible scar.

The findings come from a small pilot trial that set out to determine the biopsy size limit at which healing occurs without a scar, as well as demonstrate the safety of performing multiple skin microbiopsies. “The broader purpose of this work is to contribute to the development of techniques for harvesting skin tissue with less morbidity than conventional methods,” lead study author Amanda H. Champlain, MD, said in an interview in advance of the annual conference of the American Society for Laser Medicine and Surgery. “The size threshold at which a full-thickness skin wound can heal without scarring had not been determined prior to this study.”

Dr. Champlain, a fellow at Massachusetts General Hospital and The Wellman Center for Photomedicine, both in Boston, and her colleagues designed a way to evaluate healing responses and safety after collecting skin microbiopsies of different sizes from preabdominoplasty skin. According to the study abstract, the concept “is based on fractional photothermolysis in which a multitude of small, full-thickness thermal burns are produced by a laser on the skin with rapid healing and no scarring.” Measures included the Patient and Observer Scar Assessment Scale (POSAS), donor site pain scale, subject satisfaction survey, and an assessment of side effects, clinical photographs, and histology.

Preliminary data are available for five subjects. The POSAS-Observer scale ranges from 5 to 50 while the POSAS-Patient scale ranges from 6 to 60. The researchers observed that average final POSAS-Observer scores were 5.6 for scars 200 mcm in diameter, 5.2 for scars 400 mcm in diameter, 7.0 for scars 500 mcm in diameter, 6.8 for scars 600 mcm in diameter, 8.2 for scars 800 mcm in diameter, 9.6 for scars 1 mm in diameter, and 13.2 for those 2 mm in diameter. Meanwhile, the average final POSAS-Subject scores were 6.0 for scars 200 mcm in diameter, 6.0 for scars 400 mcm in diameter, 6.6 for scars 500 mcm in diameter, 6.4 for those 600 mcm in diameter, 7.2 for scars 800 mcm in diameter, 7.4 for scars 1 mm in diameter, and 10.0 for those 2 mm in diameter.

The maximum donor site pain reported was 4 out of 10 in one subject. “The procedure was very well tolerated by the subjects,” Dr. Champlain said. “They healed quickly, and the majority were happy with the cosmetic outcome regardless of the diameter of the microbiopsy used.”

The most common side effects of the study procedures included mild bleeding, scabbing, redness, and hyper/hypopigmentation. “The majority of study participants strongly agree that the study procedure was safe, tolerable, and cosmetically sound,” she said.

Dr. Champlain does not have any disclosures, but she said that the study was funded by the Department of Defense.

[email protected]

Dehydrated human umbilical cord allograft may have benefit over alginate wound dressings as a treatment for chronic, nonhealing diabetic foot ulcers (DFU), findings from an industry-funded, randomized controlled study suggest.

The findings “provide additional evidence of the safety and efficacy of dehydrated placental tissues,” wrote William Tettelbach, MD, and his colleagues. Their report is in International Wound Journal.

The burden of diabetic foot disease in the United States is immense. A 2014 study estimated that treatment of DFUs alone cost public and private insurers as much as $13 billion per year (Diabetes Care. 2014;37(3):651-8).

MiMedx, which funded the new study, has developed a product called EpiCord to protect the DFU wound site. The product’s website describes it as a “unique, thick membrane derived from umbilical cord” that’s “minimally manipulated, dehydrated, [and] non-viable” (www.mimedx.com/epicord). The study authors noted that “immunogenicity of placental tissue lends credence to its use as an allograft material for difficult-to-heal wounds.”

For the new study, which was conducted from 2016 to 2018 and led by Dr. Tettelbach, an infectious disease specialist who is now an employee of MiMedx, the researchers enlisted 155 adult patients with stubborn DFUs at 11 centers in the United States.

All the ulcers had 30% or less wound area reduction after 14 days of standard care. The majority of patients (81%) were male; 63% were obese, 43% were smokers, and 17% had a prior amputation.

The patients were randomly assigned to receive a weekly application of EpiCord (n = 101) or treatment with an alginate wound dressing (n = 54) in addition to standard care. The percentage of patients whose wounds healed completely by 12 weeks later was higher in the study group than in those who were treated with alginate dressings (70% vs. 48%, respectively; P = .0089), per an intent-to-treat analysis.

The researchers also focused purely on patients who had received adequate debridement (107/155 ulcers, 69%). Of those ulcers, 64/67 (96%), in the study group healed completely at 12 weeks, compared with 26/40 (65%) of the alginate group (P less than .0001.)

The researchers did not notice any adverse effects related to either dressing.

According to the study, the findings regarding EpiCord are comparable with a sister study of a similar product by the same company that was tested in diabetic lower-extremity ulcers. That study, of a product called EpiFix, was published in the same issue of the journal (Int Wound J. 2019 Feb;16[1]:19-29).

“A thicker and more durable allograft such as EpiCord may be a good choice for implantation into deeper wounds and in situations where suturing the allograft in place is desired,” the authors wrote of the EpiCord study.

MiMedx provided research funding to all of the authors.

SOURCE: Tettelbach W et al. Int Wound J. 2019;16(1):122-130. doi: 10.1111/iwj.12976.

Dehydrated human umbilical cord allograft may have benefit over alginate wound dressings as a treatment for chronic, nonhealing diabetic foot ulcers (DFU), findings from an industry-funded, randomized controlled study suggest.

The findings “provide additional evidence of the safety and efficacy of dehydrated placental tissues,” wrote William Tettelbach, MD, and his colleagues. Their report is in International Wound Journal.

The burden of diabetic foot disease in the United States is immense. A 2014 study estimated that treatment of DFUs alone cost public and private insurers as much as $13 billion per year (Diabetes Care. 2014;37(3):651-8).

MiMedx, which funded the new study, has developed a product called EpiCord to protect the DFU wound site. The product’s website describes it as a “unique, thick membrane derived from umbilical cord” that’s “minimally manipulated, dehydrated, [and] non-viable” (www.mimedx.com/epicord). The study authors noted that “immunogenicity of placental tissue lends credence to its use as an allograft material for difficult-to-heal wounds.”

For the new study, which was conducted from 2016 to 2018 and led by Dr. Tettelbach, an infectious disease specialist who is now an employee of MiMedx, the researchers enlisted 155 adult patients with stubborn DFUs at 11 centers in the United States.

All the ulcers had 30% or less wound area reduction after 14 days of standard care. The majority of patients (81%) were male; 63% were obese, 43% were smokers, and 17% had a prior amputation.

