Wounds

Case Reports

Patient 1

A 16-year-old adolescent boy presented to the emergency department with painful, pruritic, erythematous nodules on the bilateral legs of 1 week’s duration. The lesions had developed 1 week after returning from a monthlong trip to Senegal with a volunteer youth group. He did not recall sustaining any painful insect bites or illnesses while traveling in Africa and only noticed the erythematous papules on the legs when he returned home to the United States. After consulting with his primary care physician and a local dermatologist, the patient began taking oral cephalexin for suspected bacterial furunculosis with no considerable improvement. Over the course of 1 week, the lesions became increasingly painful and pruritic, prompting a visit to the emergency department. Prior to his arrival, the patient reported squeezing a live worm from one of the lesions on the right ankle.

On presentation, the patient was afebrile (temperature, 36.7°C) and his vital signs revealed no abnormalities. Physical examination revealed tender erythematous nodules on the bilateral heels, ankles, and shins with pinpoint puncta noted at the center of many of the lesions (Figure 1). The nodules were warm and indurated and no pulsatile movement was appreciated. The legs appeared to be well perfused with intact sensation and motor function. The patient brought in the live mobile larva that he extruded from the lesion on the right ankle. Both the departments of infectious diseases and dermatology were consulted and a preliminary diagnosis of furuncular myiasis was made.

Figure 1. Tender erythematous nodules on the bilateral heels, ankles, and shins.

The lesions were occluded with petroleum jelly and the patient was instructed to follow-up with the dermatology department later that same day. On follow-up in the dermatology clinic, the tips of intact larvae were appreciated at the central puncta of some of the lesions (Figure 2). Lidocaine adrenaline tetracaine gel was applied to lesions on the legs for 40 minutes, then lidocaine gel 1% was injected into each lesion. On injection, immobile larvae were ejected from the central puncta of most of the lesions; the remaining lesions were treated via 3-mm punch biopsy as a means of extraction. Each nodule contained only a single larva, all of which were dead at the time of removal (Figure 3). The wounds were left open and the patient was instructed to continue treatment with cephalexin with leg elevation and rest. Pathologic examination of deep dermal skin sections revealed larval fragments encased by a thick chitinous cuticle with spines that were consistent with furuncular myiasis (Figures 4 and 5). Given the patient’s recent history of travel to Africa along with the morphology of the extracted specimens, the larvae were identified as Cordylobia anthropophaga, a common cause of furuncular myiasis in that region.

Patient 2

The next week, a 17-year-old adolescent girl who had been on the same trip to Senegal as patient 1 presented with 2 similar erythematous nodules with central crusts on the left inner thigh and buttock. On noticing the lesions approximately 3 days prior to presentation, the patient applied topical antibiotic ointment to each nodule, which incited the evacuation of white tube-shaped structures that were presented for examination. On presentation, the nodules were healing well. Given the patient’s travel history and physical examination, a presumptive diagnosis of furuncular myiasis from C anthropophaga also was made.

Figure 2. The tips of intact larvae were appreciated at the central puncta of some of the lesions following occlusion with petroleum jelly. Figure 3. Dead larva extracted by lidocaine injection and punch biopsy.

Comment

The term myiasis stems from the Greek term for fly and is used to describe the infestation of fly larvae in living vertebrates.¹ Myiasis has many classifications, the 3 most common being furuncular, migratory, and wound myiasis, which are differentiated by the different fly species found in distinct regions of the world. Furuncular myiasis is the most benign form, usually affecting only a localized region of the skin; migratory myiasis is characterized by larvae traveling substantial distances from one anatomic site to another within the lower layers of the epidermis; and wound myiasis involves rapid reproduction of larvae in necrotic tissue with subsequent tissue destruction.²

The clinical presentation of the lesions noted in our patients suggested a diagnosis of furuncular myiasis, which commonly is caused by Dermatobia hominis, C anthropophaga, Cuterebra species, Wohlfahrtia vigil, and Wohlfahrtia opaca larvae.³Dermatobia hominis is the most common cause of furuncular myiasis and usually is found in Central and South America. Our patients likely developed an infestation of C anthropophaga (also known as the tumbu fly), a yellow-brown, 7- to 12-mm blowfly commonly found throughout tropical Africa.³ Although C anthropophaga is historically limited to sub-Saharan Africa, there has been a report of a case acquired in Portugal.⁴

In a review of the literature, C anthropophaga myiasis was documented in Italian travelers returning from Senegal^5-7; our cases are unique because they represent North American travelers returning from Senegal with furuncular myiasis. Furuncular myiasis from C anthropophaga has been reported in travelers returning to North America from other African countries, including Angola,⁸ Tanzania,^9-11 Kenya,⁹ Sierra Leone,¹² and Ivory Coast.¹³ Several cases of ocular myiasis from D hominis and Oestrus ovis have been reported in European travelers returning from Tunisia.^14,15

Tumbu fly infestations typically affect dogs and rodents but can arise in human hosts.³ Children may be affected by C anthropophaga furuncular myiasis more often than adults because they have thinner skin and less immunity to the larvae.²

Figure 4. Deep dermal cavity containing larval fragments encased by a thick chitinous cuticle with spines surrounded by mixed dermal inflammation (H&E, original magnification ×40). Figure 5. Larval intestinal components were visualized as well as striated muscle (H&E, original magnification ×200).

There are 2 mechanisms by which infestation of human hosts by C anthropophaga can occur. Most commonly, female flies lay eggs in shady areas in soil that is contaminated by feces or urine. The hatched larvae can survive in the ground for up to 2 weeks and later attach to a host when prompted by heat or movement.³ Therefore, clothing set out to dry may be contaminated by this soil. Alternatively, female flies can lay eggs directly onto clothing that is contaminated by feces or urine and the larvae subsequently hatch outside the soil with easy access to human skin once the clothing is worn.²

Common penetration sites are the head, neck, and back, as well as areas covered by contaminated or infested clothing.^2,3 Penetration of the human skin occurs instantly and is a painless process that is rarely noticed by the human host.³ The larvae burrow into the skin for 8 to 12 days, resulting in a furuncle that occasionally secretes a serous fluid.² Within the first 2 days of infestation, the host may experience symptoms ranging from local pruritus to severe pain. Six days following initial onset, an intense inflammatory response may result in local lymphadenopathy along with fever and fatigue.² The larvae use their posterior spiracles to create openings in the skin to create air holes that allow them to breathe.³ On physical examination, the spiracles generally appear as 1- to 3-mm dark linear streaks within furuncles, which is important in the diagnosis of C anthropophaga furuncular myiasis.^1,3 If spiracles are not appreciated on initial examination, diagnosis can be made by submerging the affected areas in water or saliva to look for air bubbles arising from the central puncta of the lesions.¹

All causes of furuncular myiasis are characterized by a ratio of 1 larva to 1 furuncle.¹⁶ Although most of these types of larvae that can cause furuncular myiasis result in single lesions, C anthropophaga infestation often produces several furuncles that may coalesce into plaques.^1,2 The differential diagnosis for C anthropophaga furuncular myiasis includes pyoderma, impetigo, staphylococcal furunculosis, cutaneous leishmaniasis, infected cyst, retained foreign body, and facticial disease.^2,3 Dracunculiasis also may be considered, which occurs after ingestion of contaminated water.² Ultrasonography may be helpful for the diagnosis of furuncular myiasis, as it can facilitate identification of foreign bodies, abscesses, and even larvae in some cases.¹⁷ Definitive diagnosis of any type of myiasis involves extraction of the larva and identification of the family, genus, and species by a parasitologist.¹ Some experts suggest rearing preserved live larvae with raw meat after extraction because adult specimens are more reliable than larvae for species diagnosis.¹

Treatment of furuncular myiasis involves occlusion and extraction of the larvae from the skin. Suffocation of the larvae by occlusion of air holes with petroleum jelly, paraffin oil, bacon fat, glue, and other obstructing substances forces the larvae to emerge in search of oxygen, though immature larvae may be more reluctant than mature ones.^2,3 Definitive treatment involves the direct removal of the larvae by surgery or expulsion by pressure, though it is recommended that lesions are pretreated with occlusive techniques.^1,3 Other reported methods of extraction include injection of lidocaine and the use of a commercial venom extractor.¹ It should be noted that rupture and incomplete extraction of larvae can lead to secondary infections and allergic reactions. Lesions can be pretreated with lidocaine gel prior to extraction, and antibiotics should be used in cases of secondary bacterial infection. Ivermectin also has been reported as a treatment of furuncular myiasis and other types of myiasis.¹ Prevention of infestation by C anthropophaga includes avoidance of endemic areas, maintaining good hygiene, and ironing clothing or drying it in sunny locations.^1,2 Overall, furuncular myiasis has a good prognosis with rapid recovery and a low incidence of complications.¹

Conclusion

We present 2 cases of travelers returning to North America from Senegal with C anthropophaga furuncular myiasis. Careful review of travel history, physical examination, and identification of fly larvae are important for diagnosis. Individuals traveling to sub-Saharan Africa should avoid drying clothes in shady places and lying on the ground. They also are urged to iron their clothing before wearing it.

Case Reports

Patient 1

A 16-year-old adolescent boy presented to the emergency department with painful, pruritic, erythematous nodules on the bilateral legs of 1 week’s duration. The lesions had developed 1 week after returning from a monthlong trip to Senegal with a volunteer youth group. He did not recall sustaining any painful insect bites or illnesses while traveling in Africa and only noticed the erythematous papules on the legs when he returned home to the United States. After consulting with his primary care physician and a local dermatologist, the patient began taking oral cephalexin for suspected bacterial furunculosis with no considerable improvement. Over the course of 1 week, the lesions became increasingly painful and pruritic, prompting a visit to the emergency department. Prior to his arrival, the patient reported squeezing a live worm from one of the lesions on the right ankle.

On presentation, the patient was afebrile (temperature, 36.7°C) and his vital signs revealed no abnormalities. Physical examination revealed tender erythematous nodules on the bilateral heels, ankles, and shins with pinpoint puncta noted at the center of many of the lesions (Figure 1). The nodules were warm and indurated and no pulsatile movement was appreciated. The legs appeared to be well perfused with intact sensation and motor function. The patient brought in the live mobile larva that he extruded from the lesion on the right ankle. Both the departments of infectious diseases and dermatology were consulted and a preliminary diagnosis of furuncular myiasis was made.

Figure 1. Tender erythematous nodules on the bilateral heels, ankles, and shins.

The lesions were occluded with petroleum jelly and the patient was instructed to follow-up with the dermatology department later that same day. On follow-up in the dermatology clinic, the tips of intact larvae were appreciated at the central puncta of some of the lesions (Figure 2). Lidocaine adrenaline tetracaine gel was applied to lesions on the legs for 40 minutes, then lidocaine gel 1% was injected into each lesion. On injection, immobile larvae were ejected from the central puncta of most of the lesions; the remaining lesions were treated via 3-mm punch biopsy as a means of extraction. Each nodule contained only a single larva, all of which were dead at the time of removal (Figure 3). The wounds were left open and the patient was instructed to continue treatment with cephalexin with leg elevation and rest. Pathologic examination of deep dermal skin sections revealed larval fragments encased by a thick chitinous cuticle with spines that were consistent with furuncular myiasis (Figures 4 and 5). Given the patient’s recent history of travel to Africa along with the morphology of the extracted specimens, the larvae were identified as Cordylobia anthropophaga, a common cause of furuncular myiasis in that region.

Patient 2

The next week, a 17-year-old adolescent girl who had been on the same trip to Senegal as patient 1 presented with 2 similar erythematous nodules with central crusts on the left inner thigh and buttock. On noticing the lesions approximately 3 days prior to presentation, the patient applied topical antibiotic ointment to each nodule, which incited the evacuation of white tube-shaped structures that were presented for examination. On presentation, the nodules were healing well. Given the patient’s travel history and physical examination, a presumptive diagnosis of furuncular myiasis from C anthropophaga also was made.

Figure 2. The tips of intact larvae were appreciated at the central puncta of some of the lesions following occlusion with petroleum jelly. Figure 3. Dead larva extracted by lidocaine injection and punch biopsy.

Comment

The term myiasis stems from the Greek term for fly and is used to describe the infestation of fly larvae in living vertebrates.¹ Myiasis has many classifications, the 3 most common being furuncular, migratory, and wound myiasis, which are differentiated by the different fly species found in distinct regions of the world. Furuncular myiasis is the most benign form, usually affecting only a localized region of the skin; migratory myiasis is characterized by larvae traveling substantial distances from one anatomic site to another within the lower layers of the epidermis; and wound myiasis involves rapid reproduction of larvae in necrotic tissue with subsequent tissue destruction.²

The clinical presentation of the lesions noted in our patients suggested a diagnosis of furuncular myiasis, which commonly is caused by Dermatobia hominis, C anthropophaga, Cuterebra species, Wohlfahrtia vigil, and Wohlfahrtia opaca larvae.³Dermatobia hominis is the most common cause of furuncular myiasis and usually is found in Central and South America. Our patients likely developed an infestation of C anthropophaga (also known as the tumbu fly), a yellow-brown, 7- to 12-mm blowfly commonly found throughout tropical Africa.³ Although C anthropophaga is historically limited to sub-Saharan Africa, there has been a report of a case acquired in Portugal.⁴

In a review of the literature, C anthropophaga myiasis was documented in Italian travelers returning from Senegal^5-7; our cases are unique because they represent North American travelers returning from Senegal with furuncular myiasis. Furuncular myiasis from C anthropophaga has been reported in travelers returning to North America from other African countries, including Angola,⁸ Tanzania,^9-11 Kenya,⁹ Sierra Leone,¹² and Ivory Coast.¹³ Several cases of ocular myiasis from D hominis and Oestrus ovis have been reported in European travelers returning from Tunisia.^14,15

Tumbu fly infestations typically affect dogs and rodents but can arise in human hosts.³ Children may be affected by C anthropophaga furuncular myiasis more often than adults because they have thinner skin and less immunity to the larvae.²

Figure 4. Deep dermal cavity containing larval fragments encased by a thick chitinous cuticle with spines surrounded by mixed dermal inflammation (H&E, original magnification ×40). Figure 5. Larval intestinal components were visualized as well as striated muscle (H&E, original magnification ×200).

There are 2 mechanisms by which infestation of human hosts by C anthropophaga can occur. Most commonly, female flies lay eggs in shady areas in soil that is contaminated by feces or urine. The hatched larvae can survive in the ground for up to 2 weeks and later attach to a host when prompted by heat or movement.³ Therefore, clothing set out to dry may be contaminated by this soil. Alternatively, female flies can lay eggs directly onto clothing that is contaminated by feces or urine and the larvae subsequently hatch outside the soil with easy access to human skin once the clothing is worn.²

Common penetration sites are the head, neck, and back, as well as areas covered by contaminated or infested clothing.^2,3 Penetration of the human skin occurs instantly and is a painless process that is rarely noticed by the human host.³ The larvae burrow into the skin for 8 to 12 days, resulting in a furuncle that occasionally secretes a serous fluid.² Within the first 2 days of infestation, the host may experience symptoms ranging from local pruritus to severe pain. Six days following initial onset, an intense inflammatory response may result in local lymphadenopathy along with fever and fatigue.² The larvae use their posterior spiracles to create openings in the skin to create air holes that allow them to breathe.³ On physical examination, the spiracles generally appear as 1- to 3-mm dark linear streaks within furuncles, which is important in the diagnosis of C anthropophaga furuncular myiasis.^1,3 If spiracles are not appreciated on initial examination, diagnosis can be made by submerging the affected areas in water or saliva to look for air bubbles arising from the central puncta of the lesions.¹

All causes of furuncular myiasis are characterized by a ratio of 1 larva to 1 furuncle.¹⁶ Although most of these types of larvae that can cause furuncular myiasis result in single lesions, C anthropophaga infestation often produces several furuncles that may coalesce into plaques.^1,2 The differential diagnosis for C anthropophaga furuncular myiasis includes pyoderma, impetigo, staphylococcal furunculosis, cutaneous leishmaniasis, infected cyst, retained foreign body, and facticial disease.^2,3 Dracunculiasis also may be considered, which occurs after ingestion of contaminated water.² Ultrasonography may be helpful for the diagnosis of furuncular myiasis, as it can facilitate identification of foreign bodies, abscesses, and even larvae in some cases.¹⁷ Definitive diagnosis of any type of myiasis involves extraction of the larva and identification of the family, genus, and species by a parasitologist.¹ Some experts suggest rearing preserved live larvae with raw meat after extraction because adult specimens are more reliable than larvae for species diagnosis.¹

Treatment of furuncular myiasis involves occlusion and extraction of the larvae from the skin. Suffocation of the larvae by occlusion of air holes with petroleum jelly, paraffin oil, bacon fat, glue, and other obstructing substances forces the larvae to emerge in search of oxygen, though immature larvae may be more reluctant than mature ones.^2,3 Definitive treatment involves the direct removal of the larvae by surgery or expulsion by pressure, though it is recommended that lesions are pretreated with occlusive techniques.^1,3 Other reported methods of extraction include injection of lidocaine and the use of a commercial venom extractor.¹ It should be noted that rupture and incomplete extraction of larvae can lead to secondary infections and allergic reactions. Lesions can be pretreated with lidocaine gel prior to extraction, and antibiotics should be used in cases of secondary bacterial infection. Ivermectin also has been reported as a treatment of furuncular myiasis and other types of myiasis.¹ Prevention of infestation by C anthropophaga includes avoidance of endemic areas, maintaining good hygiene, and ironing clothing or drying it in sunny locations.^1,2 Overall, furuncular myiasis has a good prognosis with rapid recovery and a low incidence of complications.¹

Conclusion

We present 2 cases of travelers returning to North America from Senegal with C anthropophaga furuncular myiasis. Careful review of travel history, physical examination, and identification of fly larvae are important for diagnosis. Individuals traveling to sub-Saharan Africa should avoid drying clothes in shady places and lying on the ground. They also are urged to iron their clothing before wearing it.

Case Reports

Patient 1

A 16-year-old adolescent boy presented to the emergency department with painful, pruritic, erythematous nodules on the bilateral legs of 1 week’s duration. The lesions had developed 1 week after returning from a monthlong trip to Senegal with a volunteer youth group. He did not recall sustaining any painful insect bites or illnesses while traveling in Africa and only noticed the erythematous papules on the legs when he returned home to the United States. After consulting with his primary care physician and a local dermatologist, the patient began taking oral cephalexin for suspected bacterial furunculosis with no considerable improvement. Over the course of 1 week, the lesions became increasingly painful and pruritic, prompting a visit to the emergency department. Prior to his arrival, the patient reported squeezing a live worm from one of the lesions on the right ankle.