The patients were randomly assigned to receive a weekly application of EpiCord (n = 101) or treatment with an alginate wound dressing (n = 54) in addition to standard care. The percentage of patients whose wounds healed completely by 12 weeks later was higher in the study group than in those who were treated with alginate dressings (70% vs. 48%, respectively; P = .0089), per an intent-to-treat analysis.

The researchers also focused purely on patients who had received adequate debridement (107/155 ulcers, 69%). Of those ulcers, 64/67 (96%), in the study group healed completely at 12 weeks, compared with 26/40 (65%) of the alginate group (P less than .0001.)

The researchers did not notice any adverse effects related to either dressing.

According to the study, the findings regarding EpiCord are comparable with a sister study of a similar product by the same company that was tested in diabetic lower-extremity ulcers. That study, of a product called EpiFix, was published in the same issue of the journal (Int Wound J. 2019 Feb;16[1]:19-29).

“A thicker and more durable allograft such as EpiCord may be a good choice for implantation into deeper wounds and in situations where suturing the allograft in place is desired,” the authors wrote of the EpiCord study.

MiMedx provided research funding to all of the authors.

SOURCE: Tettelbach W et al. Int Wound J. 2019;16(1):122-130. doi: 10.1111/iwj.12976.

Dehydrated human umbilical cord allograft may have benefit over alginate wound dressings as a treatment for chronic, nonhealing diabetic foot ulcers (DFU), findings from an industry-funded, randomized controlled study suggest.

The findings “provide additional evidence of the safety and efficacy of dehydrated placental tissues,” wrote William Tettelbach, MD, and his colleagues. Their report is in International Wound Journal.

The burden of diabetic foot disease in the United States is immense. A 2014 study estimated that treatment of DFUs alone cost public and private insurers as much as $13 billion per year (Diabetes Care. 2014;37(3):651-8).

MiMedx, which funded the new study, has developed a product called EpiCord to protect the DFU wound site. The product’s website describes it as a “unique, thick membrane derived from umbilical cord” that’s “minimally manipulated, dehydrated, [and] non-viable” (www.mimedx.com/epicord). The study authors noted that “immunogenicity of placental tissue lends credence to its use as an allograft material for difficult-to-heal wounds.”

For the new study, which was conducted from 2016 to 2018 and led by Dr. Tettelbach, an infectious disease specialist who is now an employee of MiMedx, the researchers enlisted 155 adult patients with stubborn DFUs at 11 centers in the United States.

All the ulcers had 30% or less wound area reduction after 14 days of standard care. The majority of patients (81%) were male; 63% were obese, 43% were smokers, and 17% had a prior amputation.

The patients were randomly assigned to receive a weekly application of EpiCord (n = 101) or treatment with an alginate wound dressing (n = 54) in addition to standard care. The percentage of patients whose wounds healed completely by 12 weeks later was higher in the study group than in those who were treated with alginate dressings (70% vs. 48%, respectively; P = .0089), per an intent-to-treat analysis.

The researchers also focused purely on patients who had received adequate debridement (107/155 ulcers, 69%). Of those ulcers, 64/67 (96%), in the study group healed completely at 12 weeks, compared with 26/40 (65%) of the alginate group (P less than .0001.)

The researchers did not notice any adverse effects related to either dressing.

According to the study, the findings regarding EpiCord are comparable with a sister study of a similar product by the same company that was tested in diabetic lower-extremity ulcers. That study, of a product called EpiFix, was published in the same issue of the journal (Int Wound J. 2019 Feb;16[1]:19-29).

“A thicker and more durable allograft such as EpiCord may be a good choice for implantation into deeper wounds and in situations where suturing the allograft in place is desired,” the authors wrote of the EpiCord study.

MiMedx provided research funding to all of the authors.

SOURCE: Tettelbach W et al. Int Wound J. 2019;16(1):122-130. doi: 10.1111/iwj.12976.

Incidence and Characteristics

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

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

Injury Clinical Presentation

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

Management

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

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

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

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

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

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

Avoidance and Prevention

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

Incidence and Characteristics

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

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

Injury Clinical Presentation

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

Management

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

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

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

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

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

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

Avoidance and Prevention

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

Incidence and Characteristics

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

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

Injury Clinical Presentation

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

Management

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

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

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

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

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

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

Avoidance and Prevention

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

The Diagnosis: Bullous/Hemorrhagic Lichen Sclerosus et Atrophicus

Histopathologic examination revealed hyperkeratosis of the stratum corneum and thinning of the epidermis (Figure). Subepidermal edema and hemorrhage in the papillary dermis were seen. There were dilated vessels beneath the edema in the reticular dermis, as well as perivascular, perifollicular, and interstitial lymphocytic inflammation. No cytologic atypia characteristic of squamous cell carcinoma (SCC) and angiosarcoma or large lymphatic channels characteristic of lymphangioma were noted. Based on clinicopathologic correlation, the diagnosis of the bullous/hemorrhagic form of lichen sclerosus et atrophicus (LS&A) was made. The patient was treated with high-potency topical steroids with notable symptomatic improvement and rapid resolution of the hemorrhagic lesion.

Lichen sclerosus et atrophicus is a chronic inflammatory condition with a predilection for the anogenital region, though rare cases of extragenital involvement have been reported. It is seen in both sexes and across all age groups, with notably higher prevalence in females in the fifth and sixth decades of life.^1,2 Lichen sclerosus et atrophicus can be difficult to diagnose, as these patients may present to a variety of specialists, may be embarrassed by the condition and reluctant for full evaluation, or may have asymptomatic lesions.^2,3 Rare cases of isolated extragenital involvement and hemorrhagic or bullous lesions further complicate the diagnosis.^1,2 Despite these difficulties, diagnosis is essential, as there is potential for cosmetically and functionally detrimental scarring as well as atrophy and development of overlying malignancies. Lichen sclerosus et atrophicus is not curable and rarely remits spontaneously, but appropriate treatment strategies can help control the symptoms of the condition as well as its most devastating sequelae.³

For females, classic LS&A is most common in theprepubertal, perimenopausal, or postmenopausal periods, commonly involving the vulva or perineum. Symptoms include pruritus, burning sensation, dysuria, dyspareunia, and labial stenosis, among others. For males, most cases involve the glans penis in prepubertal boys or middleaged men, and symptoms include pruritus, new-onset phimosis, decreased sensation, painful erections, dysuria, and urinary obstruction.^1-3 An estimated 97% of patients have some form of genital involvement with only 2.5% showing isolated extragenital involvement, though the latter may be underdiagnosed, as this area is more likely to be asymptomatic.^3-6 Extragenital LS&A most often involves the neck and shoulders. The classic appearance of LS&A includes shiny, white-red macules and papules that ultimately coalesce into atrophic plaques and can be accompanied by fissuring or scarring, especially in the genital area.² There is an increased risk for SCC associated with genital LS&A.¹