On presentation, the patient was afebrile (temperature, 36.7°C) and his vital signs revealed no abnormalities. Physical examination revealed tender erythematous nodules on the bilateral heels, ankles, and shins with pinpoint puncta noted at the center of many of the lesions (Figure 1). The nodules were warm and indurated and no pulsatile movement was appreciated. The legs appeared to be well perfused with intact sensation and motor function. The patient brought in the live mobile larva that he extruded from the lesion on the right ankle. Both the departments of infectious diseases and dermatology were consulted and a preliminary diagnosis of furuncular myiasis was made.

Figure 1. Tender erythematous nodules on the bilateral heels, ankles, and shins.

The lesions were occluded with petroleum jelly and the patient was instructed to follow-up with the dermatology department later that same day. On follow-up in the dermatology clinic, the tips of intact larvae were appreciated at the central puncta of some of the lesions (Figure 2). Lidocaine adrenaline tetracaine gel was applied to lesions on the legs for 40 minutes, then lidocaine gel 1% was injected into each lesion. On injection, immobile larvae were ejected from the central puncta of most of the lesions; the remaining lesions were treated via 3-mm punch biopsy as a means of extraction. Each nodule contained only a single larva, all of which were dead at the time of removal (Figure 3). The wounds were left open and the patient was instructed to continue treatment with cephalexin with leg elevation and rest. Pathologic examination of deep dermal skin sections revealed larval fragments encased by a thick chitinous cuticle with spines that were consistent with furuncular myiasis (Figures 4 and 5). Given the patient’s recent history of travel to Africa along with the morphology of the extracted specimens, the larvae were identified as Cordylobia anthropophaga, a common cause of furuncular myiasis in that region.

Patient 2

The next week, a 17-year-old adolescent girl who had been on the same trip to Senegal as patient 1 presented with 2 similar erythematous nodules with central crusts on the left inner thigh and buttock. On noticing the lesions approximately 3 days prior to presentation, the patient applied topical antibiotic ointment to each nodule, which incited the evacuation of white tube-shaped structures that were presented for examination. On presentation, the nodules were healing well. Given the patient’s travel history and physical examination, a presumptive diagnosis of furuncular myiasis from C anthropophaga also was made.

Figure 2. The tips of intact larvae were appreciated at the central puncta of some of the lesions following occlusion with petroleum jelly. Figure 3. Dead larva extracted by lidocaine injection and punch biopsy.

Comment

The term myiasis stems from the Greek term for fly and is used to describe the infestation of fly larvae in living vertebrates.¹ Myiasis has many classifications, the 3 most common being furuncular, migratory, and wound myiasis, which are differentiated by the different fly species found in distinct regions of the world. Furuncular myiasis is the most benign form, usually affecting only a localized region of the skin; migratory myiasis is characterized by larvae traveling substantial distances from one anatomic site to another within the lower layers of the epidermis; and wound myiasis involves rapid reproduction of larvae in necrotic tissue with subsequent tissue destruction.²

The clinical presentation of the lesions noted in our patients suggested a diagnosis of furuncular myiasis, which commonly is caused by Dermatobia hominis, C anthropophaga, Cuterebra species, Wohlfahrtia vigil, and Wohlfahrtia opaca larvae.³Dermatobia hominis is the most common cause of furuncular myiasis and usually is found in Central and South America. Our patients likely developed an infestation of C anthropophaga (also known as the tumbu fly), a yellow-brown, 7- to 12-mm blowfly commonly found throughout tropical Africa.³ Although C anthropophaga is historically limited to sub-Saharan Africa, there has been a report of a case acquired in Portugal.⁴

In a review of the literature, C anthropophaga myiasis was documented in Italian travelers returning from Senegal^5-7; our cases are unique because they represent North American travelers returning from Senegal with furuncular myiasis. Furuncular myiasis from C anthropophaga has been reported in travelers returning to North America from other African countries, including Angola,⁸ Tanzania,^9-11 Kenya,⁹ Sierra Leone,¹² and Ivory Coast.¹³ Several cases of ocular myiasis from D hominis and Oestrus ovis have been reported in European travelers returning from Tunisia.^14,15

Tumbu fly infestations typically affect dogs and rodents but can arise in human hosts.³ Children may be affected by C anthropophaga furuncular myiasis more often than adults because they have thinner skin and less immunity to the larvae.²

Figure 4. Deep dermal cavity containing larval fragments encased by a thick chitinous cuticle with spines surrounded by mixed dermal inflammation (H&E, original magnification ×40). Figure 5. Larval intestinal components were visualized as well as striated muscle (H&E, original magnification ×200).

There are 2 mechanisms by which infestation of human hosts by C anthropophaga can occur. Most commonly, female flies lay eggs in shady areas in soil that is contaminated by feces or urine. The hatched larvae can survive in the ground for up to 2 weeks and later attach to a host when prompted by heat or movement.³ Therefore, clothing set out to dry may be contaminated by this soil. Alternatively, female flies can lay eggs directly onto clothing that is contaminated by feces or urine and the larvae subsequently hatch outside the soil with easy access to human skin once the clothing is worn.²

Common penetration sites are the head, neck, and back, as well as areas covered by contaminated or infested clothing.^2,3 Penetration of the human skin occurs instantly and is a painless process that is rarely noticed by the human host.³ The larvae burrow into the skin for 8 to 12 days, resulting in a furuncle that occasionally secretes a serous fluid.² Within the first 2 days of infestation, the host may experience symptoms ranging from local pruritus to severe pain. Six days following initial onset, an intense inflammatory response may result in local lymphadenopathy along with fever and fatigue.² The larvae use their posterior spiracles to create openings in the skin to create air holes that allow them to breathe.³ On physical examination, the spiracles generally appear as 1- to 3-mm dark linear streaks within furuncles, which is important in the diagnosis of C anthropophaga furuncular myiasis.^1,3 If spiracles are not appreciated on initial examination, diagnosis can be made by submerging the affected areas in water or saliva to look for air bubbles arising from the central puncta of the lesions.¹

All causes of furuncular myiasis are characterized by a ratio of 1 larva to 1 furuncle.¹⁶ Although most of these types of larvae that can cause furuncular myiasis result in single lesions, C anthropophaga infestation often produces several furuncles that may coalesce into plaques.^1,2 The differential diagnosis for C anthropophaga furuncular myiasis includes pyoderma, impetigo, staphylococcal furunculosis, cutaneous leishmaniasis, infected cyst, retained foreign body, and facticial disease.^2,3 Dracunculiasis also may be considered, which occurs after ingestion of contaminated water.² Ultrasonography may be helpful for the diagnosis of furuncular myiasis, as it can facilitate identification of foreign bodies, abscesses, and even larvae in some cases.¹⁷ Definitive diagnosis of any type of myiasis involves extraction of the larva and identification of the family, genus, and species by a parasitologist.¹ Some experts suggest rearing preserved live larvae with raw meat after extraction because adult specimens are more reliable than larvae for species diagnosis.¹

Treatment of furuncular myiasis involves occlusion and extraction of the larvae from the skin. Suffocation of the larvae by occlusion of air holes with petroleum jelly, paraffin oil, bacon fat, glue, and other obstructing substances forces the larvae to emerge in search of oxygen, though immature larvae may be more reluctant than mature ones.^2,3 Definitive treatment involves the direct removal of the larvae by surgery or expulsion by pressure, though it is recommended that lesions are pretreated with occlusive techniques.^1,3 Other reported methods of extraction include injection of lidocaine and the use of a commercial venom extractor.¹ It should be noted that rupture and incomplete extraction of larvae can lead to secondary infections and allergic reactions. Lesions can be pretreated with lidocaine gel prior to extraction, and antibiotics should be used in cases of secondary bacterial infection. Ivermectin also has been reported as a treatment of furuncular myiasis and other types of myiasis.¹ Prevention of infestation by C anthropophaga includes avoidance of endemic areas, maintaining good hygiene, and ironing clothing or drying it in sunny locations.^1,2 Overall, furuncular myiasis has a good prognosis with rapid recovery and a low incidence of complications.¹

Conclusion

We present 2 cases of travelers returning to North America from Senegal with C anthropophaga furuncular myiasis. Careful review of travel history, physical examination, and identification of fly larvae are important for diagnosis. Individuals traveling to sub-Saharan Africa should avoid drying clothes in shady places and lying on the ground. They also are urged to iron their clothing before wearing it.

To the Editor:
A 42-year-old man with hypertension, hypothyroidism, and alcohol-related cirrhosis was admitted for evaluation of rapidly deteriorating mental status. He was referred from a rehabilitation facility where he had been admitted 4 days earlier after a hospitalization for hepatorenal syndrome and pneumonia. He was alert and ambulating until the day of the current admission. On arrival he was hypotensive(54/42 mm Hg); hypothermic (35°C, rectally); and unresponsive, except to painful stimuli. Jaundice, hepatosplenomegaly, ascites, and bilateral lower extremity edema were noted. There were multiple tense and flaccid bullous lesions containing serosanguineous fluid over both tibias and calves, without crepitus (Figure 1).

Figure 1. Left tibia with multiple hemorrhagic bullae and surrounding erythema and edema. The characteristic serosanguineous drainage was seen at the lower edge of the distal bulla.

Figure 2. Computed tomography of the legs with extensive subcutaneous edema and fluid collections around the knees.

Figure 3. Computed tomography of the legs with edematous changes of the anterior compart-ment muscles.

Laboratory test results revealed leukocytosis (total leukocytes, 10,900/mm³ [reference range, 4500–10,800/mm³), hypoglycemia (glucose, <20 mg/dL [reference range, 74–106 mg/dL]), renal insufficiency (serum creatinine, 2.5 mg/dL [reference range, 0.66–1.25 mg/dL]), metabolic acidosis (pH, 7.1 [reference range, 7.35–7.45]; bicarbonate, 13 mmol/L [reference range, 22–30 mmol/L]; lactic acid, 11.9 mmol/L [reference range, 0.7–2.1 mmol/L]), liver dysfunction (aspartate aminotransferase, 576 IU/L [reference range, 15–46 IU/L]), and coagulopathy with evidence of diffuse intravascular coagulation (total platelets, 75,000/mm³ [reference range, 150,000–450,000/mm³];  international normalized ratio, 9.5 [reference range, 0.8–1.2]; partial thromboplastin time, 108 seconds [reference range 23.0–35.0 seconds]; fibrinogen, 145 mg/dL [reference range, 228–501 mg/dL]; D-dimer, >20 µg/mL [reference range, 0.01–0.58 μg/mL]). Computed tomography of the pelvis and legs showed ascites, extensive subcutaneous edema, and cutaneous blisterlike lesions superior to the level of the ankles bilaterally. No gas, foreign bodies, collections, asymmetric facial thickening, or evidence of infection across tissue planes was present (Figures 2 and 3).

Specimens of blood and aspirates from the bullae at multiple lower leg sites were sent for microbiologic evaluation. The blood specimens were inoculated at bedside into aerobic and anaerobic blood culture bottles and incubated in an automated blood culture system. The aspirate samples were inoculated to trypticase soy agar with 5% sheep blood, Columbia-nalidixic acid agar, chocolate agar, MacConkey agar, and thioglycollate broth, which were incubated at 37ºC in air supplemented with 5% CO₂, and to CDC anaerobic blood agar, which was incubated under anaerobic conditions. Gram-stained smears of the aspirates from the bullae demonstrated few granulocytes and numerous large gram-positive bacilli (Figure 4). By the next day, growth of large gram-positive bacilli was detected in both aerobic and anaerobic blood culture bottles and in pure culture from all the bullae samples. The bacterial colonies on sheep blood agar were opaque and white-gray in color, with a rough surface, undulate margins, and surrounding β hemolysis. The isolate was a motile, catalase-positive, arginine-positive, salicin-positive, lecithinase-positive, and penicillin-resistant organism that was identified as Bacillus cereus.

Antimicrobial susceptibility testing for B cereus has not been standardized, but evaluation by broth microdilution suggested decreased susceptibility to penicillin (minimum inhibitory concentration [MIC], 2 µg/mL) and clindamycin (MIC, 2 µg/mL), but retained susceptibility to ciprofloxacin (MIC, ≤0.25 µg/mL), tetracycline (MIC, ≤1 µg/mL), rifampin (MIC, ≤1 µg/mL), and vancomycin (MIC, ≤2 µg/mL).

The patient was admitted to the intensive care unit and was treated initially with fluid resuscitation; transfusions; ventilatory support; and intravenous vancomycin, clindamycin, and imipenem. This regimen was changed to vancomycin and ciprofloxacin when culture and susceptibility results became available to complete a 14-day course. Signs of sepsis resolved and the mental status and skin lesions improved. Ultimately, the patient died due to complications of hepatic failure.

Bacillus cereus is a rod-shaped, gram-positive, facultative, aerobic organism that is widely distributed in the environment.¹ Spore formation makes B cereus resistant to most physical and chemical disinfection methods; as a consequence, it is a frequent contaminant in materials (eg, plants, dust, soil, sediment), foodstuffs, and clinical specimens.¹

Traditionally considered in the context of foodborne illness, B cereus is recognized increasingly as a cause of systemic and local infections in both immunosuppressed and immunocompetent patients. Nongastrointestinal infections reported include fulminant bacteremia, pneumonia, meningitis, brain abscesses, endophthalmitis, necrotizing fasciitis, and central line catheter–related and cutaneous infections.^1,2

Figure 4. Gram-stained smears of bulla aspirate revealed large gram-positive bacilli and debris in material aspirated from a left lower leg bulla (original magnification ×100 [oil immersion]).

Cutaneous lesions may have a variety of forms and appearance at initial presentation, including small papules or vesicles that progress into a rapidly spreading cellulitis^1,2 with a characteristic serosanguineous draining fluid,² single necrotic bullae,³ and gas-gangrenelike infections with extensive soft tissue involvement resembling clostridial myonecrosis.^1,4 Single or multiple papulovesicular lesions can even mimic cutaneous anthrax.^1-4 Necrotic or hemorrhagic bullous lesions,³ such as those observed in our patient, are rare.

Exposed areas such as extremities and digits are most often affected, presumably due to entrance of spores from soil, water, decaying organic material, or fomites through skin microabrasions or trauma-induced wounds.¹ Once in the tissue, the crystalline surface protein layer (S-layer) of the bacilli promotes adhesion to human epithelial cells and neutrophils,⁵ followed by release of virulence factors including proteases, collagenases, lecithinaselike enzymes, necrotizing exotoxinlike hemolysins, phospholipases, and most importantly a dermonecrotic vascular permeability factor.^1,5 Toxins produced by B cereus are similar to those closely related to Bacillus anthracis, the agent of anthrax.^1,2

When large gram-positive bacilli are observed in tissue or wound specimens, initial therapy should address both aerobic (Bacillus species) and anaerobic (Clostridium species) organisms.^1,4,6 Once B cereus is recovered, treatment should rely on susceptibility testing of the isolate. Bacillus cereus produces ß-lactamase, thus penicillin and cephalosporin should be avoided.¹ Vancomycin, clindamycin, aminoglycosides, and fluoroquinolones are the drugs of choice.^1,3,4,6 Daptomycin and linezolid also are active in vitro,¹ but clinical experience with these agents is limited. Necrotic infection or deep tissue involvement requires surgical intervention.

Numerous other organisms can cause cellulitis and soft tissue infections with hemorrhagic bullae.^1,3,6 Streptococci, particularly Streptococcus pyogenes, and occasionally staphylococci are the primary consideration in normal hosts without trauma.^3,6 In immunocompromised patients, including those with cirrhosis, diabetes mellitus, and malignancy, Clostridium perfringens and gram-negative organisms such as Escherichia coli, other enteric bacteria including Pseudomonas aeruginosa, Aeromonas, and halophilic Vibrio species are more frequent.^3,6

We describe a patient with underlying cirrhosis who developed bilateral lower extremity hemorrhagic bullous lesions and sepsis due to infection with B cereus, an emerging cause of serious infections in patients with underlying immunocompromising conditions such as cirrhosis, diabetes mellitus, and malignancy. Hemorrhagic bullae in immunocompromised patients are associated with sepsis and rapidly progressive illness, and rapid treatment is essential. Bacillus cereus should be included as a consideration in the differential diagnosis and management of patients presenting with bullous cellulitis and sepsis.

To the Editor:
A 42-year-old man with hypertension, hypothyroidism, and alcohol-related cirrhosis was admitted for evaluation of rapidly deteriorating mental status. He was referred from a rehabilitation facility where he had been admitted 4 days earlier after a hospitalization for hepatorenal syndrome and pneumonia. He was alert and ambulating until the day of the current admission. On arrival he was hypotensive(54/42 mm Hg); hypothermic (35°C, rectally); and unresponsive, except to painful stimuli. Jaundice, hepatosplenomegaly, ascites, and bilateral lower extremity edema were noted. There were multiple tense and flaccid bullous lesions containing serosanguineous fluid over both tibias and calves, without crepitus (Figure 1).

Figure 1. Left tibia with multiple hemorrhagic bullae and surrounding erythema and edema. The characteristic serosanguineous drainage was seen at the lower edge of the distal bulla.

Figure 2. Computed tomography of the legs with extensive subcutaneous edema and fluid collections around the knees.

Figure 3. Computed tomography of the legs with edematous changes of the anterior compart-ment muscles.

Laboratory test results revealed leukocytosis (total leukocytes, 10,900/mm³ [reference range, 4500–10,800/mm³), hypoglycemia (glucose, <20 mg/dL [reference range, 74–106 mg/dL]), renal insufficiency (serum creatinine, 2.5 mg/dL [reference range, 0.66–1.25 mg/dL]), metabolic acidosis (pH, 7.1 [reference range, 7.35–7.45]; bicarbonate, 13 mmol/L [reference range, 22–30 mmol/L]; lactic acid, 11.9 mmol/L [reference range, 0.7–2.1 mmol/L]), liver dysfunction (aspartate aminotransferase, 576 IU/L [reference range, 15–46 IU/L]), and coagulopathy with evidence of diffuse intravascular coagulation (total platelets, 75,000/mm³ [reference range, 150,000–450,000/mm³];  international normalized ratio, 9.5 [reference range, 0.8–1.2]; partial thromboplastin time, 108 seconds [reference range 23.0–35.0 seconds]; fibrinogen, 145 mg/dL [reference range, 228–501 mg/dL]; D-dimer, >20 µg/mL [reference range, 0.01–0.58 μg/mL]). Computed tomography of the pelvis and legs showed ascites, extensive subcutaneous edema, and cutaneous blisterlike lesions superior to the level of the ankles bilaterally. No gas, foreign bodies, collections, asymmetric facial thickening, or evidence of infection across tissue planes was present (Figures 2 and 3).

Specimens of blood and aspirates from the bullae at multiple lower leg sites were sent for microbiologic evaluation. The blood specimens were inoculated at bedside into aerobic and anaerobic blood culture bottles and incubated in an automated blood culture system. The aspirate samples were inoculated to trypticase soy agar with 5% sheep blood, Columbia-nalidixic acid agar, chocolate agar, MacConkey agar, and thioglycollate broth, which were incubated at 37ºC in air supplemented with 5% CO₂, and to CDC anaerobic blood agar, which was incubated under anaerobic conditions. Gram-stained smears of the aspirates from the bullae demonstrated few granulocytes and numerous large gram-positive bacilli (Figure 4). By the next day, growth of large gram-positive bacilli was detected in both aerobic and anaerobic blood culture bottles and in pure culture from all the bullae samples. The bacterial colonies on sheep blood agar were opaque and white-gray in color, with a rough surface, undulate margins, and surrounding β hemolysis. The isolate was a motile, catalase-positive, arginine-positive, salicin-positive, lecithinase-positive, and penicillin-resistant organism that was identified as Bacillus cereus.

Antimicrobial susceptibility testing for B cereus has not been standardized, but evaluation by broth microdilution suggested decreased susceptibility to penicillin (minimum inhibitory concentration [MIC], 2 µg/mL) and clindamycin (MIC, 2 µg/mL), but retained susceptibility to ciprofloxacin (MIC, ≤0.25 µg/mL), tetracycline (MIC, ≤1 µg/mL), rifampin (MIC, ≤1 µg/mL), and vancomycin (MIC, ≤2 µg/mL).

The patient was admitted to the intensive care unit and was treated initially with fluid resuscitation; transfusions; ventilatory support; and intravenous vancomycin, clindamycin, and imipenem. This regimen was changed to vancomycin and ciprofloxacin when culture and susceptibility results became available to complete a 14-day course. Signs of sepsis resolved and the mental status and skin lesions improved. Ultimately, the patient died due to complications of hepatic failure.

Bacillus cereus is a rod-shaped, gram-positive, facultative, aerobic organism that is widely distributed in the environment.¹ Spore formation makes B cereus resistant to most physical and chemical disinfection methods; as a consequence, it is a frequent contaminant in materials (eg, plants, dust, soil, sediment), foodstuffs, and clinical specimens.¹

Traditionally considered in the context of foodborne illness, B cereus is recognized increasingly as a cause of systemic and local infections in both immunosuppressed and immunocompetent patients. Nongastrointestinal infections reported include fulminant bacteremia, pneumonia, meningitis, brain abscesses, endophthalmitis, necrotizing fasciitis, and central line catheter–related and cutaneous infections.^1,2

Figure 4. Gram-stained smears of bulla aspirate revealed large gram-positive bacilli and debris in material aspirated from a left lower leg bulla (original magnification ×100 [oil immersion]).

Cutaneous lesions may have a variety of forms and appearance at initial presentation, including small papules or vesicles that progress into a rapidly spreading cellulitis^1,2 with a characteristic serosanguineous draining fluid,² single necrotic bullae,³ and gas-gangrenelike infections with extensive soft tissue involvement resembling clostridial myonecrosis.^1,4 Single or multiple papulovesicular lesions can even mimic cutaneous anthrax.^1-4 Necrotic or hemorrhagic bullous lesions,³ such as those observed in our patient, are rare.

Exposed areas such as extremities and digits are most often affected, presumably due to entrance of spores from soil, water, decaying organic material, or fomites through skin microabrasions or trauma-induced wounds.¹ Once in the tissue, the crystalline surface protein layer (S-layer) of the bacilli promotes adhesion to human epithelial cells and neutrophils,⁵ followed by release of virulence factors including proteases, collagenases, lecithinaselike enzymes, necrotizing exotoxinlike hemolysins, phospholipases, and most importantly a dermonecrotic vascular permeability factor.^1,5 Toxins produced by B cereus are similar to those closely related to Bacillus anthracis, the agent of anthrax.^1,2

When large gram-positive bacilli are observed in tissue or wound specimens, initial therapy should address both aerobic (Bacillus species) and anaerobic (Clostridium species) organisms.^1,4,6 Once B cereus is recovered, treatment should rely on susceptibility testing of the isolate. Bacillus cereus produces ß-lactamase, thus penicillin and cephalosporin should be avoided.¹ Vancomycin, clindamycin, aminoglycosides, and fluoroquinolones are the drugs of choice.^1,3,4,6 Daptomycin and linezolid also are active in vitro,¹ but clinical experience with these agents is limited. Necrotic infection or deep tissue involvement requires surgical intervention.

Numerous other organisms can cause cellulitis and soft tissue infections with hemorrhagic bullae.^1,3,6 Streptococci, particularly Streptococcus pyogenes, and occasionally staphylococci are the primary consideration in normal hosts without trauma.^3,6 In immunocompromised patients, including those with cirrhosis, diabetes mellitus, and malignancy, Clostridium perfringens and gram-negative organisms such as Escherichia coli, other enteric bacteria including Pseudomonas aeruginosa, Aeromonas, and halophilic Vibrio species are more frequent.^3,6

We describe a patient with underlying cirrhosis who developed bilateral lower extremity hemorrhagic bullous lesions and sepsis due to infection with B cereus, an emerging cause of serious infections in patients with underlying immunocompromising conditions such as cirrhosis, diabetes mellitus, and malignancy. Hemorrhagic bullae in immunocompromised patients are associated with sepsis and rapidly progressive illness, and rapid treatment is essential. Bacillus cereus should be included as a consideration in the differential diagnosis and management of patients presenting with bullous cellulitis and sepsis.

To the Editor:
A 42-year-old man with hypertension, hypothyroidism, and alcohol-related cirrhosis was admitted for evaluation of rapidly deteriorating mental status. He was referred from a rehabilitation facility where he had been admitted 4 days earlier after a hospitalization for hepatorenal syndrome and pneumonia. He was alert and ambulating until the day of the current admission. On arrival he was hypotensive(54/42 mm Hg); hypothermic (35°C, rectally); and unresponsive, except to painful stimuli. Jaundice, hepatosplenomegaly, ascites, and bilateral lower extremity edema were noted. There were multiple tense and flaccid bullous lesions containing serosanguineous fluid over both tibias and calves, without crepitus (Figure 1).

Figure 1. Left tibia with multiple hemorrhagic bullae and surrounding erythema and edema. The characteristic serosanguineous drainage was seen at the lower edge of the distal bulla.

Figure 2. Computed tomography of the legs with extensive subcutaneous edema and fluid collections around the knees.

Figure 3. Computed tomography of the legs with edematous changes of the anterior compart-ment muscles.

Laboratory test results revealed leukocytosis (total leukocytes, 10,900/mm³ [reference range, 4500–10,800/mm³), hypoglycemia (glucose, <20 mg/dL [reference range, 74–106 mg/dL]), renal insufficiency (serum creatinine, 2.5 mg/dL [reference range, 0.66–1.25 mg/dL]), metabolic acidosis (pH, 7.1 [reference range, 7.35–7.45]; bicarbonate, 13 mmol/L [reference range, 22–30 mmol/L]; lactic acid, 11.9 mmol/L [reference range, 0.7–2.1 mmol/L]), liver dysfunction (aspartate aminotransferase, 576 IU/L [reference range, 15–46 IU/L]), and coagulopathy with evidence of diffuse intravascular coagulation (total platelets, 75,000/mm³ [reference range, 150,000–450,000/mm³];  international normalized ratio, 9.5 [reference range, 0.8–1.2]; partial thromboplastin time, 108 seconds [reference range 23.0–35.0 seconds]; fibrinogen, 145 mg/dL [reference range, 228–501 mg/dL]; D-dimer, >20 µg/mL [reference range, 0.01–0.58 μg/mL]). Computed tomography of the pelvis and legs showed ascites, extensive subcutaneous edema, and cutaneous blisterlike lesions superior to the level of the ankles bilaterally. No gas, foreign bodies, collections, asymmetric facial thickening, or evidence of infection across tissue planes was present (Figures 2 and 3).

Specimens of blood and aspirates from the bullae at multiple lower leg sites were sent for microbiologic evaluation. The blood specimens were inoculated at bedside into aerobic and anaerobic blood culture bottles and incubated in an automated blood culture system. The aspirate samples were inoculated to trypticase soy agar with 5% sheep blood, Columbia-nalidixic acid agar, chocolate agar, MacConkey agar, and thioglycollate broth, which were incubated at 37ºC in air supplemented with 5% CO₂, and to CDC anaerobic blood agar, which was incubated under anaerobic conditions. Gram-stained smears of the aspirates from the bullae demonstrated few granulocytes and numerous large gram-positive bacilli (Figure 4). By the next day, growth of large gram-positive bacilli was detected in both aerobic and anaerobic blood culture bottles and in pure culture from all the bullae samples. The bacterial colonies on sheep blood agar were opaque and white-gray in color, with a rough surface, undulate margins, and surrounding β hemolysis. The isolate was a motile, catalase-positive, arginine-positive, salicin-positive, lecithinase-positive, and penicillin-resistant organism that was identified as Bacillus cereus.

Antimicrobial susceptibility testing for B cereus has not been standardized, but evaluation by broth microdilution suggested decreased susceptibility to penicillin (minimum inhibitory concentration [MIC], 2 µg/mL) and clindamycin (MIC, 2 µg/mL), but retained susceptibility to ciprofloxacin (MIC, ≤0.25 µg/mL), tetracycline (MIC, ≤1 µg/mL), rifampin (MIC, ≤1 µg/mL), and vancomycin (MIC, ≤2 µg/mL).

The patient was admitted to the intensive care unit and was treated initially with fluid resuscitation; transfusions; ventilatory support; and intravenous vancomycin, clindamycin, and imipenem. This regimen was changed to vancomycin and ciprofloxacin when culture and susceptibility results became available to complete a 14-day course. Signs of sepsis resolved and the mental status and skin lesions improved. Ultimately, the patient died due to complications of hepatic failure.

Bacillus cereus is a rod-shaped, gram-positive, facultative, aerobic organism that is widely distributed in the environment.¹ Spore formation makes B cereus resistant to most physical and chemical disinfection methods; as a consequence, it is a frequent contaminant in materials (eg, plants, dust, soil, sediment), foodstuffs, and clinical specimens.¹

Traditionally considered in the context of foodborne illness, B cereus is recognized increasingly as a cause of systemic and local infections in both immunosuppressed and immunocompetent patients. Nongastrointestinal infections reported include fulminant bacteremia, pneumonia, meningitis, brain abscesses, endophthalmitis, necrotizing fasciitis, and central line catheter–related and cutaneous infections.^1,2

Figure 4. Gram-stained smears of bulla aspirate revealed large gram-positive bacilli and debris in material aspirated from a left lower leg bulla (original magnification ×100 [oil immersion]).

Cutaneous lesions may have a variety of forms and appearance at initial presentation, including small papules or vesicles that progress into a rapidly spreading cellulitis^1,2 with a characteristic serosanguineous draining fluid,² single necrotic bullae,³ and gas-gangrenelike infections with extensive soft tissue involvement resembling clostridial myonecrosis.^1,4 Single or multiple papulovesicular lesions can even mimic cutaneous anthrax.^1-4 Necrotic or hemorrhagic bullous lesions,³ such as those observed in our patient, are rare.

Exposed areas such as extremities and digits are most often affected, presumably due to entrance of spores from soil, water, decaying organic material, or fomites through skin microabrasions or trauma-induced wounds.¹ Once in the tissue, the crystalline surface protein layer (S-layer) of the bacilli promotes adhesion to human epithelial cells and neutrophils,⁵ followed by release of virulence factors including proteases, collagenases, lecithinaselike enzymes, necrotizing exotoxinlike hemolysins, phospholipases, and most importantly a dermonecrotic vascular permeability factor.^1,5 Toxins produced by B cereus are similar to those closely related to Bacillus anthracis, the agent of anthrax.^1,2

When large gram-positive bacilli are observed in tissue or wound specimens, initial therapy should address both aerobic (Bacillus species) and anaerobic (Clostridium species) organisms.^1,4,6 Once B cereus is recovered, treatment should rely on susceptibility testing of the isolate. Bacillus cereus produces ß-lactamase, thus penicillin and cephalosporin should be avoided.¹ Vancomycin, clindamycin, aminoglycosides, and fluoroquinolones are the drugs of choice.^1,3,4,6 Daptomycin and linezolid also are active in vitro,¹ but clinical experience with these agents is limited. Necrotic infection or deep tissue involvement requires surgical intervention.

Numerous other organisms can cause cellulitis and soft tissue infections with hemorrhagic bullae.^1,3,6 Streptococci, particularly Streptococcus pyogenes, and occasionally staphylococci are the primary consideration in normal hosts without trauma.^3,6 In immunocompromised patients, including those with cirrhosis, diabetes mellitus, and malignancy, Clostridium perfringens and gram-negative organisms such as Escherichia coli, other enteric bacteria including Pseudomonas aeruginosa, Aeromonas, and halophilic Vibrio species are more frequent.^3,6

We describe a patient with underlying cirrhosis who developed bilateral lower extremity hemorrhagic bullous lesions and sepsis due to infection with B cereus, an emerging cause of serious infections in patients with underlying immunocompromising conditions such as cirrhosis, diabetes mellitus, and malignancy. Hemorrhagic bullae in immunocompromised patients are associated with sepsis and rapidly progressive illness, and rapid treatment is essential. Bacillus cereus should be included as a consideration in the differential diagnosis and management of patients presenting with bullous cellulitis and sepsis.

Cyanoacrylates are widely used in adhesive products, with applications ranging from household products to nail and beauty salons and even dentistry. A topical skin adhesive containing 2-octyl cyanoacrylate was approved in 1998 for topical application for closure of skin edges of wounds from surgical incisions.¹ Usually cyanoacrylates are not strong sensitizers, and despite their extensive use, there have been relatively few reports of associated allergic contact dermatitis (ACD).^2-5 We report 4 cases of ACD to 2-octyl cyanoacrylate used in postsurgical wound closures as confirmed by patch tests.

Case Reports

Patient 1

A 33-year-old woman presented with an intensely pruritic peri-incisional rash on the lower back and right buttock of 1 week’s duration. The eruption started roughly 1 week following surgical implantation of a spinal cord stimulator for treatment of chronic back pain. Both incisions made during the implantation were closed with 2-octyl cyanoacrylate. The patient denied any prior exposure to topical skin adhesives or any history of contact dermatitis to nickel or other materials. The patient did not dress the wounds and did not apply topical agents to the area.

Physical examination revealed 6- to 8-cm linear surgical scars on the midline lumbar back and superior right buttock with surrounding excoriated erythematous papules coalescing into plaques consistent with acute eczematous dermatitis (Figure 1). Similar papules and plaques were scattered across the abdomen and chest. She was given triamcinolone acetonide ointment 0.1% twice daily and hydroxyzine pamoate 25 mg 3 times daily for itching. The surgical wounds healed within 2 weeks of presentation with postinflammatory hyperpigmentation surrounding the scars.

Figure 1. Surgical scars with surrounding excoriated erythematous papules coalescing into plaques on the midline lumbar back (A) and superior right buttock (B).

Six weeks later she underwent patch testing to confirm the diagnosis. She was screened using the North American Contact Dermatitis Group standard 65-allergen series and a miscellaneous tray including hardware obtained from the spinal cord stimulator device manufacturer. A use test to 2-octyl cyanoacrylate also was performed. At 96 hours, true positives included cinnamic aldehyde (1+), nickel (1+), bacitracin (1+), fragrance mix (2+), disperse blue dyes 106 and 124 (2+), and 2-octyl cyanoacrylate (3+)(1+=weak positive; 2+=strong positive; 3+=extreme reaction). There was no response to any components of the device. The pattern of dermatitis and positive patch-test results strongly supported the diagnosis of ACD to 2-octyl cyanoacrylate.

Patients 2, 3, and 4

Three patients—a 65-year-old woman, a 35-year-old woman, and a 44-year-old woman—presented to us with eczematous dermatitis at laparoscopic portal sites that were closed with 2-octyl cyanoacrylate (Figures 2 and 3). They presented approximately 1 week following laparoscopic Nissen fundoplication, laparoscopic left hepatectomy, and laparoscopic cholecystectomy, respectively. None of these  3 patients had been using any topical medications. All of them had a positive reaction (2+) to 2-octyl cyanoacrylate on use testing. Interestingly, use tests for 2 other cyanoacrylates containing 2-butyl cyanoacrylate were negative in 2 patients.

Figure 2. Acute eczematous plaques at wound closures.

Figure 3. Coalescing acute eczematous plaques focused at wound closures.

Although patient 1 reported no prior exposure to 2-octyl cyanoacrylate, these 3 additional patients reported prior exposure with no reaction. Other possible contact allergens associated with wound closure included iodine, topical antibiotics, and dressing tape.

Comment

Contact allergies to acrylates are not uncommon. In a series of 275 patients, Kanerva et al⁶ found that 17.5% of patients had an allergic reaction to at least 1 acrylate or methacrylate. In the same series, no allergic reactions to cyanoacrylates were noted.⁶ The role of methacrylates in the development of occupational ACD and irritant dermatitis has been well characterized among dentists, orthopedic surgeons, beauticians, and industrial workers who are commonly exposed to these agents.^7-12 Partially because of their longer carbon chains, cyanoacrylates have reduced toxicity and improved bonding strength as well as flexibility. Given their availability and the ease and speed of their use, skin adhesives have become widely used in the closure of surgical wounds.^13-16

Postoperative contact dermatitis is problematic, as patients are exposed to many potential allergens during surgery. In our clinical practice, the most common allergens causing ACD associated with surgery are iodine, topical antibiotics (ie, bacitracin, neomycin), tape adhesives, suture materials, and less commonly surgical hardware. Although they are rarely reported, contact allergies to skin adhesives such as cyanoacrylates are of particular importance because they may complicate surgical wounds, leading to dehiscence, infection, and scarring, among other complications. In our patients, there were no adverse outcomes in wound healing with the exception of postinflammatory hyperpigmentation.

Under ideal conditions, 2-octyl cyanoacrylate generally is not a strong sensitizer; however, application to open wounds or thinner skin such as the eyelids may permit exposure of antigen-presenting cells to cyanoacrylate monomers, thereby initiating sensitization. Postsurgical occlusive dressings, which often are left in place for 7 to 14 days, also may contribute to sensitization. The role of the degradation of skin adhesive products in the development of contact dermatitis is unknown.

Management of ACD from skin adhesives should involve the immediate removal of any remaining adhesive. One manufacturer recommends removal of the product using acetone or petroleum jelly.¹ In our experience, rubbing the adhesive with 2×2-in gauze pads or using forceps have been successful methods for removal. The use of petroleum jelly prior to rubbing with gauze also can aid in removal of the adhesive. Warm water soaks and soap also may be helpful but are not expected to immediately loosen the bond. A mid-potency steroid ointment such as triamcinolone may be effective in treating dermatitis, though the use of higher-potency steroids such as clobetasol may be needed for severe reactions.^1,2

As members of the cyano group, cyanoacrylates are highly reactive molecules that polymerize and rapidly bind to the stratum corneum when they come in contact with traces of water. During polymerization, the individual constituents or monomer cyanoacrylate molecules are joined into a polymer chain, which should be trapped by keratinocytes and not reach immunomodulators^2,10; however, as postulated during the first report of contact dermatitis, an arid environment could delay polymerization and increase the risk of sensitization.² The first report was made in Las Vegas, Nevada,² and our cases presented in San Antonio, Texas.