Bullous/hemorrhagic LS&A has been described as a rare phenotype. One case report cited an increased incidence of this subtype in patients with exclusively extragenital lesions, and the authors considered blister formation to be a characteristic feature of extragenital LS&A. The pathogenesis of blister formation and hemorrhage in LS&A is not completely understood, but trauma is thought to play a role due to decreased stress tolerance from atrophic skin.⁴ Furthermore, distortion of blood vessel architecture in LS&A has been described with loss of the capillary network and enlargement of vessels along  the dermoepidermal junction, which also could play a role in hemorrhage. Differential diagnosis of the bullous/hemorrhagic type of LS&A includes bullous pemphigoid, bullous lichen planus, or bullous scleroderma.⁷ In our more exophytic hemorrhagic case, malignancies such as SCC or angiosarcoma also had to be considered. Unlike genital LS&A, extragenital LS&A including the bullous/hemorrhagic variant has not been linked to an increasedrisk for malignancy.^1,5

The mainstay of treatment of all forms of LS&A is high-potency topical steroids, but topical retinoids, tacrolimus, and UVA phototherapy also have been used. Bullous/hemorrhagic lesions often resolve quickly with topical steroids, leaving behind more classic plaques in their place, which can be more refractory to treatment.^5,7

The Diagnosis: Bullous/Hemorrhagic Lichen Sclerosus et Atrophicus

Histopathologic examination revealed hyperkeratosis of the stratum corneum and thinning of the epidermis (Figure). Subepidermal edema and hemorrhage in the papillary dermis were seen. There were dilated vessels beneath the edema in the reticular dermis, as well as perivascular, perifollicular, and interstitial lymphocytic inflammation. No cytologic atypia characteristic of squamous cell carcinoma (SCC) and angiosarcoma or large lymphatic channels characteristic of lymphangioma were noted. Based on clinicopathologic correlation, the diagnosis of the bullous/hemorrhagic form of lichen sclerosus et atrophicus (LS&A) was made. The patient was treated with high-potency topical steroids with notable symptomatic improvement and rapid resolution of the hemorrhagic lesion.

Lichen sclerosus et atrophicus is a chronic inflammatory condition with a predilection for the anogenital region, though rare cases of extragenital involvement have been reported. It is seen in both sexes and across all age groups, with notably higher prevalence in females in the fifth and sixth decades of life.^1,2 Lichen sclerosus et atrophicus can be difficult to diagnose, as these patients may present to a variety of specialists, may be embarrassed by the condition and reluctant for full evaluation, or may have asymptomatic lesions.^2,3 Rare cases of isolated extragenital involvement and hemorrhagic or bullous lesions further complicate the diagnosis.^1,2 Despite these difficulties, diagnosis is essential, as there is potential for cosmetically and functionally detrimental scarring as well as atrophy and development of overlying malignancies. Lichen sclerosus et atrophicus is not curable and rarely remits spontaneously, but appropriate treatment strategies can help control the symptoms of the condition as well as its most devastating sequelae.³

For females, classic LS&A is most common in theprepubertal, perimenopausal, or postmenopausal periods, commonly involving the vulva or perineum. Symptoms include pruritus, burning sensation, dysuria, dyspareunia, and labial stenosis, among others. For males, most cases involve the glans penis in prepubertal boys or middleaged men, and symptoms include pruritus, new-onset phimosis, decreased sensation, painful erections, dysuria, and urinary obstruction.^1-3 An estimated 97% of patients have some form of genital involvement with only 2.5% showing isolated extragenital involvement, though the latter may be underdiagnosed, as this area is more likely to be asymptomatic.^3-6 Extragenital LS&A most often involves the neck and shoulders. The classic appearance of LS&A includes shiny, white-red macules and papules that ultimately coalesce into atrophic plaques and can be accompanied by fissuring or scarring, especially in the genital area.² There is an increased risk for SCC associated with genital LS&A.¹

Bullous/hemorrhagic LS&A has been described as a rare phenotype. One case report cited an increased incidence of this subtype in patients with exclusively extragenital lesions, and the authors considered blister formation to be a characteristic feature of extragenital LS&A. The pathogenesis of blister formation and hemorrhage in LS&A is not completely understood, but trauma is thought to play a role due to decreased stress tolerance from atrophic skin.⁴ Furthermore, distortion of blood vessel architecture in LS&A has been described with loss of the capillary network and enlargement of vessels along  the dermoepidermal junction, which also could play a role in hemorrhage. Differential diagnosis of the bullous/hemorrhagic type of LS&A includes bullous pemphigoid, bullous lichen planus, or bullous scleroderma.⁷ In our more exophytic hemorrhagic case, malignancies such as SCC or angiosarcoma also had to be considered. Unlike genital LS&A, extragenital LS&A including the bullous/hemorrhagic variant has not been linked to an increasedrisk for malignancy.^1,5

The mainstay of treatment of all forms of LS&A is high-potency topical steroids, but topical retinoids, tacrolimus, and UVA phototherapy also have been used. Bullous/hemorrhagic lesions often resolve quickly with topical steroids, leaving behind more classic plaques in their place, which can be more refractory to treatment.^5,7

The Diagnosis: Bullous/Hemorrhagic Lichen Sclerosus et Atrophicus

Histopathologic examination revealed hyperkeratosis of the stratum corneum and thinning of the epidermis (Figure). Subepidermal edema and hemorrhage in the papillary dermis were seen. There were dilated vessels beneath the edema in the reticular dermis, as well as perivascular, perifollicular, and interstitial lymphocytic inflammation. No cytologic atypia characteristic of squamous cell carcinoma (SCC) and angiosarcoma or large lymphatic channels characteristic of lymphangioma were noted. Based on clinicopathologic correlation, the diagnosis of the bullous/hemorrhagic form of lichen sclerosus et atrophicus (LS&A) was made. The patient was treated with high-potency topical steroids with notable symptomatic improvement and rapid resolution of the hemorrhagic lesion.