There currently are 2 main cutaneous adhesives containing cyanoacrylate on the market, including 2-octyl cyanoacrylate and 2-butyl cyanoacrylate. These products are known by various trade names and differ primarily in the length of the carbon chain in the cyanoacrylate. A dye is added to allow better visibility of the glue during application, and a plasticizer increases viscosity and accelerates polymerization. The 2 most widely used products contain the same dye (D&C Violet No. 2) and similar but proprietary plasticizers.

Figure 4. When conducting use tests to determine if plasticizers or dyes in acrylate adhesive products may be potential allergens, a reaction only to product 1 would suggest that 2-octyl cyanoacrylate is to blame. A reaction to products 2 and 3 but not product 1 would suggest 2-butyl cyanoacrylate as a sensitizer, while a reaction to products 1 and 2 but not product 3 would suggest that the dye is responsible.

Although plasticizers and dyes may be potential contact allergens, we postulated that the cyanoacrylate was the responsible sensitizer in our cases. Because the individual ingredients were not readily available for use testing, we devised a logical method to attempt to determine the specific component of the skin adhesive that was responsible for contact sensitization (Figure 4). Patients 3 and 4 in our series were tested using this method and were found to be sensitive to the product containing 2-octyl cyanoacrylate but not the products containing 2-butyl cyanoacrylate.

Conclusion

Given the many advantages of cyanoacrylates, it is likely that their use in skin adhesive products will continue to increase. Our 4 patients may represent a rise in the incidence of ACD associated with increased use of skin adhesives, but it is important to look critically at this agent when patients present with postoperative pruritus in the absence of topical bacitracin or neomycin use and surgical dressing irritation. By using the technique we described, it is possible to identify the component responsible for the reaction; however, in the future, the exact mechanisms of sensitization and the specific components should be further elucidated by researchers working in conjunction with the manufacturers. Use testing on abraded skin and/or under occlusive dressings more closely mimics the initial exposure and may have a role in determining true allergy.

Cyanoacrylates are widely used in adhesive products, with applications ranging from household products to nail and beauty salons and even dentistry. A topical skin adhesive containing 2-octyl cyanoacrylate was approved in 1998 for topical application for closure of skin edges of wounds from surgical incisions.¹ Usually cyanoacrylates are not strong sensitizers, and despite their extensive use, there have been relatively few reports of associated allergic contact dermatitis (ACD).^2-5 We report 4 cases of ACD to 2-octyl cyanoacrylate used in postsurgical wound closures as confirmed by patch tests.

Case Reports

Patient 1

A 33-year-old woman presented with an intensely pruritic peri-incisional rash on the lower back and right buttock of 1 week’s duration. The eruption started roughly 1 week following surgical implantation of a spinal cord stimulator for treatment of chronic back pain. Both incisions made during the implantation were closed with 2-octyl cyanoacrylate. The patient denied any prior exposure to topical skin adhesives or any history of contact dermatitis to nickel or other materials. The patient did not dress the wounds and did not apply topical agents to the area.

Physical examination revealed 6- to 8-cm linear surgical scars on the midline lumbar back and superior right buttock with surrounding excoriated erythematous papules coalescing into plaques consistent with acute eczematous dermatitis (Figure 1). Similar papules and plaques were scattered across the abdomen and chest. She was given triamcinolone acetonide ointment 0.1% twice daily and hydroxyzine pamoate 25 mg 3 times daily for itching. The surgical wounds healed within 2 weeks of presentation with postinflammatory hyperpigmentation surrounding the scars.

Figure 1. Surgical scars with surrounding excoriated erythematous papules coalescing into plaques on the midline lumbar back (A) and superior right buttock (B).

Six weeks later she underwent patch testing to confirm the diagnosis. She was screened using the North American Contact Dermatitis Group standard 65-allergen series and a miscellaneous tray including hardware obtained from the spinal cord stimulator device manufacturer. A use test to 2-octyl cyanoacrylate also was performed. At 96 hours, true positives included cinnamic aldehyde (1+), nickel (1+), bacitracin (1+), fragrance mix (2+), disperse blue dyes 106 and 124 (2+), and 2-octyl cyanoacrylate (3+)(1+=weak positive; 2+=strong positive; 3+=extreme reaction). There was no response to any components of the device. The pattern of dermatitis and positive patch-test results strongly supported the diagnosis of ACD to 2-octyl cyanoacrylate.

Patients 2, 3, and 4

Three patients—a 65-year-old woman, a 35-year-old woman, and a 44-year-old woman—presented to us with eczematous dermatitis at laparoscopic portal sites that were closed with 2-octyl cyanoacrylate (Figures 2 and 3). They presented approximately 1 week following laparoscopic Nissen fundoplication, laparoscopic left hepatectomy, and laparoscopic cholecystectomy, respectively. None of these  3 patients had been using any topical medications. All of them had a positive reaction (2+) to 2-octyl cyanoacrylate on use testing. Interestingly, use tests for 2 other cyanoacrylates containing 2-butyl cyanoacrylate were negative in 2 patients.

Figure 2. Acute eczematous plaques at wound closures.

Figure 3. Coalescing acute eczematous plaques focused at wound closures.

Although patient 1 reported no prior exposure to 2-octyl cyanoacrylate, these 3 additional patients reported prior exposure with no reaction. Other possible contact allergens associated with wound closure included iodine, topical antibiotics, and dressing tape.

Comment

Contact allergies to acrylates are not uncommon. In a series of 275 patients, Kanerva et al⁶ found that 17.5% of patients had an allergic reaction to at least 1 acrylate or methacrylate. In the same series, no allergic reactions to cyanoacrylates were noted.⁶ The role of methacrylates in the development of occupational ACD and irritant dermatitis has been well characterized among dentists, orthopedic surgeons, beauticians, and industrial workers who are commonly exposed to these agents.^7-12 Partially because of their longer carbon chains, cyanoacrylates have reduced toxicity and improved bonding strength as well as flexibility. Given their availability and the ease and speed of their use, skin adhesives have become widely used in the closure of surgical wounds.^13-16

Postoperative contact dermatitis is problematic, as patients are exposed to many potential allergens during surgery. In our clinical practice, the most common allergens causing ACD associated with surgery are iodine, topical antibiotics (ie, bacitracin, neomycin), tape adhesives, suture materials, and less commonly surgical hardware. Although they are rarely reported, contact allergies to skin adhesives such as cyanoacrylates are of particular importance because they may complicate surgical wounds, leading to dehiscence, infection, and scarring, among other complications. In our patients, there were no adverse outcomes in wound healing with the exception of postinflammatory hyperpigmentation.

Under ideal conditions, 2-octyl cyanoacrylate generally is not a strong sensitizer; however, application to open wounds or thinner skin such as the eyelids may permit exposure of antigen-presenting cells to cyanoacrylate monomers, thereby initiating sensitization. Postsurgical occlusive dressings, which often are left in place for 7 to 14 days, also may contribute to sensitization. The role of the degradation of skin adhesive products in the development of contact dermatitis is unknown.

Management of ACD from skin adhesives should involve the immediate removal of any remaining adhesive. One manufacturer recommends removal of the product using acetone or petroleum jelly.¹ In our experience, rubbing the adhesive with 2×2-in gauze pads or using forceps have been successful methods for removal. The use of petroleum jelly prior to rubbing with gauze also can aid in removal of the adhesive. Warm water soaks and soap also may be helpful but are not expected to immediately loosen the bond. A mid-potency steroid ointment such as triamcinolone may be effective in treating dermatitis, though the use of higher-potency steroids such as clobetasol may be needed for severe reactions.^1,2

As members of the cyano group, cyanoacrylates are highly reactive molecules that polymerize and rapidly bind to the stratum corneum when they come in contact with traces of water. During polymerization, the individual constituents or monomer cyanoacrylate molecules are joined into a polymer chain, which should be trapped by keratinocytes and not reach immunomodulators^2,10; however, as postulated during the first report of contact dermatitis, an arid environment could delay polymerization and increase the risk of sensitization.² The first report was made in Las Vegas, Nevada,² and our cases presented in San Antonio, Texas.

There currently are 2 main cutaneous adhesives containing cyanoacrylate on the market, including 2-octyl cyanoacrylate and 2-butyl cyanoacrylate. These products are known by various trade names and differ primarily in the length of the carbon chain in the cyanoacrylate. A dye is added to allow better visibility of the glue during application, and a plasticizer increases viscosity and accelerates polymerization. The 2 most widely used products contain the same dye (D&C Violet No. 2) and similar but proprietary plasticizers.

Figure 4. When conducting use tests to determine if plasticizers or dyes in acrylate adhesive products may be potential allergens, a reaction only to product 1 would suggest that 2-octyl cyanoacrylate is to blame. A reaction to products 2 and 3 but not product 1 would suggest 2-butyl cyanoacrylate as a sensitizer, while a reaction to products 1 and 2 but not product 3 would suggest that the dye is responsible.

Although plasticizers and dyes may be potential contact allergens, we postulated that the cyanoacrylate was the responsible sensitizer in our cases. Because the individual ingredients were not readily available for use testing, we devised a logical method to attempt to determine the specific component of the skin adhesive that was responsible for contact sensitization (Figure 4). Patients 3 and 4 in our series were tested using this method and were found to be sensitive to the product containing 2-octyl cyanoacrylate but not the products containing 2-butyl cyanoacrylate.

Conclusion

Given the many advantages of cyanoacrylates, it is likely that their use in skin adhesive products will continue to increase. Our 4 patients may represent a rise in the incidence of ACD associated with increased use of skin adhesives, but it is important to look critically at this agent when patients present with postoperative pruritus in the absence of topical bacitracin or neomycin use and surgical dressing irritation. By using the technique we described, it is possible to identify the component responsible for the reaction; however, in the future, the exact mechanisms of sensitization and the specific components should be further elucidated by researchers working in conjunction with the manufacturers. Use testing on abraded skin and/or under occlusive dressings more closely mimics the initial exposure and may have a role in determining true allergy.

Cyanoacrylates are widely used in adhesive products, with applications ranging from household products to nail and beauty salons and even dentistry. A topical skin adhesive containing 2-octyl cyanoacrylate was approved in 1998 for topical application for closure of skin edges of wounds from surgical incisions.¹ Usually cyanoacrylates are not strong sensitizers, and despite their extensive use, there have been relatively few reports of associated allergic contact dermatitis (ACD).^2-5 We report 4 cases of ACD to 2-octyl cyanoacrylate used in postsurgical wound closures as confirmed by patch tests.

Case Reports

Patient 1

A 33-year-old woman presented with an intensely pruritic peri-incisional rash on the lower back and right buttock of 1 week’s duration. The eruption started roughly 1 week following surgical implantation of a spinal cord stimulator for treatment of chronic back pain. Both incisions made during the implantation were closed with 2-octyl cyanoacrylate. The patient denied any prior exposure to topical skin adhesives or any history of contact dermatitis to nickel or other materials. The patient did not dress the wounds and did not apply topical agents to the area.

Physical examination revealed 6- to 8-cm linear surgical scars on the midline lumbar back and superior right buttock with surrounding excoriated erythematous papules coalescing into plaques consistent with acute eczematous dermatitis (Figure 1). Similar papules and plaques were scattered across the abdomen and chest. She was given triamcinolone acetonide ointment 0.1% twice daily and hydroxyzine pamoate 25 mg 3 times daily for itching. The surgical wounds healed within 2 weeks of presentation with postinflammatory hyperpigmentation surrounding the scars.

Figure 1. Surgical scars with surrounding excoriated erythematous papules coalescing into plaques on the midline lumbar back (A) and superior right buttock (B).

Six weeks later she underwent patch testing to confirm the diagnosis. She was screened using the North American Contact Dermatitis Group standard 65-allergen series and a miscellaneous tray including hardware obtained from the spinal cord stimulator device manufacturer. A use test to 2-octyl cyanoacrylate also was performed. At 96 hours, true positives included cinnamic aldehyde (1+), nickel (1+), bacitracin (1+), fragrance mix (2+), disperse blue dyes 106 and 124 (2+), and 2-octyl cyanoacrylate (3+)(1+=weak positive; 2+=strong positive; 3+=extreme reaction). There was no response to any components of the device. The pattern of dermatitis and positive patch-test results strongly supported the diagnosis of ACD to 2-octyl cyanoacrylate.

Patients 2, 3, and 4

Three patients—a 65-year-old woman, a 35-year-old woman, and a 44-year-old woman—presented to us with eczematous dermatitis at laparoscopic portal sites that were closed with 2-octyl cyanoacrylate (Figures 2 and 3). They presented approximately 1 week following laparoscopic Nissen fundoplication, laparoscopic left hepatectomy, and laparoscopic cholecystectomy, respectively. None of these  3 patients had been using any topical medications. All of them had a positive reaction (2+) to 2-octyl cyanoacrylate on use testing. Interestingly, use tests for 2 other cyanoacrylates containing 2-butyl cyanoacrylate were negative in 2 patients.

Figure 2. Acute eczematous plaques at wound closures.

Figure 3. Coalescing acute eczematous plaques focused at wound closures.

Although patient 1 reported no prior exposure to 2-octyl cyanoacrylate, these 3 additional patients reported prior exposure with no reaction. Other possible contact allergens associated with wound closure included iodine, topical antibiotics, and dressing tape.

Comment

Contact allergies to acrylates are not uncommon. In a series of 275 patients, Kanerva et al⁶ found that 17.5% of patients had an allergic reaction to at least 1 acrylate or methacrylate. In the same series, no allergic reactions to cyanoacrylates were noted.⁶ The role of methacrylates in the development of occupational ACD and irritant dermatitis has been well characterized among dentists, orthopedic surgeons, beauticians, and industrial workers who are commonly exposed to these agents.^7-12 Partially because of their longer carbon chains, cyanoacrylates have reduced toxicity and improved bonding strength as well as flexibility. Given their availability and the ease and speed of their use, skin adhesives have become widely used in the closure of surgical wounds.^13-16

Postoperative contact dermatitis is problematic, as patients are exposed to many potential allergens during surgery. In our clinical practice, the most common allergens causing ACD associated with surgery are iodine, topical antibiotics (ie, bacitracin, neomycin), tape adhesives, suture materials, and less commonly surgical hardware. Although they are rarely reported, contact allergies to skin adhesives such as cyanoacrylates are of particular importance because they may complicate surgical wounds, leading to dehiscence, infection, and scarring, among other complications. In our patients, there were no adverse outcomes in wound healing with the exception of postinflammatory hyperpigmentation.

Under ideal conditions, 2-octyl cyanoacrylate generally is not a strong sensitizer; however, application to open wounds or thinner skin such as the eyelids may permit exposure of antigen-presenting cells to cyanoacrylate monomers, thereby initiating sensitization. Postsurgical occlusive dressings, which often are left in place for 7 to 14 days, also may contribute to sensitization. The role of the degradation of skin adhesive products in the development of contact dermatitis is unknown.

Management of ACD from skin adhesives should involve the immediate removal of any remaining adhesive. One manufacturer recommends removal of the product using acetone or petroleum jelly.¹ In our experience, rubbing the adhesive with 2×2-in gauze pads or using forceps have been successful methods for removal. The use of petroleum jelly prior to rubbing with gauze also can aid in removal of the adhesive. Warm water soaks and soap also may be helpful but are not expected to immediately loosen the bond. A mid-potency steroid ointment such as triamcinolone may be effective in treating dermatitis, though the use of higher-potency steroids such as clobetasol may be needed for severe reactions.^1,2

As members of the cyano group, cyanoacrylates are highly reactive molecules that polymerize and rapidly bind to the stratum corneum when they come in contact with traces of water. During polymerization, the individual constituents or monomer cyanoacrylate molecules are joined into a polymer chain, which should be trapped by keratinocytes and not reach immunomodulators^2,10; however, as postulated during the first report of contact dermatitis, an arid environment could delay polymerization and increase the risk of sensitization.² The first report was made in Las Vegas, Nevada,² and our cases presented in San Antonio, Texas.

There currently are 2 main cutaneous adhesives containing cyanoacrylate on the market, including 2-octyl cyanoacrylate and 2-butyl cyanoacrylate. These products are known by various trade names and differ primarily in the length of the carbon chain in the cyanoacrylate. A dye is added to allow better visibility of the glue during application, and a plasticizer increases viscosity and accelerates polymerization. The 2 most widely used products contain the same dye (D&C Violet No. 2) and similar but proprietary plasticizers.

Figure 4. When conducting use tests to determine if plasticizers or dyes in acrylate adhesive products may be potential allergens, a reaction only to product 1 would suggest that 2-octyl cyanoacrylate is to blame. A reaction to products 2 and 3 but not product 1 would suggest 2-butyl cyanoacrylate as a sensitizer, while a reaction to products 1 and 2 but not product 3 would suggest that the dye is responsible.

Although plasticizers and dyes may be potential contact allergens, we postulated that the cyanoacrylate was the responsible sensitizer in our cases. Because the individual ingredients were not readily available for use testing, we devised a logical method to attempt to determine the specific component of the skin adhesive that was responsible for contact sensitization (Figure 4). Patients 3 and 4 in our series were tested using this method and were found to be sensitive to the product containing 2-octyl cyanoacrylate but not the products containing 2-butyl cyanoacrylate.

Conclusion

Given the many advantages of cyanoacrylates, it is likely that their use in skin adhesive products will continue to increase. Our 4 patients may represent a rise in the incidence of ACD associated with increased use of skin adhesives, but it is important to look critically at this agent when patients present with postoperative pruritus in the absence of topical bacitracin or neomycin use and surgical dressing irritation. By using the technique we described, it is possible to identify the component responsible for the reaction; however, in the future, the exact mechanisms of sensitization and the specific components should be further elucidated by researchers working in conjunction with the manufacturers. Use testing on abraded skin and/or under occlusive dressings more closely mimics the initial exposure and may have a role in determining true allergy.

Today’s cosmetic patient wants to look more youthful every day without spending a lot of money, feeling any pain, or having any postprocedure downtime. With continued technological improvements, dermatologists have been able to provide our patients with the more youthful appearance they desire; however, many of these procedures still are costly, painful, and may require some downtime. New cosmeceutical therapies can be used as adjuncts to these procedures, making antiaging regimens less painful for patients and requiring less postprocedure healing time. In this article, the use of cosmeceuticals in conjunction with chemical peels, lasers, and injectables will be discussed.