Lichen sclerosus et atrophicus is a chronic inflammatory condition with a predilection for the anogenital region, though rare cases of extragenital involvement have been reported. It is seen in both sexes and across all age groups, with notably higher prevalence in females in the fifth and sixth decades of life.^1,2 Lichen sclerosus et atrophicus can be difficult to diagnose, as these patients may present to a variety of specialists, may be embarrassed by the condition and reluctant for full evaluation, or may have asymptomatic lesions.^2,3 Rare cases of isolated extragenital involvement and hemorrhagic or bullous lesions further complicate the diagnosis.^1,2 Despite these difficulties, diagnosis is essential, as there is potential for cosmetically and functionally detrimental scarring as well as atrophy and development of overlying malignancies. Lichen sclerosus et atrophicus is not curable and rarely remits spontaneously, but appropriate treatment strategies can help control the symptoms of the condition as well as its most devastating sequelae.³

For females, classic LS&A is most common in theprepubertal, perimenopausal, or postmenopausal periods, commonly involving the vulva or perineum. Symptoms include pruritus, burning sensation, dysuria, dyspareunia, and labial stenosis, among others. For males, most cases involve the glans penis in prepubertal boys or middleaged men, and symptoms include pruritus, new-onset phimosis, decreased sensation, painful erections, dysuria, and urinary obstruction.^1-3 An estimated 97% of patients have some form of genital involvement with only 2.5% showing isolated extragenital involvement, though the latter may be underdiagnosed, as this area is more likely to be asymptomatic.^3-6 Extragenital LS&A most often involves the neck and shoulders. The classic appearance of LS&A includes shiny, white-red macules and papules that ultimately coalesce into atrophic plaques and can be accompanied by fissuring or scarring, especially in the genital area.² There is an increased risk for SCC associated with genital LS&A.¹

Bullous/hemorrhagic LS&A has been described as a rare phenotype. One case report cited an increased incidence of this subtype in patients with exclusively extragenital lesions, and the authors considered blister formation to be a characteristic feature of extragenital LS&A. The pathogenesis of blister formation and hemorrhage in LS&A is not completely understood, but trauma is thought to play a role due to decreased stress tolerance from atrophic skin.⁴ Furthermore, distortion of blood vessel architecture in LS&A has been described with loss of the capillary network and enlargement of vessels along  the dermoepidermal junction, which also could play a role in hemorrhage. Differential diagnosis of the bullous/hemorrhagic type of LS&A includes bullous pemphigoid, bullous lichen planus, or bullous scleroderma.⁷ In our more exophytic hemorrhagic case, malignancies such as SCC or angiosarcoma also had to be considered. Unlike genital LS&A, extragenital LS&A including the bullous/hemorrhagic variant has not been linked to an increasedrisk for malignancy.^1,5

The mainstay of treatment of all forms of LS&A is high-potency topical steroids, but topical retinoids, tacrolimus, and UVA phototherapy also have been used. Bullous/hemorrhagic lesions often resolve quickly with topical steroids, leaving behind more classic plaques in their place, which can be more refractory to treatment.^5,7

Limb amputation is a major life-changing event that markedly affects a patient’s quality of life as well as his/her ability to participate in activities of daily living. The most prevalent causes for amputation include vascular diseases, diabetes mellitus, trauma, and cancer, respectively.^1,2 For amputees, maintaining prosthetic use is a major physical and psychological undertaking that benefits from a multidisciplinary team approach. Although individuals with lower limb amputations are disproportionately impacted by skin disease due to the increased mechanical forces exerted over the lower limbs, patients with upper limb amputations also develop dermatologic conditions secondary to wearing prostheses.

Approximately 185,000 amputations occur each year in the United States.³ Although amputations resulting from peripheral vascular disease or diabetes mellitus tend to occur in older individuals, amputations in younger patients usually occur from trauma.² The US military has experienced increasing numbers of amputations from trauma due to the ongoing combat operations in the Middle East. Although improvements in body armor and tactical combat casualty care have reduced the number of preventable deaths, the number of casualties surviving with extremity injuries requiring amputation has increased.^4,5 As of October 2017, 1705 US servicemembers underwent major limb amputations, with 1914 lower limb amputations and 302 upper limb amputations. These amputations mainly impacted men aged 21 to 29 years, but female servicemembers also were affected, and a small group of servicemembers had multiple amputations.⁶

One of the most common medical problems that amputees face during long-term care is skin disease, with approximately 75% of amputees using a lower limb prosthesis experiencing skin problems. In general, amputees experience nearly 65% more dermatologic concerns than the general population.⁷ In one study of 97 individuals with transfemoral amputations, some of the most common issues associated with socket prosthetics included heat and sweating in the prosthetic socket (72%) as well as sores and skin irritation from the socket (62%).⁸ Given the high incidence of skin disease on residual limbs, dermatologists are uniquely positioned to keep the amputee in his/her prosthesis and prevent prosthetic abandonment.

Complications Following Amputation

Although US military servicemembers who undergo amputations receive the very best prosthetic devices and rehabilitation resources, they still experience prosthesis abandonment.⁹ Despite the fact that prosthetic limbs and prosthesis technology have substantially improved over the last 2 decades, one study indicated that the high frequency of problems affecting tissue viability at residual limbs is due to the age-old problem of prosthetic fit.¹⁰ In patients with the most advanced prostheses, poor fit still results in mechanical damage to the skin, as the residual limb is exposed to unequal and shearing forces across the amputation site as well as high pressures that cause a vaso-occlusive effect.^11,12 Issues with poor fit are especially important for more active patients, as they normally want to immediately return to their vigorous preinjury lifestyles. In these patients, even a properly fitting prosthetic may not be able to overcome the fact that the residual limb skin is not well suited for the mechanical forces generated by the prosthesis and the humid environment of the socket.^1,13 Another complicating factor is the dynamic nature of the residual limb. Muscle atrophy, changes in gait, and weight gain or loss can lead to an ill-fitting prosthetic and subsequent skin breakdown.

There are many case reports and review articles describing the skin problems in amputees.^1,14-17 The Table summarizes these conditions and outlines treatment options for each.^15,18-20

Most skin diseases on residual limbs are the result of mechanical skin breakdown, inflammation, infection, or combinations of these processes. Overall, amputees with diabetes mellitus and peripheral vascular disease tend to have skin disease related to poor perfusion, whereas amputees who are active and healthy tend to have conditions related to mechanical stress.^{7,13,14,17,21,22} Bui et al¹⁷ reported ulcers, abscesses, and blisters as the most common skin conditions that occur at the site of residual limbs; however, other less common dermatologic disorders such as skin malignancies, verrucous hyperplasia and carcinoma, granulomatous cutaneous lesions, acroangiodermatitis, and bullous pemphigoid also are seen.^23-26 Buikema and Meyerle¹⁵ hypothesize that these conditions, as well as the more common skin diseases, are partly from the amputation disrupting blood and lymphatic flow in the residual limb, which causes the site to act as an immunocompromised district that induces dysregulation of neuroimmune regulators.

It is important to note that skin disease on residual limbs is not just an acute problem. Long-term follow-up of 247 traumatic amputees from the Vietnam War showed that almost half of prosthesis users (48.2%) reported a skin problem in the preceding year, more than 38 years after the amputation. Additionally, one-quarter of these individuals experienced skin problems approximately 50% of the time, which unfortunately led to limited use or total abandonment of the prosthesis for the preceding year in 56% of the veterans surveyed.²¹

Other complications following amputation indirectly lead to skin problems. Heterotopic ossification, or the formation of bone at extraskeletal sites, has been observed in up to 65% of military amputees from recent operations in Iraq and Afghanistan.^27,28 If symptomatic, heterotopic ossification can lead to poor prosthetic fit and subsequent skin breakdown. As a result, it has been reported that up to 40% of combat-related lower extremity amputations may require excision of heterotopic ossificiation.²⁹

Amputation also can result in psychologic concerns that indirectly affect skin health. A systematic review by Mckechnie and John³⁰ suggested that despite heterogeneity between studies, even using the lowest figures demonstrated the significance anxiety and depression play in the lives of traumatic amputees. If left untreated, these mental health issues can lead to poor residual limb hygiene and prosthetic maintenance due to reductions in the patient’s energy and motivation. Studies have shown that proper hygiene of residual limbs and silicone liners reduces associated skin problems.^19,31

Role of the Dermatologist

Routine care and conservative management of amputee skin problems often are accomplished by prosthetists, primary care physicians, nurses, and physical therapists. In one study, more than 80% of the most common skin problems affecting amputees could be attributed to the prosthesis itself, which highlights the importance of the continued involvement of the prosthetist beyond the initial fitting period.¹³ However, when a skin problem becomes refractory to conservative management, referral to a dermatologist is prudent; therefore, the dermatologist is an integral member of the multidisciplinary team that provides care for amputees.

The dermatologist often is best positioned to diagnose skin diseases that result from wearing prostheses and is well versed in treatments for short-term and long-term management of skin disease on residual limbs. The dermatologist also can offer prophylactic treatments to decrease sweating and hair growth to prevent potential infections and subsequent skin breakdown. Additionally, proper education on self-care has been shown to decrease the amount of skin problems and increase functional status and quality of life for amputees.^32,33 Dermatologists can assist with the patient education process as well as refer amputees to a useful resource from the Amputee Coalition website (www.amputee-coalition.org) to provide specific patient education on how to maintain skin on the residual limb to prevent skin disease.

Current Treatments and Future Directions

Skin disorders affecting residual limbs usually are conditions that dermatologists commonly encounter and are comfortable managing in general practice. Additionally, dermatologists routinely treat hyperhidrosis and conduct laser hair removal, both of which are effective prophylactic adjuncts for amputee skin health. There are a few treatments for reducing residual limb hyperhidrosis that are particularly useful. Although first-line treatment of residual limb hyperhidrosis often is topical aluminum chloride, it requires frequent application and often causes considerable skin irritation when applied to residual limbs. Alternatively, intradermal botulinum toxin has been shown to successfully reduce sweat production in individuals with residual limb hyperhidrosis and is well tolerated.³⁴ A 2017 case report discussed the use of microwave thermal ablation of eccrine coils using a noninvasive 3-step hyperhidrosis treatment system on a bilateral below-the-knee amputee. The authors reported the patient tolerated the procedure well with decreased dermatitis and folliculitis, leading to his ability to wear a prosthetic for longer periods of time.³⁵

Ablative fractional resurfacing with a CO₂ laser is another key treatment modality central to amputees, more specifically to traumatic amputees. A CO₂ laser can decrease skin tension and increase skin mobility associated with traumatic scars as well as decrease skin vulnerability to biofilms present in chronic wounds on residual limbs. It is believed that the pattern of injury caused by ablative fractional lasers disrupts biofilms and stimulates growth factor secretion and collagen remodeling through the concept of photomicrodebridement.³⁶ The ablative fractional resurfacing approach to scar therapy and chronic wound debridement can result in less skin injury, allowing the amputee to continue rehabilitation and return more quickly to prosthetic use.³⁷

One interesting area of research in amputee care involves the study of novel ways to increase the skin’s ability to adapt to mechanical stress and load bearing and accelerate wound healing on the residual limb. Multiple studies have identified collagen fibril enlargement as an important component of skin adaptation, and biomolecules such as decorin may enhance this process.^38-40 The concept of increasing these biomolecules at the correct time during wound healing to strengthen the residual limb tissue currently is being studied.³⁹

Another encouraging area of research is the involvement of fibroblasts in cutaneous wound healing and their role in determining the phenotype of residual limb skin in amputees. The clinical application of autologous fibroblasts is approved by the US Food and Drug Administration for cosmetic use as a filler material and currently is under research for other applications, such as skin regeneration after surgery or manipulating skin characteristics to enhance the durability of residual limbs.⁴¹

Future preventative care of amputee skin may rely on tracking residual limb health before severe tissue injury occurs. For instance, Rink et al⁴² described an approach to monitor residual limb health using noninvasive imaging (eg, hyperspectral imaging, laser speckle imaging) and noninvasive probes that measure oxygenation, perfusion, skin barrier function, and skin hydration to the residual limb. Although these limb surveillance sensors would be employed by prosthetists, the dermatologist, as part of the multispecialty team, also could leverage the data for diagnosis and treatment considerations.

Final Thoughts

The dermatologist is an important member of the multidisciplinary team involved in the care of amputees. Skin disease is prevalent in amputees throughout their lives and often leads to abandonment of prostheses. Although current therapies and preventative treatments are for the most part successful, future research involving advanced technology to monitor skin health, increasing residual limb skin durability at the molecular level, and targeted laser therapies are promising. Through engagement and effective collaboration with the entire multidisciplinary team, dermatologists will have a considerable impact on amputee skin health.