Chemical Peels

Chemical peels are used to create an injury of specific skin depth with a goal of stimulating new skin growth and improving surface texture and appearance. They generally are classified as superficial, medium, or deep according to the depth of action. Currently available agents for superficial chemical peels include α-hydroxy acids (AHAs)(eg, glycolic acid [GA]) and β-hydroxy acids (BHAs)(eg, salicylic acid). β-Lipohydroxy acid (up to 10%), a derivative of salicylic acid, is widely used in Europe. Trichloroacetic acid (TCA) can be used for superficial peels (10%–20%) and for medium-depth peels (35%). Combination peels such as Monheit combination (Jessner solution plus TCA), Brody combination (solid CO₂ plus TCA), Coleman combination (GA 70% plus TCA), and Jessner solution with GA can be used as medium-depth peels. Deep peels typically are performed with phenol-based solutions, including the Baker-Gordon phenol peel and the Hetter peel (phenol or croton oil peel).

Specific agents for chemical peels should be selected based on the disorder being treated and should be administered using an appropriate peel depth determined by the histologic level or severity of skin pathology to maximize treatment success.¹ However, other considerations, such as skin characteristics, area of skin to be treated, safety concerns, healing time, and patient adherence also should be taken into account to achieve the best overall results. Although many of the deeper peels recently have been replaced by laser-based ablative treatments, superficial to medium-depth peels still are commonly used in the treatment of fine lines, uneven texture, and dyspigmentation.²

Superficial peels are reasonably safe and well tolerated, usually with only mild discomfort (eg, transient burning, irritation, erythema). Scarring, postinflammatory hyperpigmentation (PIH), and infection are rare with superficial peels.¹ Postinflammatory hyperpigmentation can be exacerbated by sun exposure, making it important for patients to be educated about sun protection and closely monitored during the recovery phase. In medium and deep peels, lines of demarcation related to the administration technique can occur. Feathering the chemical peel solution at junctions with nonpeeled skin can help to avoid this effect.¹ Side effects associated with deeper chemical peels can include pigmentary changes, infections, allergic reactions, improper healing, hypersensitivity, and underlying disease exacerbation. The best way to prevent complications is to identify patients who are at risk and maintain an appropriate peel depth that balances efficacy with known adverse events.¹ 

Many adjunctive agents (eg, AHAs, BHAs, retinoids, skin-bleaching preparations) can be used to enhance chemical peels and decrease the incidence of PIH. α-Hydroxy acids and BHAs can be beneficial when applied prior to chemical peels. Moisturizers containing AHAs and BHAs can be used for 2 to 3 weeks before superficial or medium-depth chemical peels.² These agents cause thinning of the stratum corneum, thereby creating a more uniform cutaneous surface and allowing for deeper penetration of the chemical peeling agent. Retinoids also are superior prepeeling agents; however, retinoids also can increase the likelihood of irritation, which can be minimized by discontinuing retinoids for 1 week following chemical peels.² A combination of chemical peels and topical bleaching agents has been shown to be effective in treating hyperpigmentation. The chemical peel causes superficial exfoliation, which allows the lightening agent to penetrate more deeply.²

Hydroquinone (HQ) is the gold standard for improvement of existing pigmentation.³ It is one of the most effective inhibitors of melanogenesis both in vitro and in vivo and is widely used for the treatment of melanosis and other hyperpigmentary disorders. It is widely accepted that the depigmentation activity of HQ may partly be related to its ability to act as an alternate substrate of tyrosinase, thereby competing for tyrosine oxidation in active melanocytes.³ Using HQ at a 4% concentration and combining it with retinoids is quite efficacious.² Other commonly used depigmenting agents include kojic acid, ascorbic acid (vitamin C), and niacinamide, which often can be used as adjuncts with or maintenance therapy after HQ treatment.^2,3

The risk for PIH is imminent for chemical peels and cosmetic laser treatments; therefore, it is crucial to educate patients about the importance of daily and aggressive sun protection. There are several methods of reducing or eliminating postprocedure melanin formation, such as inhibiting tyrosinase synthesis, using complex copper to inhibit tyrosinase function, eliminating oxidation reactions that lead to polymer formation, slowing down the transfer of melanosomes to keratinocytes, or acting upstream on the hormone that stimulates melanogenesis.³ Most of the depigmenting agents presently on the market act by inhibiting tyrosinase via one of these mechanisms. 

Skin-lightening agents are primarily formulated as emulsions that have a higher aesthetic appeal. Many of the ingredients get better dispersions with emulsions, which is an added feature of these products. Recently, gel-based formulations also are being considered for their suitability in certain skin types. Efficacy studies for skin-lightening formulations are being carried out through clinical trials that utilize devices that measure skin color in addition to the dermatologist’s assessment.⁴ Other skin parameters (eg, moisturization, texture, barrier integrity, pH) also are being evaluated to give physicians a picture of skin health after the use of skin-lightening agents. With advances in technology and measurement techniques, it is becoming easier to identify the efficacy of these formulations in different skin types.⁴

Lasers

The ultimate goal of laser therapy often is to improve the canvas and color of the skin. Ablative laser resurfacing is reliably the most effective procedure for sun-damaged skin.² This technique causes thermally induced full-thickness epidermal and dermal denudation, which in turn facilitates cytokine-led dermal collagen formation and reepithelialization. Various nonablative modalities also are used for treating photodamaged skin. The epidermis remains unaffected by these nonablative methods, thus decreasing the need for extensive wound care and downtime that is required with ablative treatments. Combining nonablative laser treatments with topical cosmeceuticals has been proven more effective than using either method alone.² The use of topical retinoids prior to ablative laser resurfacing often results in remarkably faster postprocedure healing and reepithelialization (Figure). Retinoids are best applied nightly for at least 2 weeks and optimally for 3 months before ablative laser treatment. Application should be discontinued for 1 week immediately prior to the procedure.

Before (A) and after (B) treatment with a fractional laser in combination with a pre- and postprocedure skin care regimen consisting of retinoids and sunscreen.

Topical retinoids also are effective in reducing erythema and increasing dermal thickness after nonablative treatments. When used prior to laser treatments, retinoids have been shown to decrease the risk for postoperative milia and hyperpigmentation as well as to allow for better penetration of the laser beam secondary to a thinner stratum corneum.² Following ablative resurfacing, retinoid use should be discontinued for several weeks to allow for reepithelialization and adequate healing.

Postprocedure Wound Healing

Most of the recommended products that help decrease postprocedural inflammation are cosmeceuticals containing both antioxidants and anti-inflammatories to help decrease redness and inflammation, including various barrier repair moisturizers. Restoring barrier integrity improves the overall appearance of the skin. The ingredients normally recommended in barrier repair moisturizers are epidermal lipids such as ceramides; hyaluronic acid (HA), which is a humectant; and occlusives for patients with very dry skin. Some of the ingredients in over-the-counter cosmeceuticals that can help decrease redness and inflammation include vitamin C, vitamin E, and vitamin B or niacinamide, which will help plump the barrier and also have anti-inflammatory properties. Additionally, polyphenolic flavonoids such as soy and green tea can help decrease inflammation, along with a number of other organic ingredients, such as caffeine, feverfew, and licorice.⁵ If topical vitamin C is being considered for postprocedure use, the non–ascorbic acid variant should be administered. The magnesium ascorbyl phosphate and ascorbyl palmitate forms of vitamin C have a neutral pH and tend to be better tolerated by patients.

In addition to current prescription and over-the-counter cosmeceuticals used for postprocedure irritation and inflammation, copper peptides and other well-tolerated and effective naturally occurring compounds are being investigated and tried. Copper is a biocide that regulates keratinocyte integrins for epithelization and extracellular matrix remodeling. The extracellular matrix consists of the structural fibrillar collagens and is remodeled or degraded by matrix metalloproteinases (MMPs) that facilitate epithelization. The predominant classes of MMPs include collagenases (ie, MMP-1) and gelatinases (ie, MMP-2, MMP-9) that degrade interstitial collagen and basement membrane proteins.⁶ The MMPs are endogenously inhibited by tissue inhibitors of metalloproteinases (TIMPs). Copper is a cofactor to lysyl oxidase, which cross-links collagen and stimulates expression of MMP-2 and collagen in a complex with a matrix-derived tripeptide (glycyl-histidyl-lysine or Gly-His-Lys [GHK]) in fibroblasts.⁶ Much attention has been focused on the tripeptides, such as GHK and Gly-Gly-His, and their copper complexes, which have high activity and good skin tolerance. These complexes have been shown to play a physiological role in the process of wound healing, tissue repair, and skin inflammation. Gly-Gly-His, GHK, copper chloride, and their copper complexes decrease tumor necrosis factor α–dependent IL-6 secretion in fibroblasts.⁷ IL-6 is crucial for normal wound healing, skin inflammation, and UVB-induced erythema. Because of their anti-inflammatory properties, these copper peptides could potentially be used in place of corticosteroids or nonsteroidal anti-inflammatory drugs, which have more side effects.

Botulinum Neurotoxin and Other Injectable Fillers

Acetyl Hexapeptide-3: A Topical Complement to Botulinum Neurotoxin

Acetyl hexapeptide-3 (Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂) was discovered when looking for a less toxic variation of botulinum neurotoxin (BoNT) to treat aging skin.⁸ It is patterned from the N-terminal end of the synaptosome-associated protein of molecular weight 25 kDa (SNAP-25), which is essential for docking and fusion of synaptic vesicles to the presynaptic membrane for acetylcholine release.⁹ It prevents formation and stability of the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex, inhibiting vesicle docking and calcium-dependent catecholamine exocytosis.⁸ It also has been found to substantially inhibit the repetitive muscular contraction of facial expression similar to BoNT type A but with somewhat lower efficacy. Acetyl hexapeptide-3 was shown to inhibit 30% of total catecholamine exocytosis and had a remarkable capacity to permeate the skin.¹⁰ Thus this topical form of BoNT is a useful complement to intramuscular BoNT.

Studies showing the efficacy and safety of acetyl hexapeptide-3 have demonstrated reductions in wrinkle intensity, mainly in the lateral periorbital areas. In one early study, 10 women applied an emulsion containing 10% of the hexapeptide to one lateral periorbital region and the same emulsion without the hexapeptide to the contralateral side, both twice daily for 30 days.¹⁰ A 30% decrease in the depth of skin wrinkles was seen on the hexapeptide side compared with a 10% decrease in the depth of wrinkles on the side treated without hexapeptide. No irritation or toxicity was noted.¹⁰ In another trial, 10 women applied an acetyl hexapeptide-3 cream 5% twice daily to lateral periorbital rhytides, with a 27% improvement in wrinkle depth after a 30-day treatment period.⁹ A double-blind, placebo-controlled study of 60 women assessing the safety and efficacy of topical hexapeptide showed a total antiwrinkle efficacy of 48.9% on the side treated with an emulsion containing 10% of the hexapeptide compared with 0% efficacy on the placebo side.⁸ Similar to Blanes-Mira et al,¹⁰ no adverse events such as skin irritation or toxicity were seen.⁸ In all of these studies, wrinkle depth was measured by silicone replica analysis.

Topical acetyl hexapeptide-3 is effective in decreasing wrinkles, and its best use will likely be as an adjunct to intramuscular BoNT, as the intramuscular form likely has higher efficacy with the toxin injected directly into the target muscle; however, patients who want the effects of BoNT without the pain of injections may choose to use topical acetyl hexapeptide-3 alone. Patients who do use acetyl hexapeptide-3 as a complement to their intramuscular BoNT regimen may not need as many units of BoNT with each treatment or may not need certain areas injected as often, leading to fewer injections and less pain with each visit. Skin irritation was not seen as a side effect in these trials. Additionally, the topical form has insignificant acute toxicity (≥2000 mg/kg) compared to BoNT type A (20 ng/kg), and genotoxicity was not seen with testing, making it a safe complementary option to an injectable regimen.⁸

Topical Hyaluronic Acid: A Complement to Injectable Fillers

Hyaluronic acid (HA) is a glycosaminoglycan found in the extracellular matrix of the skin that greatly contributes to tissue hydration. Additionally, it plays a crucial role in the synthesis of extracellular matrix molecules and epidermal cell interaction with the environment.¹¹ The water-binding capacity of HA approximates 1000 times its volume or 6 L of water per gram of HA; however, once an individual reaches adulthood, the amount of HA decreases to 5% of baseline levels, thus contributing to xerosis, loss of skin elasticity, and atrophy.^11,12 Although photoaged skin can have increased glycosaminoglycans due to an increase in chondroitin sulfate proteoglycans, they are abnormally deposited on elastotic material in the superficial dermis rather than diffusely scattered, as seen in youthful skin.¹²

Many topical antiaging products contain HA, though evidence for efficacy in reducing wrinkles has been lacking, along with concerns that HA cannot penetrate the skin. This concern stems from the fact that the original molecule is 3000 nm in diameter and the intercellular space is only 15 to 50 nm. This space is only 6 to 10 nm at the hyaline membrane. Recently, scientists in Japan found a way to reduce the size of HA molecules to 5 nm (nano-HA) without changing its structure. A study of 33 women who applied the topical nano-HA twice daily for 8 weeks to one periorbital area while the contralateral side was left untreated showed improved hydration of the treated side that continued to increase when measured at 2, 4, and 8 weeks using corneometry.¹¹ Roughness decreased and elasticity increased after week 2, which were maintained throughout the study. Additionally, erythema was measured using a chroma meter, which was found to have decreased at day 57 versus day 1.¹¹ An earlier study by Pavicic et al¹² evaluated the efficacy of topical hyalu-ronan 0.1% formulations of different molecular weights—50, 130, 300, 800, or 2000 kDa—in the periocular area. A randomized group of 76 women were treated twice daily for 2 months with HA cream on one side of the periocular area and placebo cream on the other. With regard to antiwrinkle properties, only the 50- and 130-kDa HA formulations showed marked effects compared with placebo after 2 months.¹²

Topical HA would be an effective addition to an antiwrinkle regimen, especially in patients who are averse to needles or are just starting to get wrinkles and are looking for a noninvasive therapy. Additionally, it would be beneficial for patients who have an injectable filler and BoNT regimen, as these patients will be able to target wrinkles simultaneously with both topical cosmeceuticals and injectables and likely will need fewer units of BoNT and/or filler and possibly fewer injections over time, which translates to decreased pain and adverse outcomes for patients.

Conclusion

The myriad of options dermatologists have to offer patients for cosmetic enhancement provides alternatives for patients who have contraindications to certain treatments, are needle averse, or have lifestyles that do not afford them a great deal of postprocedural healing time. Being knowledgeable about these options and how to combine them for improved outcomes is essential to any cosmetic practice.

Today’s cosmetic patient wants to look more youthful every day without spending a lot of money, feeling any pain, or having any postprocedure downtime. With continued technological improvements, dermatologists have been able to provide our patients with the more youthful appearance they desire; however, many of these procedures still are costly, painful, and may require some downtime. New cosmeceutical therapies can be used as adjuncts to these procedures, making antiaging regimens less painful for patients and requiring less postprocedure healing time. In this article, the use of cosmeceuticals in conjunction with chemical peels, lasers, and injectables will be discussed.

Chemical Peels

Chemical peels are used to create an injury of specific skin depth with a goal of stimulating new skin growth and improving surface texture and appearance. They generally are classified as superficial, medium, or deep according to the depth of action. Currently available agents for superficial chemical peels include α-hydroxy acids (AHAs)(eg, glycolic acid [GA]) and β-hydroxy acids (BHAs)(eg, salicylic acid). β-Lipohydroxy acid (up to 10%), a derivative of salicylic acid, is widely used in Europe. Trichloroacetic acid (TCA) can be used for superficial peels (10%–20%) and for medium-depth peels (35%). Combination peels such as Monheit combination (Jessner solution plus TCA), Brody combination (solid CO₂ plus TCA), Coleman combination (GA 70% plus TCA), and Jessner solution with GA can be used as medium-depth peels. Deep peels typically are performed with phenol-based solutions, including the Baker-Gordon phenol peel and the Hetter peel (phenol or croton oil peel).

Specific agents for chemical peels should be selected based on the disorder being treated and should be administered using an appropriate peel depth determined by the histologic level or severity of skin pathology to maximize treatment success.¹ However, other considerations, such as skin characteristics, area of skin to be treated, safety concerns, healing time, and patient adherence also should be taken into account to achieve the best overall results. Although many of the deeper peels recently have been replaced by laser-based ablative treatments, superficial to medium-depth peels still are commonly used in the treatment of fine lines, uneven texture, and dyspigmentation.²

Superficial peels are reasonably safe and well tolerated, usually with only mild discomfort (eg, transient burning, irritation, erythema). Scarring, postinflammatory hyperpigmentation (PIH), and infection are rare with superficial peels.¹ Postinflammatory hyperpigmentation can be exacerbated by sun exposure, making it important for patients to be educated about sun protection and closely monitored during the recovery phase. In medium and deep peels, lines of demarcation related to the administration technique can occur. Feathering the chemical peel solution at junctions with nonpeeled skin can help to avoid this effect.¹ Side effects associated with deeper chemical peels can include pigmentary changes, infections, allergic reactions, improper healing, hypersensitivity, and underlying disease exacerbation. The best way to prevent complications is to identify patients who are at risk and maintain an appropriate peel depth that balances efficacy with known adverse events.¹ 

Many adjunctive agents (eg, AHAs, BHAs, retinoids, skin-bleaching preparations) can be used to enhance chemical peels and decrease the incidence of PIH. α-Hydroxy acids and BHAs can be beneficial when applied prior to chemical peels. Moisturizers containing AHAs and BHAs can be used for 2 to 3 weeks before superficial or medium-depth chemical peels.² These agents cause thinning of the stratum corneum, thereby creating a more uniform cutaneous surface and allowing for deeper penetration of the chemical peeling agent. Retinoids also are superior prepeeling agents; however, retinoids also can increase the likelihood of irritation, which can be minimized by discontinuing retinoids for 1 week following chemical peels.² A combination of chemical peels and topical bleaching agents has been shown to be effective in treating hyperpigmentation. The chemical peel causes superficial exfoliation, which allows the lightening agent to penetrate more deeply.²

Hydroquinone (HQ) is the gold standard for improvement of existing pigmentation.³ It is one of the most effective inhibitors of melanogenesis both in vitro and in vivo and is widely used for the treatment of melanosis and other hyperpigmentary disorders. It is widely accepted that the depigmentation activity of HQ may partly be related to its ability to act as an alternate substrate of tyrosinase, thereby competing for tyrosine oxidation in active melanocytes.³ Using HQ at a 4% concentration and combining it with retinoids is quite efficacious.² Other commonly used depigmenting agents include kojic acid, ascorbic acid (vitamin C), and niacinamide, which often can be used as adjuncts with or maintenance therapy after HQ treatment.^2,3

The risk for PIH is imminent for chemical peels and cosmetic laser treatments; therefore, it is crucial to educate patients about the importance of daily and aggressive sun protection. There are several methods of reducing or eliminating postprocedure melanin formation, such as inhibiting tyrosinase synthesis, using complex copper to inhibit tyrosinase function, eliminating oxidation reactions that lead to polymer formation, slowing down the transfer of melanosomes to keratinocytes, or acting upstream on the hormone that stimulates melanogenesis.³ Most of the depigmenting agents presently on the market act by inhibiting tyrosinase via one of these mechanisms. 