Limb amputation is a major life-changing event that markedly affects a patient’s quality of life as well as his/her ability to participate in activities of daily living. The most prevalent causes for amputation include vascular diseases, diabetes mellitus, trauma, and cancer, respectively.^1,2 For amputees, maintaining prosthetic use is a major physical and psychological undertaking that benefits from a multidisciplinary team approach. Although individuals with lower limb amputations are disproportionately impacted by skin disease due to the increased mechanical forces exerted over the lower limbs, patients with upper limb amputations also develop dermatologic conditions secondary to wearing prostheses.

Approximately 185,000 amputations occur each year in the United States.³ Although amputations resulting from peripheral vascular disease or diabetes mellitus tend to occur in older individuals, amputations in younger patients usually occur from trauma.² The US military has experienced increasing numbers of amputations from trauma due to the ongoing combat operations in the Middle East. Although improvements in body armor and tactical combat casualty care have reduced the number of preventable deaths, the number of casualties surviving with extremity injuries requiring amputation has increased.^4,5 As of October 2017, 1705 US servicemembers underwent major limb amputations, with 1914 lower limb amputations and 302 upper limb amputations. These amputations mainly impacted men aged 21 to 29 years, but female servicemembers also were affected, and a small group of servicemembers had multiple amputations.⁶

One of the most common medical problems that amputees face during long-term care is skin disease, with approximately 75% of amputees using a lower limb prosthesis experiencing skin problems. In general, amputees experience nearly 65% more dermatologic concerns than the general population.⁷ In one study of 97 individuals with transfemoral amputations, some of the most common issues associated with socket prosthetics included heat and sweating in the prosthetic socket (72%) as well as sores and skin irritation from the socket (62%).⁸ Given the high incidence of skin disease on residual limbs, dermatologists are uniquely positioned to keep the amputee in his/her prosthesis and prevent prosthetic abandonment.

Complications Following Amputation

Although US military servicemembers who undergo amputations receive the very best prosthetic devices and rehabilitation resources, they still experience prosthesis abandonment.⁹ Despite the fact that prosthetic limbs and prosthesis technology have substantially improved over the last 2 decades, one study indicated that the high frequency of problems affecting tissue viability at residual limbs is due to the age-old problem of prosthetic fit.¹⁰ In patients with the most advanced prostheses, poor fit still results in mechanical damage to the skin, as the residual limb is exposed to unequal and shearing forces across the amputation site as well as high pressures that cause a vaso-occlusive effect.^11,12 Issues with poor fit are especially important for more active patients, as they normally want to immediately return to their vigorous preinjury lifestyles. In these patients, even a properly fitting prosthetic may not be able to overcome the fact that the residual limb skin is not well suited for the mechanical forces generated by the prosthesis and the humid environment of the socket.^1,13 Another complicating factor is the dynamic nature of the residual limb. Muscle atrophy, changes in gait, and weight gain or loss can lead to an ill-fitting prosthetic and subsequent skin breakdown.

There are many case reports and review articles describing the skin problems in amputees.^1,14-17 The Table summarizes these conditions and outlines treatment options for each.^15,18-20

Most skin diseases on residual limbs are the result of mechanical skin breakdown, inflammation, infection, or combinations of these processes. Overall, amputees with diabetes mellitus and peripheral vascular disease tend to have skin disease related to poor perfusion, whereas amputees who are active and healthy tend to have conditions related to mechanical stress.^{7,13,14,17,21,22} Bui et al¹⁷ reported ulcers, abscesses, and blisters as the most common skin conditions that occur at the site of residual limbs; however, other less common dermatologic disorders such as skin malignancies, verrucous hyperplasia and carcinoma, granulomatous cutaneous lesions, acroangiodermatitis, and bullous pemphigoid also are seen.^23-26 Buikema and Meyerle¹⁵ hypothesize that these conditions, as well as the more common skin diseases, are partly from the amputation disrupting blood and lymphatic flow in the residual limb, which causes the site to act as an immunocompromised district that induces dysregulation of neuroimmune regulators.

It is important to note that skin disease on residual limbs is not just an acute problem. Long-term follow-up of 247 traumatic amputees from the Vietnam War showed that almost half of prosthesis users (48.2%) reported a skin problem in the preceding year, more than 38 years after the amputation. Additionally, one-quarter of these individuals experienced skin problems approximately 50% of the time, which unfortunately led to limited use or total abandonment of the prosthesis for the preceding year in 56% of the veterans surveyed.²¹

Other complications following amputation indirectly lead to skin problems. Heterotopic ossification, or the formation of bone at extraskeletal sites, has been observed in up to 65% of military amputees from recent operations in Iraq and Afghanistan.^27,28 If symptomatic, heterotopic ossification can lead to poor prosthetic fit and subsequent skin breakdown. As a result, it has been reported that up to 40% of combat-related lower extremity amputations may require excision of heterotopic ossificiation.²⁹

Amputation also can result in psychologic concerns that indirectly affect skin health. A systematic review by Mckechnie and John³⁰ suggested that despite heterogeneity between studies, even using the lowest figures demonstrated the significance anxiety and depression play in the lives of traumatic amputees. If left untreated, these mental health issues can lead to poor residual limb hygiene and prosthetic maintenance due to reductions in the patient’s energy and motivation. Studies have shown that proper hygiene of residual limbs and silicone liners reduces associated skin problems.^19,31

Role of the Dermatologist

Routine care and conservative management of amputee skin problems often are accomplished by prosthetists, primary care physicians, nurses, and physical therapists. In one study, more than 80% of the most common skin problems affecting amputees could be attributed to the prosthesis itself, which highlights the importance of the continued involvement of the prosthetist beyond the initial fitting period.¹³ However, when a skin problem becomes refractory to conservative management, referral to a dermatologist is prudent; therefore, the dermatologist is an integral member of the multidisciplinary team that provides care for amputees.

The dermatologist often is best positioned to diagnose skin diseases that result from wearing prostheses and is well versed in treatments for short-term and long-term management of skin disease on residual limbs. The dermatologist also can offer prophylactic treatments to decrease sweating and hair growth to prevent potential infections and subsequent skin breakdown. Additionally, proper education on self-care has been shown to decrease the amount of skin problems and increase functional status and quality of life for amputees.^32,33 Dermatologists can assist with the patient education process as well as refer amputees to a useful resource from the Amputee Coalition website (www.amputee-coalition.org) to provide specific patient education on how to maintain skin on the residual limb to prevent skin disease.

Current Treatments and Future Directions

Skin disorders affecting residual limbs usually are conditions that dermatologists commonly encounter and are comfortable managing in general practice. Additionally, dermatologists routinely treat hyperhidrosis and conduct laser hair removal, both of which are effective prophylactic adjuncts for amputee skin health. There are a few treatments for reducing residual limb hyperhidrosis that are particularly useful. Although first-line treatment of residual limb hyperhidrosis often is topical aluminum chloride, it requires frequent application and often causes considerable skin irritation when applied to residual limbs. Alternatively, intradermal botulinum toxin has been shown to successfully reduce sweat production in individuals with residual limb hyperhidrosis and is well tolerated.³⁴ A 2017 case report discussed the use of microwave thermal ablation of eccrine coils using a noninvasive 3-step hyperhidrosis treatment system on a bilateral below-the-knee amputee. The authors reported the patient tolerated the procedure well with decreased dermatitis and folliculitis, leading to his ability to wear a prosthetic for longer periods of time.³⁵

Ablative fractional resurfacing with a CO₂ laser is another key treatment modality central to amputees, more specifically to traumatic amputees. A CO₂ laser can decrease skin tension and increase skin mobility associated with traumatic scars as well as decrease skin vulnerability to biofilms present in chronic wounds on residual limbs. It is believed that the pattern of injury caused by ablative fractional lasers disrupts biofilms and stimulates growth factor secretion and collagen remodeling through the concept of photomicrodebridement.³⁶ The ablative fractional resurfacing approach to scar therapy and chronic wound debridement can result in less skin injury, allowing the amputee to continue rehabilitation and return more quickly to prosthetic use.³⁷

One interesting area of research in amputee care involves the study of novel ways to increase the skin’s ability to adapt to mechanical stress and load bearing and accelerate wound healing on the residual limb. Multiple studies have identified collagen fibril enlargement as an important component of skin adaptation, and biomolecules such as decorin may enhance this process.^38-40 The concept of increasing these biomolecules at the correct time during wound healing to strengthen the residual limb tissue currently is being studied.³⁹

Another encouraging area of research is the involvement of fibroblasts in cutaneous wound healing and their role in determining the phenotype of residual limb skin in amputees. The clinical application of autologous fibroblasts is approved by the US Food and Drug Administration for cosmetic use as a filler material and currently is under research for other applications, such as skin regeneration after surgery or manipulating skin characteristics to enhance the durability of residual limbs.⁴¹

Future preventative care of amputee skin may rely on tracking residual limb health before severe tissue injury occurs. For instance, Rink et al⁴² described an approach to monitor residual limb health using noninvasive imaging (eg, hyperspectral imaging, laser speckle imaging) and noninvasive probes that measure oxygenation, perfusion, skin barrier function, and skin hydration to the residual limb. Although these limb surveillance sensors would be employed by prosthetists, the dermatologist, as part of the multispecialty team, also could leverage the data for diagnosis and treatment considerations.

Final Thoughts

The dermatologist is an important member of the multidisciplinary team involved in the care of amputees. Skin disease is prevalent in amputees throughout their lives and often leads to abandonment of prostheses. Although current therapies and preventative treatments are for the most part successful, future research involving advanced technology to monitor skin health, increasing residual limb skin durability at the molecular level, and targeted laser therapies are promising. Through engagement and effective collaboration with the entire multidisciplinary team, dermatologists will have a considerable impact on amputee skin health.

Limb amputation is a major life-changing event that markedly affects a patient’s quality of life as well as his/her ability to participate in activities of daily living. The most prevalent causes for amputation include vascular diseases, diabetes mellitus, trauma, and cancer, respectively.^1,2 For amputees, maintaining prosthetic use is a major physical and psychological undertaking that benefits from a multidisciplinary team approach. Although individuals with lower limb amputations are disproportionately impacted by skin disease due to the increased mechanical forces exerted over the lower limbs, patients with upper limb amputations also develop dermatologic conditions secondary to wearing prostheses.

Approximately 185,000 amputations occur each year in the United States.³ Although amputations resulting from peripheral vascular disease or diabetes mellitus tend to occur in older individuals, amputations in younger patients usually occur from trauma.² The US military has experienced increasing numbers of amputations from trauma due to the ongoing combat operations in the Middle East. Although improvements in body armor and tactical combat casualty care have reduced the number of preventable deaths, the number of casualties surviving with extremity injuries requiring amputation has increased.^4,5 As of October 2017, 1705 US servicemembers underwent major limb amputations, with 1914 lower limb amputations and 302 upper limb amputations. These amputations mainly impacted men aged 21 to 29 years, but female servicemembers also were affected, and a small group of servicemembers had multiple amputations.⁶

One of the most common medical problems that amputees face during long-term care is skin disease, with approximately 75% of amputees using a lower limb prosthesis experiencing skin problems. In general, amputees experience nearly 65% more dermatologic concerns than the general population.⁷ In one study of 97 individuals with transfemoral amputations, some of the most common issues associated with socket prosthetics included heat and sweating in the prosthetic socket (72%) as well as sores and skin irritation from the socket (62%).⁸ Given the high incidence of skin disease on residual limbs, dermatologists are uniquely positioned to keep the amputee in his/her prosthesis and prevent prosthetic abandonment.

Complications Following Amputation

Although US military servicemembers who undergo amputations receive the very best prosthetic devices and rehabilitation resources, they still experience prosthesis abandonment.⁹ Despite the fact that prosthetic limbs and prosthesis technology have substantially improved over the last 2 decades, one study indicated that the high frequency of problems affecting tissue viability at residual limbs is due to the age-old problem of prosthetic fit.¹⁰ In patients with the most advanced prostheses, poor fit still results in mechanical damage to the skin, as the residual limb is exposed to unequal and shearing forces across the amputation site as well as high pressures that cause a vaso-occlusive effect.^11,12 Issues with poor fit are especially important for more active patients, as they normally want to immediately return to their vigorous preinjury lifestyles. In these patients, even a properly fitting prosthetic may not be able to overcome the fact that the residual limb skin is not well suited for the mechanical forces generated by the prosthesis and the humid environment of the socket.^1,13 Another complicating factor is the dynamic nature of the residual limb. Muscle atrophy, changes in gait, and weight gain or loss can lead to an ill-fitting prosthetic and subsequent skin breakdown.