Skin-lightening agents are primarily formulated as emulsions that have a higher aesthetic appeal. Many of the ingredients get better dispersions with emulsions, which is an added feature of these products. Recently, gel-based formulations also are being considered for their suitability in certain skin types. Efficacy studies for skin-lightening formulations are being carried out through clinical trials that utilize devices that measure skin color in addition to the dermatologist’s assessment.⁴ Other skin parameters (eg, moisturization, texture, barrier integrity, pH) also are being evaluated to give physicians a picture of skin health after the use of skin-lightening agents. With advances in technology and measurement techniques, it is becoming easier to identify the efficacy of these formulations in different skin types.⁴

Lasers

The ultimate goal of laser therapy often is to improve the canvas and color of the skin. Ablative laser resurfacing is reliably the most effective procedure for sun-damaged skin.² This technique causes thermally induced full-thickness epidermal and dermal denudation, which in turn facilitates cytokine-led dermal collagen formation and reepithelialization. Various nonablative modalities also are used for treating photodamaged skin. The epidermis remains unaffected by these nonablative methods, thus decreasing the need for extensive wound care and downtime that is required with ablative treatments. Combining nonablative laser treatments with topical cosmeceuticals has been proven more effective than using either method alone.² The use of topical retinoids prior to ablative laser resurfacing often results in remarkably faster postprocedure healing and reepithelialization (Figure). Retinoids are best applied nightly for at least 2 weeks and optimally for 3 months before ablative laser treatment. Application should be discontinued for 1 week immediately prior to the procedure.

Before (A) and after (B) treatment with a fractional laser in combination with a pre- and postprocedure skin care regimen consisting of retinoids and sunscreen.

Topical retinoids also are effective in reducing erythema and increasing dermal thickness after nonablative treatments. When used prior to laser treatments, retinoids have been shown to decrease the risk for postoperative milia and hyperpigmentation as well as to allow for better penetration of the laser beam secondary to a thinner stratum corneum.² Following ablative resurfacing, retinoid use should be discontinued for several weeks to allow for reepithelialization and adequate healing.

Postprocedure Wound Healing

Most of the recommended products that help decrease postprocedural inflammation are cosmeceuticals containing both antioxidants and anti-inflammatories to help decrease redness and inflammation, including various barrier repair moisturizers. Restoring barrier integrity improves the overall appearance of the skin. The ingredients normally recommended in barrier repair moisturizers are epidermal lipids such as ceramides; hyaluronic acid (HA), which is a humectant; and occlusives for patients with very dry skin. Some of the ingredients in over-the-counter cosmeceuticals that can help decrease redness and inflammation include vitamin C, vitamin E, and vitamin B or niacinamide, which will help plump the barrier and also have anti-inflammatory properties. Additionally, polyphenolic flavonoids such as soy and green tea can help decrease inflammation, along with a number of other organic ingredients, such as caffeine, feverfew, and licorice.⁵ If topical vitamin C is being considered for postprocedure use, the non–ascorbic acid variant should be administered. The magnesium ascorbyl phosphate and ascorbyl palmitate forms of vitamin C have a neutral pH and tend to be better tolerated by patients.

In addition to current prescription and over-the-counter cosmeceuticals used for postprocedure irritation and inflammation, copper peptides and other well-tolerated and effective naturally occurring compounds are being investigated and tried. Copper is a biocide that regulates keratinocyte integrins for epithelization and extracellular matrix remodeling. The extracellular matrix consists of the structural fibrillar collagens and is remodeled or degraded by matrix metalloproteinases (MMPs) that facilitate epithelization. The predominant classes of MMPs include collagenases (ie, MMP-1) and gelatinases (ie, MMP-2, MMP-9) that degrade interstitial collagen and basement membrane proteins.⁶ The MMPs are endogenously inhibited by tissue inhibitors of metalloproteinases (TIMPs). Copper is a cofactor to lysyl oxidase, which cross-links collagen and stimulates expression of MMP-2 and collagen in a complex with a matrix-derived tripeptide (glycyl-histidyl-lysine or Gly-His-Lys [GHK]) in fibroblasts.⁶ Much attention has been focused on the tripeptides, such as GHK and Gly-Gly-His, and their copper complexes, which have high activity and good skin tolerance. These complexes have been shown to play a physiological role in the process of wound healing, tissue repair, and skin inflammation. Gly-Gly-His, GHK, copper chloride, and their copper complexes decrease tumor necrosis factor α–dependent IL-6 secretion in fibroblasts.⁷ IL-6 is crucial for normal wound healing, skin inflammation, and UVB-induced erythema. Because of their anti-inflammatory properties, these copper peptides could potentially be used in place of corticosteroids or nonsteroidal anti-inflammatory drugs, which have more side effects.

Botulinum Neurotoxin and Other Injectable Fillers

Acetyl Hexapeptide-3: A Topical Complement to Botulinum Neurotoxin

Acetyl hexapeptide-3 (Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂) was discovered when looking for a less toxic variation of botulinum neurotoxin (BoNT) to treat aging skin.⁸ It is patterned from the N-terminal end of the synaptosome-associated protein of molecular weight 25 kDa (SNAP-25), which is essential for docking and fusion of synaptic vesicles to the presynaptic membrane for acetylcholine release.⁹ It prevents formation and stability of the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex, inhibiting vesicle docking and calcium-dependent catecholamine exocytosis.⁸ It also has been found to substantially inhibit the repetitive muscular contraction of facial expression similar to BoNT type A but with somewhat lower efficacy. Acetyl hexapeptide-3 was shown to inhibit 30% of total catecholamine exocytosis and had a remarkable capacity to permeate the skin.¹⁰ Thus this topical form of BoNT is a useful complement to intramuscular BoNT.

Studies showing the efficacy and safety of acetyl hexapeptide-3 have demonstrated reductions in wrinkle intensity, mainly in the lateral periorbital areas. In one early study, 10 women applied an emulsion containing 10% of the hexapeptide to one lateral periorbital region and the same emulsion without the hexapeptide to the contralateral side, both twice daily for 30 days.¹⁰ A 30% decrease in the depth of skin wrinkles was seen on the hexapeptide side compared with a 10% decrease in the depth of wrinkles on the side treated without hexapeptide. No irritation or toxicity was noted.¹⁰ In another trial, 10 women applied an acetyl hexapeptide-3 cream 5% twice daily to lateral periorbital rhytides, with a 27% improvement in wrinkle depth after a 30-day treatment period.⁹ A double-blind, placebo-controlled study of 60 women assessing the safety and efficacy of topical hexapeptide showed a total antiwrinkle efficacy of 48.9% on the side treated with an emulsion containing 10% of the hexapeptide compared with 0% efficacy on the placebo side.⁸ Similar to Blanes-Mira et al,¹⁰ no adverse events such as skin irritation or toxicity were seen.⁸ In all of these studies, wrinkle depth was measured by silicone replica analysis.

Topical acetyl hexapeptide-3 is effective in decreasing wrinkles, and its best use will likely be as an adjunct to intramuscular BoNT, as the intramuscular form likely has higher efficacy with the toxin injected directly into the target muscle; however, patients who want the effects of BoNT without the pain of injections may choose to use topical acetyl hexapeptide-3 alone. Patients who do use acetyl hexapeptide-3 as a complement to their intramuscular BoNT regimen may not need as many units of BoNT with each treatment or may not need certain areas injected as often, leading to fewer injections and less pain with each visit. Skin irritation was not seen as a side effect in these trials. Additionally, the topical form has insignificant acute toxicity (≥2000 mg/kg) compared to BoNT type A (20 ng/kg), and genotoxicity was not seen with testing, making it a safe complementary option to an injectable regimen.⁸

Topical Hyaluronic Acid: A Complement to Injectable Fillers

Hyaluronic acid (HA) is a glycosaminoglycan found in the extracellular matrix of the skin that greatly contributes to tissue hydration. Additionally, it plays a crucial role in the synthesis of extracellular matrix molecules and epidermal cell interaction with the environment.¹¹ The water-binding capacity of HA approximates 1000 times its volume or 6 L of water per gram of HA; however, once an individual reaches adulthood, the amount of HA decreases to 5% of baseline levels, thus contributing to xerosis, loss of skin elasticity, and atrophy.^11,12 Although photoaged skin can have increased glycosaminoglycans due to an increase in chondroitin sulfate proteoglycans, they are abnormally deposited on elastotic material in the superficial dermis rather than diffusely scattered, as seen in youthful skin.¹²

Many topical antiaging products contain HA, though evidence for efficacy in reducing wrinkles has been lacking, along with concerns that HA cannot penetrate the skin. This concern stems from the fact that the original molecule is 3000 nm in diameter and the intercellular space is only 15 to 50 nm. This space is only 6 to 10 nm at the hyaline membrane. Recently, scientists in Japan found a way to reduce the size of HA molecules to 5 nm (nano-HA) without changing its structure. A study of 33 women who applied the topical nano-HA twice daily for 8 weeks to one periorbital area while the contralateral side was left untreated showed improved hydration of the treated side that continued to increase when measured at 2, 4, and 8 weeks using corneometry.¹¹ Roughness decreased and elasticity increased after week 2, which were maintained throughout the study. Additionally, erythema was measured using a chroma meter, which was found to have decreased at day 57 versus day 1.¹¹ An earlier study by Pavicic et al¹² evaluated the efficacy of topical hyalu-ronan 0.1% formulations of different molecular weights—50, 130, 300, 800, or 2000 kDa—in the periocular area. A randomized group of 76 women were treated twice daily for 2 months with HA cream on one side of the periocular area and placebo cream on the other. With regard to antiwrinkle properties, only the 50- and 130-kDa HA formulations showed marked effects compared with placebo after 2 months.¹²

Topical HA would be an effective addition to an antiwrinkle regimen, especially in patients who are averse to needles or are just starting to get wrinkles and are looking for a noninvasive therapy. Additionally, it would be beneficial for patients who have an injectable filler and BoNT regimen, as these patients will be able to target wrinkles simultaneously with both topical cosmeceuticals and injectables and likely will need fewer units of BoNT and/or filler and possibly fewer injections over time, which translates to decreased pain and adverse outcomes for patients.

Conclusion

The myriad of options dermatologists have to offer patients for cosmetic enhancement provides alternatives for patients who have contraindications to certain treatments, are needle averse, or have lifestyles that do not afford them a great deal of postprocedural healing time. Being knowledgeable about these options and how to combine them for improved outcomes is essential to any cosmetic practice.

Today’s cosmetic patient wants to look more youthful every day without spending a lot of money, feeling any pain, or having any postprocedure downtime. With continued technological improvements, dermatologists have been able to provide our patients with the more youthful appearance they desire; however, many of these procedures still are costly, painful, and may require some downtime. New cosmeceutical therapies can be used as adjuncts to these procedures, making antiaging regimens less painful for patients and requiring less postprocedure healing time. In this article, the use of cosmeceuticals in conjunction with chemical peels, lasers, and injectables will be discussed.

Chemical Peels

Chemical peels are used to create an injury of specific skin depth with a goal of stimulating new skin growth and improving surface texture and appearance. They generally are classified as superficial, medium, or deep according to the depth of action. Currently available agents for superficial chemical peels include α-hydroxy acids (AHAs)(eg, glycolic acid [GA]) and β-hydroxy acids (BHAs)(eg, salicylic acid). β-Lipohydroxy acid (up to 10%), a derivative of salicylic acid, is widely used in Europe. Trichloroacetic acid (TCA) can be used for superficial peels (10%–20%) and for medium-depth peels (35%). Combination peels such as Monheit combination (Jessner solution plus TCA), Brody combination (solid CO₂ plus TCA), Coleman combination (GA 70% plus TCA), and Jessner solution with GA can be used as medium-depth peels. Deep peels typically are performed with phenol-based solutions, including the Baker-Gordon phenol peel and the Hetter peel (phenol or croton oil peel).

Specific agents for chemical peels should be selected based on the disorder being treated and should be administered using an appropriate peel depth determined by the histologic level or severity of skin pathology to maximize treatment success.¹ However, other considerations, such as skin characteristics, area of skin to be treated, safety concerns, healing time, and patient adherence also should be taken into account to achieve the best overall results. Although many of the deeper peels recently have been replaced by laser-based ablative treatments, superficial to medium-depth peels still are commonly used in the treatment of fine lines, uneven texture, and dyspigmentation.²

Superficial peels are reasonably safe and well tolerated, usually with only mild discomfort (eg, transient burning, irritation, erythema). Scarring, postinflammatory hyperpigmentation (PIH), and infection are rare with superficial peels.¹ Postinflammatory hyperpigmentation can be exacerbated by sun exposure, making it important for patients to be educated about sun protection and closely monitored during the recovery phase. In medium and deep peels, lines of demarcation related to the administration technique can occur. Feathering the chemical peel solution at junctions with nonpeeled skin can help to avoid this effect.¹ Side effects associated with deeper chemical peels can include pigmentary changes, infections, allergic reactions, improper healing, hypersensitivity, and underlying disease exacerbation. The best way to prevent complications is to identify patients who are at risk and maintain an appropriate peel depth that balances efficacy with known adverse events.¹ 

Many adjunctive agents (eg, AHAs, BHAs, retinoids, skin-bleaching preparations) can be used to enhance chemical peels and decrease the incidence of PIH. α-Hydroxy acids and BHAs can be beneficial when applied prior to chemical peels. Moisturizers containing AHAs and BHAs can be used for 2 to 3 weeks before superficial or medium-depth chemical peels.² These agents cause thinning of the stratum corneum, thereby creating a more uniform cutaneous surface and allowing for deeper penetration of the chemical peeling agent. Retinoids also are superior prepeeling agents; however, retinoids also can increase the likelihood of irritation, which can be minimized by discontinuing retinoids for 1 week following chemical peels.² A combination of chemical peels and topical bleaching agents has been shown to be effective in treating hyperpigmentation. The chemical peel causes superficial exfoliation, which allows the lightening agent to penetrate more deeply.²

Hydroquinone (HQ) is the gold standard for improvement of existing pigmentation.³ It is one of the most effective inhibitors of melanogenesis both in vitro and in vivo and is widely used for the treatment of melanosis and other hyperpigmentary disorders. It is widely accepted that the depigmentation activity of HQ may partly be related to its ability to act as an alternate substrate of tyrosinase, thereby competing for tyrosine oxidation in active melanocytes.³ Using HQ at a 4% concentration and combining it with retinoids is quite efficacious.² Other commonly used depigmenting agents include kojic acid, ascorbic acid (vitamin C), and niacinamide, which often can be used as adjuncts with or maintenance therapy after HQ treatment.^2,3

The risk for PIH is imminent for chemical peels and cosmetic laser treatments; therefore, it is crucial to educate patients about the importance of daily and aggressive sun protection. There are several methods of reducing or eliminating postprocedure melanin formation, such as inhibiting tyrosinase synthesis, using complex copper to inhibit tyrosinase function, eliminating oxidation reactions that lead to polymer formation, slowing down the transfer of melanosomes to keratinocytes, or acting upstream on the hormone that stimulates melanogenesis.³ Most of the depigmenting agents presently on the market act by inhibiting tyrosinase via one of these mechanisms. 

Skin-lightening agents are primarily formulated as emulsions that have a higher aesthetic appeal. Many of the ingredients get better dispersions with emulsions, which is an added feature of these products. Recently, gel-based formulations also are being considered for their suitability in certain skin types. Efficacy studies for skin-lightening formulations are being carried out through clinical trials that utilize devices that measure skin color in addition to the dermatologist’s assessment.⁴ Other skin parameters (eg, moisturization, texture, barrier integrity, pH) also are being evaluated to give physicians a picture of skin health after the use of skin-lightening agents. With advances in technology and measurement techniques, it is becoming easier to identify the efficacy of these formulations in different skin types.⁴

Lasers

The ultimate goal of laser therapy often is to improve the canvas and color of the skin. Ablative laser resurfacing is reliably the most effective procedure for sun-damaged skin.² This technique causes thermally induced full-thickness epidermal and dermal denudation, which in turn facilitates cytokine-led dermal collagen formation and reepithelialization. Various nonablative modalities also are used for treating photodamaged skin. The epidermis remains unaffected by these nonablative methods, thus decreasing the need for extensive wound care and downtime that is required with ablative treatments. Combining nonablative laser treatments with topical cosmeceuticals has been proven more effective than using either method alone.² The use of topical retinoids prior to ablative laser resurfacing often results in remarkably faster postprocedure healing and reepithelialization (Figure). Retinoids are best applied nightly for at least 2 weeks and optimally for 3 months before ablative laser treatment. Application should be discontinued for 1 week immediately prior to the procedure.

Before (A) and after (B) treatment with a fractional laser in combination with a pre- and postprocedure skin care regimen consisting of retinoids and sunscreen.

Topical retinoids also are effective in reducing erythema and increasing dermal thickness after nonablative treatments. When used prior to laser treatments, retinoids have been shown to decrease the risk for postoperative milia and hyperpigmentation as well as to allow for better penetration of the laser beam secondary to a thinner stratum corneum.² Following ablative resurfacing, retinoid use should be discontinued for several weeks to allow for reepithelialization and adequate healing.

Postprocedure Wound Healing

Most of the recommended products that help decrease postprocedural inflammation are cosmeceuticals containing both antioxidants and anti-inflammatories to help decrease redness and inflammation, including various barrier repair moisturizers. Restoring barrier integrity improves the overall appearance of the skin. The ingredients normally recommended in barrier repair moisturizers are epidermal lipids such as ceramides; hyaluronic acid (HA), which is a humectant; and occlusives for patients with very dry skin. Some of the ingredients in over-the-counter cosmeceuticals that can help decrease redness and inflammation include vitamin C, vitamin E, and vitamin B or niacinamide, which will help plump the barrier and also have anti-inflammatory properties. Additionally, polyphenolic flavonoids such as soy and green tea can help decrease inflammation, along with a number of other organic ingredients, such as caffeine, feverfew, and licorice.⁵ If topical vitamin C is being considered for postprocedure use, the non–ascorbic acid variant should be administered. The magnesium ascorbyl phosphate and ascorbyl palmitate forms of vitamin C have a neutral pH and tend to be better tolerated by patients.