There are many case reports and review articles describing the skin problems in amputees.^1,14-17 The Table summarizes these conditions and outlines treatment options for each.^15,18-20

Most skin diseases on residual limbs are the result of mechanical skin breakdown, inflammation, infection, or combinations of these processes. Overall, amputees with diabetes mellitus and peripheral vascular disease tend to have skin disease related to poor perfusion, whereas amputees who are active and healthy tend to have conditions related to mechanical stress.^{7,13,14,17,21,22} Bui et al¹⁷ reported ulcers, abscesses, and blisters as the most common skin conditions that occur at the site of residual limbs; however, other less common dermatologic disorders such as skin malignancies, verrucous hyperplasia and carcinoma, granulomatous cutaneous lesions, acroangiodermatitis, and bullous pemphigoid also are seen.^23-26 Buikema and Meyerle¹⁵ hypothesize that these conditions, as well as the more common skin diseases, are partly from the amputation disrupting blood and lymphatic flow in the residual limb, which causes the site to act as an immunocompromised district that induces dysregulation of neuroimmune regulators.

It is important to note that skin disease on residual limbs is not just an acute problem. Long-term follow-up of 247 traumatic amputees from the Vietnam War showed that almost half of prosthesis users (48.2%) reported a skin problem in the preceding year, more than 38 years after the amputation. Additionally, one-quarter of these individuals experienced skin problems approximately 50% of the time, which unfortunately led to limited use or total abandonment of the prosthesis for the preceding year in 56% of the veterans surveyed.²¹

Other complications following amputation indirectly lead to skin problems. Heterotopic ossification, or the formation of bone at extraskeletal sites, has been observed in up to 65% of military amputees from recent operations in Iraq and Afghanistan.^27,28 If symptomatic, heterotopic ossification can lead to poor prosthetic fit and subsequent skin breakdown. As a result, it has been reported that up to 40% of combat-related lower extremity amputations may require excision of heterotopic ossificiation.²⁹

Amputation also can result in psychologic concerns that indirectly affect skin health. A systematic review by Mckechnie and John³⁰ suggested that despite heterogeneity between studies, even using the lowest figures demonstrated the significance anxiety and depression play in the lives of traumatic amputees. If left untreated, these mental health issues can lead to poor residual limb hygiene and prosthetic maintenance due to reductions in the patient’s energy and motivation. Studies have shown that proper hygiene of residual limbs and silicone liners reduces associated skin problems.^19,31

Role of the Dermatologist

Routine care and conservative management of amputee skin problems often are accomplished by prosthetists, primary care physicians, nurses, and physical therapists. In one study, more than 80% of the most common skin problems affecting amputees could be attributed to the prosthesis itself, which highlights the importance of the continued involvement of the prosthetist beyond the initial fitting period.¹³ However, when a skin problem becomes refractory to conservative management, referral to a dermatologist is prudent; therefore, the dermatologist is an integral member of the multidisciplinary team that provides care for amputees.

The dermatologist often is best positioned to diagnose skin diseases that result from wearing prostheses and is well versed in treatments for short-term and long-term management of skin disease on residual limbs. The dermatologist also can offer prophylactic treatments to decrease sweating and hair growth to prevent potential infections and subsequent skin breakdown. Additionally, proper education on self-care has been shown to decrease the amount of skin problems and increase functional status and quality of life for amputees.^32,33 Dermatologists can assist with the patient education process as well as refer amputees to a useful resource from the Amputee Coalition website (www.amputee-coalition.org) to provide specific patient education on how to maintain skin on the residual limb to prevent skin disease.

Current Treatments and Future Directions

Skin disorders affecting residual limbs usually are conditions that dermatologists commonly encounter and are comfortable managing in general practice. Additionally, dermatologists routinely treat hyperhidrosis and conduct laser hair removal, both of which are effective prophylactic adjuncts for amputee skin health. There are a few treatments for reducing residual limb hyperhidrosis that are particularly useful. Although first-line treatment of residual limb hyperhidrosis often is topical aluminum chloride, it requires frequent application and often causes considerable skin irritation when applied to residual limbs. Alternatively, intradermal botulinum toxin has been shown to successfully reduce sweat production in individuals with residual limb hyperhidrosis and is well tolerated.³⁴ A 2017 case report discussed the use of microwave thermal ablation of eccrine coils using a noninvasive 3-step hyperhidrosis treatment system on a bilateral below-the-knee amputee. The authors reported the patient tolerated the procedure well with decreased dermatitis and folliculitis, leading to his ability to wear a prosthetic for longer periods of time.³⁵

Ablative fractional resurfacing with a CO₂ laser is another key treatment modality central to amputees, more specifically to traumatic amputees. A CO₂ laser can decrease skin tension and increase skin mobility associated with traumatic scars as well as decrease skin vulnerability to biofilms present in chronic wounds on residual limbs. It is believed that the pattern of injury caused by ablative fractional lasers disrupts biofilms and stimulates growth factor secretion and collagen remodeling through the concept of photomicrodebridement.³⁶ The ablative fractional resurfacing approach to scar therapy and chronic wound debridement can result in less skin injury, allowing the amputee to continue rehabilitation and return more quickly to prosthetic use.³⁷

One interesting area of research in amputee care involves the study of novel ways to increase the skin’s ability to adapt to mechanical stress and load bearing and accelerate wound healing on the residual limb. Multiple studies have identified collagen fibril enlargement as an important component of skin adaptation, and biomolecules such as decorin may enhance this process.^38-40 The concept of increasing these biomolecules at the correct time during wound healing to strengthen the residual limb tissue currently is being studied.³⁹

Another encouraging area of research is the involvement of fibroblasts in cutaneous wound healing and their role in determining the phenotype of residual limb skin in amputees. The clinical application of autologous fibroblasts is approved by the US Food and Drug Administration for cosmetic use as a filler material and currently is under research for other applications, such as skin regeneration after surgery or manipulating skin characteristics to enhance the durability of residual limbs.⁴¹

Future preventative care of amputee skin may rely on tracking residual limb health before severe tissue injury occurs. For instance, Rink et al⁴² described an approach to monitor residual limb health using noninvasive imaging (eg, hyperspectral imaging, laser speckle imaging) and noninvasive probes that measure oxygenation, perfusion, skin barrier function, and skin hydration to the residual limb. Although these limb surveillance sensors would be employed by prosthetists, the dermatologist, as part of the multispecialty team, also could leverage the data for diagnosis and treatment considerations.

Final Thoughts

The dermatologist is an important member of the multidisciplinary team involved in the care of amputees. Skin disease is prevalent in amputees throughout their lives and often leads to abandonment of prostheses. Although current therapies and preventative treatments are for the most part successful, future research involving advanced technology to monitor skin health, increasing residual limb skin durability at the molecular level, and targeted laser therapies are promising. Through engagement and effective collaboration with the entire multidisciplinary team, dermatologists will have a considerable impact on amputee skin health.