In addition to current prescription and over-the-counter cosmeceuticals used for postprocedure irritation and inflammation, copper peptides and other well-tolerated and effective naturally occurring compounds are being investigated and tried. Copper is a biocide that regulates keratinocyte integrins for epithelization and extracellular matrix remodeling. The extracellular matrix consists of the structural fibrillar collagens and is remodeled or degraded by matrix metalloproteinases (MMPs) that facilitate epithelization. The predominant classes of MMPs include collagenases (ie, MMP-1) and gelatinases (ie, MMP-2, MMP-9) that degrade interstitial collagen and basement membrane proteins.⁶ The MMPs are endogenously inhibited by tissue inhibitors of metalloproteinases (TIMPs). Copper is a cofactor to lysyl oxidase, which cross-links collagen and stimulates expression of MMP-2 and collagen in a complex with a matrix-derived tripeptide (glycyl-histidyl-lysine or Gly-His-Lys [GHK]) in fibroblasts.⁶ Much attention has been focused on the tripeptides, such as GHK and Gly-Gly-His, and their copper complexes, which have high activity and good skin tolerance. These complexes have been shown to play a physiological role in the process of wound healing, tissue repair, and skin inflammation. Gly-Gly-His, GHK, copper chloride, and their copper complexes decrease tumor necrosis factor α–dependent IL-6 secretion in fibroblasts.⁷ IL-6 is crucial for normal wound healing, skin inflammation, and UVB-induced erythema. Because of their anti-inflammatory properties, these copper peptides could potentially be used in place of corticosteroids or nonsteroidal anti-inflammatory drugs, which have more side effects.

Botulinum Neurotoxin and Other Injectable Fillers

Acetyl Hexapeptide-3: A Topical Complement to Botulinum Neurotoxin

Acetyl hexapeptide-3 (Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂) was discovered when looking for a less toxic variation of botulinum neurotoxin (BoNT) to treat aging skin.⁸ It is patterned from the N-terminal end of the synaptosome-associated protein of molecular weight 25 kDa (SNAP-25), which is essential for docking and fusion of synaptic vesicles to the presynaptic membrane for acetylcholine release.⁹ It prevents formation and stability of the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex, inhibiting vesicle docking and calcium-dependent catecholamine exocytosis.⁸ It also has been found to substantially inhibit the repetitive muscular contraction of facial expression similar to BoNT type A but with somewhat lower efficacy. Acetyl hexapeptide-3 was shown to inhibit 30% of total catecholamine exocytosis and had a remarkable capacity to permeate the skin.¹⁰ Thus this topical form of BoNT is a useful complement to intramuscular BoNT.

Studies showing the efficacy and safety of acetyl hexapeptide-3 have demonstrated reductions in wrinkle intensity, mainly in the lateral periorbital areas. In one early study, 10 women applied an emulsion containing 10% of the hexapeptide to one lateral periorbital region and the same emulsion without the hexapeptide to the contralateral side, both twice daily for 30 days.¹⁰ A 30% decrease in the depth of skin wrinkles was seen on the hexapeptide side compared with a 10% decrease in the depth of wrinkles on the side treated without hexapeptide. No irritation or toxicity was noted.¹⁰ In another trial, 10 women applied an acetyl hexapeptide-3 cream 5% twice daily to lateral periorbital rhytides, with a 27% improvement in wrinkle depth after a 30-day treatment period.⁹ A double-blind, placebo-controlled study of 60 women assessing the safety and efficacy of topical hexapeptide showed a total antiwrinkle efficacy of 48.9% on the side treated with an emulsion containing 10% of the hexapeptide compared with 0% efficacy on the placebo side.⁸ Similar to Blanes-Mira et al,¹⁰ no adverse events such as skin irritation or toxicity were seen.⁸ In all of these studies, wrinkle depth was measured by silicone replica analysis.

Topical acetyl hexapeptide-3 is effective in decreasing wrinkles, and its best use will likely be as an adjunct to intramuscular BoNT, as the intramuscular form likely has higher efficacy with the toxin injected directly into the target muscle; however, patients who want the effects of BoNT without the pain of injections may choose to use topical acetyl hexapeptide-3 alone. Patients who do use acetyl hexapeptide-3 as a complement to their intramuscular BoNT regimen may not need as many units of BoNT with each treatment or may not need certain areas injected as often, leading to fewer injections and less pain with each visit. Skin irritation was not seen as a side effect in these trials. Additionally, the topical form has insignificant acute toxicity (≥2000 mg/kg) compared to BoNT type A (20 ng/kg), and genotoxicity was not seen with testing, making it a safe complementary option to an injectable regimen.⁸

Topical Hyaluronic Acid: A Complement to Injectable Fillers

Hyaluronic acid (HA) is a glycosaminoglycan found in the extracellular matrix of the skin that greatly contributes to tissue hydration. Additionally, it plays a crucial role in the synthesis of extracellular matrix molecules and epidermal cell interaction with the environment.¹¹ The water-binding capacity of HA approximates 1000 times its volume or 6 L of water per gram of HA; however, once an individual reaches adulthood, the amount of HA decreases to 5% of baseline levels, thus contributing to xerosis, loss of skin elasticity, and atrophy.^11,12 Although photoaged skin can have increased glycosaminoglycans due to an increase in chondroitin sulfate proteoglycans, they are abnormally deposited on elastotic material in the superficial dermis rather than diffusely scattered, as seen in youthful skin.¹²

Many topical antiaging products contain HA, though evidence for efficacy in reducing wrinkles has been lacking, along with concerns that HA cannot penetrate the skin. This concern stems from the fact that the original molecule is 3000 nm in diameter and the intercellular space is only 15 to 50 nm. This space is only 6 to 10 nm at the hyaline membrane. Recently, scientists in Japan found a way to reduce the size of HA molecules to 5 nm (nano-HA) without changing its structure. A study of 33 women who applied the topical nano-HA twice daily for 8 weeks to one periorbital area while the contralateral side was left untreated showed improved hydration of the treated side that continued to increase when measured at 2, 4, and 8 weeks using corneometry.¹¹ Roughness decreased and elasticity increased after week 2, which were maintained throughout the study. Additionally, erythema was measured using a chroma meter, which was found to have decreased at day 57 versus day 1.¹¹ An earlier study by Pavicic et al¹² evaluated the efficacy of topical hyalu-ronan 0.1% formulations of different molecular weights—50, 130, 300, 800, or 2000 kDa—in the periocular area. A randomized group of 76 women were treated twice daily for 2 months with HA cream on one side of the periocular area and placebo cream on the other. With regard to antiwrinkle properties, only the 50- and 130-kDa HA formulations showed marked effects compared with placebo after 2 months.¹²

Topical HA would be an effective addition to an antiwrinkle regimen, especially in patients who are averse to needles or are just starting to get wrinkles and are looking for a noninvasive therapy. Additionally, it would be beneficial for patients who have an injectable filler and BoNT regimen, as these patients will be able to target wrinkles simultaneously with both topical cosmeceuticals and injectables and likely will need fewer units of BoNT and/or filler and possibly fewer injections over time, which translates to decreased pain and adverse outcomes for patients.

Conclusion

The myriad of options dermatologists have to offer patients for cosmetic enhancement provides alternatives for patients who have contraindications to certain treatments, are needle averse, or have lifestyles that do not afford them a great deal of postprocedural healing time. Being knowledgeable about these options and how to combine them for improved outcomes is essential to any cosmetic practice.

For more information, access Dr. Ezra's article from the August 2014 issue, "Linear Scarring Following Treatment With a 595-nm Pulsed Dye Laser."

For more information, access Dr. Ezra's article from the August 2014 issue, "Linear Scarring Following Treatment With a 595-nm Pulsed Dye Laser."

For more information, access Dr. Ezra's article from the August 2014 issue, "Linear Scarring Following Treatment With a 595-nm Pulsed Dye Laser."

To the Editor:
A 58-year-old homeless man presented to the emergency department after being found wandering in the middle of winter in Detroit, Michigan, with altered mental status. A workup for his mental incapacitation uncovered severe electrolyte disturbances, hyperglycemia, and acute renal failure, as well as both alcohol and drug intoxication. After 1 day of admission the patient reported progressive swelling, blistering, and pain in the right hand. The pain was stabbing in nature, worse with movement, and graded 10 of 10 (1=minimal; 10=severe). His medical history was notable for diabetes mellitus with peripheral neuropathy, hypertension, hyperlipidemia, and alcohol and drug abuse. The patient was not taking any medications for these conditions.

Physical examination revealed 2+ moderate pitting edema in all distal extremities, with increased edema of the dorsal aspect of the right hand. The right hand also demonstrated patchy erythema and was warm to touch. The dorsal aspect of the right ring finger had a dusky tip and was studded with several tense blisters (Figure). Vital signs were stable. Based on the patient’s history and physical examination findings, a diagnosis of frostbite was made. Our treatment process involved several modalities including immersion of the affected site in a warm water bath, surgical debridement of blistered sites, tetanus toxoid, penicillin to prevent infection, and oral ibuprofen for pain management. At 3-day follow-up, the patient’s condition substantially improved with a decreased amount of erythema, edema, and pain. All affected sites were successfully preserved with no evidence of focal, motor, or sensory impairment.

Frostbite is a form of localized tissue injury due to extreme cold that most commonly affects the hands and feet, with the greatest incidence occurring in adults aged 30 to 49 years.^1,2 Other sites commonly affected include the ears, nose, cheeks, and penis. Frostbite injuries can be categorized into 4 degrees of severity that correlate with the clinical presentation.^1,3 Rewarming the affected site is necessary to properly classify the injury, as the initial appearance may be similar among the different degrees of injury. A first-degree injury classically shows a central white plaque with peripheral erythema and is extremely cold to touch. Second-degree injuries display tense blisters filled with clear or milky fluid surrounded by erythema and edema within the first 24 hours. Third-degree injuries are associated with hemorrhagic blisters. Fourth-degree injuries involve complete tissue loss and necrosis.¹ Frostbite injuries also may be classified as superficial or deep; the former affects skin and subcutaneous tissue, while the latter affects bones, joints, and tendons.^3,4 The superficial form exhibits clear blisters, whereas hemorrhagic blisters demonstrate deep frostbite.

Factors such as the surrounding temperature, length of exposure, and alcohol consumption may exacerbate frostbite injuries.¹ Conditions such as atherosclerosis and diabetes mellitus, which can cause neuropathy and peripheral vascular disease, also are potential risks. Psychiatric patients also are at risk for frostbite given the propensity for eccentric behavior as well as the homeless due to inadequate clothing or shelter. Diagnosis often can be made based on medical history and physical examination, though techniques such as radiography, angiography, digital plethysmography, Doppler ultrasonography, and bone scintigraphy (technetium-99) also have been utilized to determine severity and prognosis.² Differential diagnoses of frostbite are listed in the Table.

Frostbite treatment begins with removal of wet clothing and region protection. Rewarming the site should not begin until refreezing is unlikely to occur and involves placing the injured area in water (temperature, 40°C–42°C) for 15 to 30 minutes to minimize tissue loss.^1,2 Analgesics, tetanus toxoid, oral ibuprofen, and benzylpenicillin also are indicated, along with daily hydrotherapy.^1,2 White blisters should be debrided, while hemorrhagic blisters should be left intact. Amputation and aggressive debridement typically are delayed until complete ischemia occurs and final demarcation is determined, usually over 1 to 3 months.¹ Combination therapy allowed for a positive outcome in our patient.

Frostnip is a mild form of cold injury characterized by localized pain, pallor, and possible numbness.³ Warming the cold area restores the function and sensation with no loss of tissue. Chilblain or pernio refers to a localized cold injury that typically presents as pruritic red-purple papules, macules, plaques, or nodules on the face, anterior tibial surface, or dorsum and tips of the hands and feet.³ The primary cause is repeated exposure to cold, not freezing, temperatures.

Trench foot or cold immersion foot (or hand) is a nonfreezing injury to the hands or feet caused by chronic exposure to wet conditions and temperatures above freezing.³ Painful burning and dysesthesia as well as tissue damage involving edema, blistering, redness, ecchymosis, and ulceration are common. Cellulitis is a bacterial infection of the skin and underlying tissues that can occur anywhere on the body, but the legs are most commonly affected. Typical presentation involves erythema, warmth, swelling, and pain in the infected area.

Although the conditions described above may be considered in the differential diagnosis, physical examination and the patient’s clinical history typically will allow for the distinction of frostbite from these other disease processes.

To the Editor:
A 58-year-old homeless man presented to the emergency department after being found wandering in the middle of winter in Detroit, Michigan, with altered mental status. A workup for his mental incapacitation uncovered severe electrolyte disturbances, hyperglycemia, and acute renal failure, as well as both alcohol and drug intoxication. After 1 day of admission the patient reported progressive swelling, blistering, and pain in the right hand. The pain was stabbing in nature, worse with movement, and graded 10 of 10 (1=minimal; 10=severe). His medical history was notable for diabetes mellitus with peripheral neuropathy, hypertension, hyperlipidemia, and alcohol and drug abuse. The patient was not taking any medications for these conditions.

Physical examination revealed 2+ moderate pitting edema in all distal extremities, with increased edema of the dorsal aspect of the right hand. The right hand also demonstrated patchy erythema and was warm to touch. The dorsal aspect of the right ring finger had a dusky tip and was studded with several tense blisters (Figure). Vital signs were stable. Based on the patient’s history and physical examination findings, a diagnosis of frostbite was made. Our treatment process involved several modalities including immersion of the affected site in a warm water bath, surgical debridement of blistered sites, tetanus toxoid, penicillin to prevent infection, and oral ibuprofen for pain management. At 3-day follow-up, the patient’s condition substantially improved with a decreased amount of erythema, edema, and pain. All affected sites were successfully preserved with no evidence of focal, motor, or sensory impairment.

Frostbite is a form of localized tissue injury due to extreme cold that most commonly affects the hands and feet, with the greatest incidence occurring in adults aged 30 to 49 years.^1,2 Other sites commonly affected include the ears, nose, cheeks, and penis. Frostbite injuries can be categorized into 4 degrees of severity that correlate with the clinical presentation.^1,3 Rewarming the affected site is necessary to properly classify the injury, as the initial appearance may be similar among the different degrees of injury. A first-degree injury classically shows a central white plaque with peripheral erythema and is extremely cold to touch. Second-degree injuries display tense blisters filled with clear or milky fluid surrounded by erythema and edema within the first 24 hours. Third-degree injuries are associated with hemorrhagic blisters. Fourth-degree injuries involve complete tissue loss and necrosis.¹ Frostbite injuries also may be classified as superficial or deep; the former affects skin and subcutaneous tissue, while the latter affects bones, joints, and tendons.^3,4 The superficial form exhibits clear blisters, whereas hemorrhagic blisters demonstrate deep frostbite.

Factors such as the surrounding temperature, length of exposure, and alcohol consumption may exacerbate frostbite injuries.¹ Conditions such as atherosclerosis and diabetes mellitus, which can cause neuropathy and peripheral vascular disease, also are potential risks. Psychiatric patients also are at risk for frostbite given the propensity for eccentric behavior as well as the homeless due to inadequate clothing or shelter. Diagnosis often can be made based on medical history and physical examination, though techniques such as radiography, angiography, digital plethysmography, Doppler ultrasonography, and bone scintigraphy (technetium-99) also have been utilized to determine severity and prognosis.² Differential diagnoses of frostbite are listed in the Table.

Frostbite treatment begins with removal of wet clothing and region protection. Rewarming the site should not begin until refreezing is unlikely to occur and involves placing the injured area in water (temperature, 40°C–42°C) for 15 to 30 minutes to minimize tissue loss.^1,2 Analgesics, tetanus toxoid, oral ibuprofen, and benzylpenicillin also are indicated, along with daily hydrotherapy.^1,2 White blisters should be debrided, while hemorrhagic blisters should be left intact. Amputation and aggressive debridement typically are delayed until complete ischemia occurs and final demarcation is determined, usually over 1 to 3 months.¹ Combination therapy allowed for a positive outcome in our patient.

Frostnip is a mild form of cold injury characterized by localized pain, pallor, and possible numbness.³ Warming the cold area restores the function and sensation with no loss of tissue. Chilblain or pernio refers to a localized cold injury that typically presents as pruritic red-purple papules, macules, plaques, or nodules on the face, anterior tibial surface, or dorsum and tips of the hands and feet.³ The primary cause is repeated exposure to cold, not freezing, temperatures.

Trench foot or cold immersion foot (or hand) is a nonfreezing injury to the hands or feet caused by chronic exposure to wet conditions and temperatures above freezing.³ Painful burning and dysesthesia as well as tissue damage involving edema, blistering, redness, ecchymosis, and ulceration are common. Cellulitis is a bacterial infection of the skin and underlying tissues that can occur anywhere on the body, but the legs are most commonly affected. Typical presentation involves erythema, warmth, swelling, and pain in the infected area.

Although the conditions described above may be considered in the differential diagnosis, physical examination and the patient’s clinical history typically will allow for the distinction of frostbite from these other disease processes.

To the Editor:
A 58-year-old homeless man presented to the emergency department after being found wandering in the middle of winter in Detroit, Michigan, with altered mental status. A workup for his mental incapacitation uncovered severe electrolyte disturbances, hyperglycemia, and acute renal failure, as well as both alcohol and drug intoxication. After 1 day of admission the patient reported progressive swelling, blistering, and pain in the right hand. The pain was stabbing in nature, worse with movement, and graded 10 of 10 (1=minimal; 10=severe). His medical history was notable for diabetes mellitus with peripheral neuropathy, hypertension, hyperlipidemia, and alcohol and drug abuse. The patient was not taking any medications for these conditions.

Physical examination revealed 2+ moderate pitting edema in all distal extremities, with increased edema of the dorsal aspect of the right hand. The right hand also demonstrated patchy erythema and was warm to touch. The dorsal aspect of the right ring finger had a dusky tip and was studded with several tense blisters (Figure). Vital signs were stable. Based on the patient’s history and physical examination findings, a diagnosis of frostbite was made. Our treatment process involved several modalities including immersion of the affected site in a warm water bath, surgical debridement of blistered sites, tetanus toxoid, penicillin to prevent infection, and oral ibuprofen for pain management. At 3-day follow-up, the patient’s condition substantially improved with a decreased amount of erythema, edema, and pain. All affected sites were successfully preserved with no evidence of focal, motor, or sensory impairment.

Frostbite is a form of localized tissue injury due to extreme cold that most commonly affects the hands and feet, with the greatest incidence occurring in adults aged 30 to 49 years.^1,2 Other sites commonly affected include the ears, nose, cheeks, and penis. Frostbite injuries can be categorized into 4 degrees of severity that correlate with the clinical presentation.^1,3 Rewarming the affected site is necessary to properly classify the injury, as the initial appearance may be similar among the different degrees of injury. A first-degree injury classically shows a central white plaque with peripheral erythema and is extremely cold to touch. Second-degree injuries display tense blisters filled with clear or milky fluid surrounded by erythema and edema within the first 24 hours. Third-degree injuries are associated with hemorrhagic blisters. Fourth-degree injuries involve complete tissue loss and necrosis.¹ Frostbite injuries also may be classified as superficial or deep; the former affects skin and subcutaneous tissue, while the latter affects bones, joints, and tendons.^3,4 The superficial form exhibits clear blisters, whereas hemorrhagic blisters demonstrate deep frostbite.

Factors such as the surrounding temperature, length of exposure, and alcohol consumption may exacerbate frostbite injuries.¹ Conditions such as atherosclerosis and diabetes mellitus, which can cause neuropathy and peripheral vascular disease, also are potential risks. Psychiatric patients also are at risk for frostbite given the propensity for eccentric behavior as well as the homeless due to inadequate clothing or shelter. Diagnosis often can be made based on medical history and physical examination, though techniques such as radiography, angiography, digital plethysmography, Doppler ultrasonography, and bone scintigraphy (technetium-99) also have been utilized to determine severity and prognosis.² Differential diagnoses of frostbite are listed in the Table.

Frostbite treatment begins with removal of wet clothing and region protection. Rewarming the site should not begin until refreezing is unlikely to occur and involves placing the injured area in water (temperature, 40°C–42°C) for 15 to 30 minutes to minimize tissue loss.^1,2 Analgesics, tetanus toxoid, oral ibuprofen, and benzylpenicillin also are indicated, along with daily hydrotherapy.^1,2 White blisters should be debrided, while hemorrhagic blisters should be left intact. Amputation and aggressive debridement typically are delayed until complete ischemia occurs and final demarcation is determined, usually over 1 to 3 months.¹ Combination therapy allowed for a positive outcome in our patient.

Frostnip is a mild form of cold injury characterized by localized pain, pallor, and possible numbness.³ Warming the cold area restores the function and sensation with no loss of tissue. Chilblain or pernio refers to a localized cold injury that typically presents as pruritic red-purple papules, macules, plaques, or nodules on the face, anterior tibial surface, or dorsum and tips of the hands and feet.³ The primary cause is repeated exposure to cold, not freezing, temperatures.

Trench foot or cold immersion foot (or hand) is a nonfreezing injury to the hands or feet caused by chronic exposure to wet conditions and temperatures above freezing.³ Painful burning and dysesthesia as well as tissue damage involving edema, blistering, redness, ecchymosis, and ulceration are common. Cellulitis is a bacterial infection of the skin and underlying tissues that can occur anywhere on the body, but the legs are most commonly affected. Typical presentation involves erythema, warmth, swelling, and pain in the infected area.

Although the conditions described above may be considered in the differential diagnosis, physical examination and the patient’s clinical history typically will allow for the distinction of frostbite from these other disease processes.

An article in Dermatologic Surgery, “Comparative Study on Bruise Reduction Treatments After Bruise Induction Using the Pulsed Dye Laser,” (2013;39:1459-1464) compared the of effectiveness different modalities in reducing time for bruise resolution. The investigators compared cold compresses; hydrogen peroxide; over-the-counter bruise serum containing primrose oil, vitamin E oil, and glycerin; and pulsed dye laser (PDL). Seventeen patients (Fitzpatrick skin types I–IV) were enrolled and had bruise induction with a PDL to produce five 2×2-cm zones of bruising on the lower abdomen. Excluding the control, bruises were randomly treated using a cold compress, bruise serum, 3% hydrogen peroxide–soaked gauze, or PDL. Subjects and 2 blinded physician evaluators graded the bruise severity using a visual scale on days 0, 3, and 7. The investigators found that treatment did not result in statistically significantly shorter bruise resolution time than in controls. They reported that PDL-treated bruises took a longer time to resolve than controls.

What’s the issue?

Although this study found that the PDL-treated bruises took a longer time to resolve, there have been other studies that have shown PDL to hasten time to bruise resolution, which could be due to the fact that the initial bruises in this particular study were actually induced by PDL. In another study, DeFatta et al (Arch Facial Plast Surg. 2009;11:99-103) found maximal efficacy when PDL was performed on or after postoperative day 5. It was reasoned that treatment before then was less effective because of the depth of red blood cell extravasation and overlying inflammation and edema. Karen and Hale (Dermatol Surg. 2010;36:1328-1331) reported that the optimal time for PDL treatment was between 48 and 72 hours, suggesting that hemoglobin predominates during this period instead of the bilirubin predominance seen in the later stages of ecchymosis. Their parameters were 7.5 J/cm², 10-mm spot, 6-millisecond pulse duration, and cryogen 30 milliseconds with a 20-millisecond delay for a single pass. What do you use for posttreatment bruising?

We want to know your views! Tell us what you think.

An article in Dermatologic Surgery, “Comparative Study on Bruise Reduction Treatments After Bruise Induction Using the Pulsed Dye Laser,” (2013;39:1459-1464) compared the of effectiveness different modalities in reducing time for bruise resolution. The investigators compared cold compresses; hydrogen peroxide; over-the-counter bruise serum containing primrose oil, vitamin E oil, and glycerin; and pulsed dye laser (PDL). Seventeen patients (Fitzpatrick skin types I–IV) were enrolled and had bruise induction with a PDL to produce five 2×2-cm zones of bruising on the lower abdomen. Excluding the control, bruises were randomly treated using a cold compress, bruise serum, 3% hydrogen peroxide–soaked gauze, or PDL. Subjects and 2 blinded physician evaluators graded the bruise severity using a visual scale on days 0, 3, and 7. The investigators found that treatment did not result in statistically significantly shorter bruise resolution time than in controls. They reported that PDL-treated bruises took a longer time to resolve than controls.

What’s the issue?

Although this study found that the PDL-treated bruises took a longer time to resolve, there have been other studies that have shown PDL to hasten time to bruise resolution, which could be due to the fact that the initial bruises in this particular study were actually induced by PDL. In another study, DeFatta et al (Arch Facial Plast Surg. 2009;11:99-103) found maximal efficacy when PDL was performed on or after postoperative day 5. It was reasoned that treatment before then was less effective because of the depth of red blood cell extravasation and overlying inflammation and edema. Karen and Hale (Dermatol Surg. 2010;36:1328-1331) reported that the optimal time for PDL treatment was between 48 and 72 hours, suggesting that hemoglobin predominates during this period instead of the bilirubin predominance seen in the later stages of ecchymosis. Their parameters were 7.5 J/cm², 10-mm spot, 6-millisecond pulse duration, and cryogen 30 milliseconds with a 20-millisecond delay for a single pass. What do you use for posttreatment bruising?

We want to know your views! Tell us what you think.

An article in Dermatologic Surgery, “Comparative Study on Bruise Reduction Treatments After Bruise Induction Using the Pulsed Dye Laser,” (2013;39:1459-1464) compared the of effectiveness different modalities in reducing time for bruise resolution. The investigators compared cold compresses; hydrogen peroxide; over-the-counter bruise serum containing primrose oil, vitamin E oil, and glycerin; and pulsed dye laser (PDL). Seventeen patients (Fitzpatrick skin types I–IV) were enrolled and had bruise induction with a PDL to produce five 2×2-cm zones of bruising on the lower abdomen. Excluding the control, bruises were randomly treated using a cold compress, bruise serum, 3% hydrogen peroxide–soaked gauze, or PDL. Subjects and 2 blinded physician evaluators graded the bruise severity using a visual scale on days 0, 3, and 7. The investigators found that treatment did not result in statistically significantly shorter bruise resolution time than in controls. They reported that PDL-treated bruises took a longer time to resolve than controls.

What’s the issue?

Although this study found that the PDL-treated bruises took a longer time to resolve, there have been other studies that have shown PDL to hasten time to bruise resolution, which could be due to the fact that the initial bruises in this particular study were actually induced by PDL. In another study, DeFatta et al (Arch Facial Plast Surg. 2009;11:99-103) found maximal efficacy when PDL was performed on or after postoperative day 5. It was reasoned that treatment before then was less effective because of the depth of red blood cell extravasation and overlying inflammation and edema. Karen and Hale (Dermatol Surg. 2010;36:1328-1331) reported that the optimal time for PDL treatment was between 48 and 72 hours, suggesting that hemoglobin predominates during this period instead of the bilirubin predominance seen in the later stages of ecchymosis. Their parameters were 7.5 J/cm², 10-mm spot, 6-millisecond pulse duration, and cryogen 30 milliseconds with a 20-millisecond delay for a single pass. What do you use for posttreatment bruising?

We want to know your views! Tell us what you think.

DENVER – Military dermatologists have played an active role in helping wounded warriors with their scars, and those physicians’ practices, including the use of ablative fractional resurfacing, are now entering the civilian world to treat injuries from fire, car crashes, or blasts.

Earlier this year, a group of dermatologists published a consensus report to highlight best practices for laser treatment of traumatic scars. The groups, which included several military dermatologists, concluded that "laser treatment, particularly ablative fractional resurfacing, deserves a prominent role in future scar treatment paradigms, with the possible inclusion of early intervention for contracture avoidance and assistance with wound healing."

In a video interview at the American Academy of Dermatology’s annual meeting, Lt. Col. Chad M. Hivnor, USAF, MC, FS, USA, a staff dermatologist for the San Antonio (Tex.) Military Health System, discussed the use of lasers in treating traumatic scars, talked about the psychology of scars, and shared a few of his own practice pearls.

[email protected]

On Twitter @naseemmiller

DENVER – Military dermatologists have played an active role in helping wounded warriors with their scars, and those physicians’ practices, including the use of ablative fractional resurfacing, are now entering the civilian world to treat injuries from fire, car crashes, or blasts.

Earlier this year, a group of dermatologists published a consensus report to highlight best practices for laser treatment of traumatic scars. The groups, which included several military dermatologists, concluded that "laser treatment, particularly ablative fractional resurfacing, deserves a prominent role in future scar treatment paradigms, with the possible inclusion of early intervention for contracture avoidance and assistance with wound healing."

In a video interview at the American Academy of Dermatology’s annual meeting, Lt. Col. Chad M. Hivnor, USAF, MC, FS, USA, a staff dermatologist for the San Antonio (Tex.) Military Health System, discussed the use of lasers in treating traumatic scars, talked about the psychology of scars, and shared a few of his own practice pearls.

[email protected]

On Twitter @naseemmiller

DENVER – Military dermatologists have played an active role in helping wounded warriors with their scars, and those physicians’ practices, including the use of ablative fractional resurfacing, are now entering the civilian world to treat injuries from fire, car crashes, or blasts.

Earlier this year, a group of dermatologists published a consensus report to highlight best practices for laser treatment of traumatic scars. The groups, which included several military dermatologists, concluded that "laser treatment, particularly ablative fractional resurfacing, deserves a prominent role in future scar treatment paradigms, with the possible inclusion of early intervention for contracture avoidance and assistance with wound healing."

In a video interview at the American Academy of Dermatology’s annual meeting, Lt. Col. Chad M. Hivnor, USAF, MC, FS, USA, a staff dermatologist for the San Antonio (Tex.) Military Health System, discussed the use of lasers in treating traumatic scars, talked about the psychology of scars, and shared a few of his own practice pearls.

[email protected]

On Twitter @naseemmiller

DENVER – Move over, gauze, bandages, and moist wound-healing techniques. Nanomaterials are making significant inroads in wound regeneration.

Dr. Adam Friedman, director of dermatologic research at the Montefiore-Einstein College of Medicine, New York, highlighted four nanotherapies in the field of wound care.

• Antimicrobial nano-based dressings. The antibacterial properties of silver have been documented since 1000 B.C., said Dr. Friedman of the departments of dermatology and of physiology and biophysics at the medical school. Silver ions are believed to directly disrupt pathogen cell walls/membranes and suppress respiratory enzymes and electron transport components. Silver has been used commercially for decades, with demonstrated antimicrobial effects (Crede’s 1% silver nitrate eyedrops were used to prevent mother to child transmission of gonococcal eye infection); anti-inflammatory properties (silver nitrate is used in pleurodesis); and infection protection (silver nanoparticle–impregnated wound dressings prevent infection and enhance wound healing).

Silver nanoparticles have an "increased likelihood of directly interacting with the target bacteria or virus," Dr. Friedman said in an interview in advance of the annual meeting of the American Academy of Dermatology. "They bind to and/or disturb bacterial cell membrane activity as well as release silver ions much more readily then their bulk counterparts." Silver dressings currently on the market include Silvercel, Aquacel, and Acticoat.

Similarly to nanometals, the biological activity of curcumin (a water-insoluble polyphenolic compound derived from tumeric) can be used in the nanoform and has been shown to both effectively clear methicillin-resistant Staphylococcus aureus in burn wound infections and accelerate the healing of thermal burn wounds.

• Immunomodulating antimicrobial nanoparticles. One of the most promising immunomodulators in wound healing is the gaseous molecule nitric oxide (NO). This potential has yet to be realized, Dr. Friedman said, as NO is highly unstable and its site of action is often microns from its source of generation. Nanotechnology can allow for controlled and sustained release of this evasive biomolecule and make therapeutic translation a reality. "At Einstein, we are utilizing NO-generating nanoparticles to accelerate wound healing and eradicate multidrug resistant pathogens," he said. "But, because NO is integral to so many biological processes, it can do so much more. This technology is also being studied for the treatment of cardiovascular disease and even the topical treatment of erectile dysfunction."

• Gene modifying/silencing technologies. RNA interference is an endogenous mechanism to control gene expression in a variety of organisms. "We can take advantage of this process using siRNA (small interfering RNA) to manipulate limitless biological processes," Dr. Friedman explained. "While a hot area, translation to the bedside has been difficult as siRNA are very unstable and have a difficult time reaching their targets inside cells. Nanoparticles have been shown to overcome these limitations." Dr. Friedman noted how siRNA encapsulate nanoparticles targeting fidgetin-like 2 (an ATPase that cleaves microtubules), can knock down this gene in vivo, resulting in accelerated epithelial cell migration and hastened wound closure in both excisional and burn wound mouse models.

• Growth factor–releasing nanoparticles. Growth factors have been found to speed the healing of acute and chronic wounds in humans, including Regranex, a analogue of platelet-derived growth factor that is FDA-approved for treating leg and foot ulcers in diabetic patients, epidermal growth factor (donor-site wounds), fibroblast growth factor (burn wounds), and growth hormone (donor sites in burned children). "Nanomaterials offer many advantages here, from allowing for temporal release depending on the wound environment to delivering multiple factors at the same or different times, to even serving as a structural foundation for wound healing while releasing factors simultaneously," Dr. Friedman said. "The possibilities are limitless."

Dr. Friedman characterized nanomedicine as "a newborn branch of science. These promising and innovative tools should help us overcome limitations of traditional wound care, improve direct intervention on phases of wound healing, and provide better solutions for wound dressing that induce favorable wound healing environments. More work – and funding – is needed."

Dr. Friedman disclosed that he is a consultant and/or a member of the scientific advisory board for SanovaWorks, Prodigy, Oakstone Institute, Liquidia Technologies, L’Oréal, Amgen, Onset, Aveeno, GSK, MicroCures, and Nano Bio-Med. He is also a speaker for Onset and Amgen.

This article was updated March 24, 2014.

[email protected]

DENVER – Move over, gauze, bandages, and moist wound-healing techniques. Nanomaterials are making significant inroads in wound regeneration.

Dr. Adam Friedman, director of dermatologic research at the Montefiore-Einstein College of Medicine, New York, highlighted four nanotherapies in the field of wound care.

• Antimicrobial nano-based dressings. The antibacterial properties of silver have been documented since 1000 B.C., said Dr. Friedman of the departments of dermatology and of physiology and biophysics at the medical school. Silver ions are believed to directly disrupt pathogen cell walls/membranes and suppress respiratory enzymes and electron transport components. Silver has been used commercially for decades, with demonstrated antimicrobial effects (Crede’s 1% silver nitrate eyedrops were used to prevent mother to child transmission of gonococcal eye infection); anti-inflammatory properties (silver nitrate is used in pleurodesis); and infection protection (silver nanoparticle–impregnated wound dressings prevent infection and enhance wound healing).

Silver nanoparticles have an "increased likelihood of directly interacting with the target bacteria or virus," Dr. Friedman said in an interview in advance of the annual meeting of the American Academy of Dermatology. "They bind to and/or disturb bacterial cell membrane activity as well as release silver ions much more readily then their bulk counterparts." Silver dressings currently on the market include Silvercel, Aquacel, and Acticoat.

Similarly to nanometals, the biological activity of curcumin (a water-insoluble polyphenolic compound derived from tumeric) can be used in the nanoform and has been shown to both effectively clear methicillin-resistant Staphylococcus aureus in burn wound infections and accelerate the healing of thermal burn wounds.

• Immunomodulating antimicrobial nanoparticles. One of the most promising immunomodulators in wound healing is the gaseous molecule nitric oxide (NO). This potential has yet to be realized, Dr. Friedman said, as NO is highly unstable and its site of action is often microns from its source of generation. Nanotechnology can allow for controlled and sustained release of this evasive biomolecule and make therapeutic translation a reality. "At Einstein, we are utilizing NO-generating nanoparticles to accelerate wound healing and eradicate multidrug resistant pathogens," he said. "But, because NO is integral to so many biological processes, it can do so much more. This technology is also being studied for the treatment of cardiovascular disease and even the topical treatment of erectile dysfunction."

• Gene modifying/silencing technologies. RNA interference is an endogenous mechanism to control gene expression in a variety of organisms. "We can take advantage of this process using siRNA (small interfering RNA) to manipulate limitless biological processes," Dr. Friedman explained. "While a hot area, translation to the bedside has been difficult as siRNA are very unstable and have a difficult time reaching their targets inside cells. Nanoparticles have been shown to overcome these limitations." Dr. Friedman noted how siRNA encapsulate nanoparticles targeting fidgetin-like 2 (an ATPase that cleaves microtubules), can knock down this gene in vivo, resulting in accelerated epithelial cell migration and hastened wound closure in both excisional and burn wound mouse models.

• Growth factor–releasing nanoparticles. Growth factors have been found to speed the healing of acute and chronic wounds in humans, including Regranex, a analogue of platelet-derived growth factor that is FDA-approved for treating leg and foot ulcers in diabetic patients, epidermal growth factor (donor-site wounds), fibroblast growth factor (burn wounds), and growth hormone (donor sites in burned children). "Nanomaterials offer many advantages here, from allowing for temporal release depending on the wound environment to delivering multiple factors at the same or different times, to even serving as a structural foundation for wound healing while releasing factors simultaneously," Dr. Friedman said. "The possibilities are limitless."

Dr. Friedman characterized nanomedicine as "a newborn branch of science. These promising and innovative tools should help us overcome limitations of traditional wound care, improve direct intervention on phases of wound healing, and provide better solutions for wound dressing that induce favorable wound healing environments. More work – and funding – is needed."

Dr. Friedman disclosed that he is a consultant and/or a member of the scientific advisory board for SanovaWorks, Prodigy, Oakstone Institute, Liquidia Technologies, L’Oréal, Amgen, Onset, Aveeno, GSK, MicroCures, and Nano Bio-Med. He is also a speaker for Onset and Amgen.

This article was updated March 24, 2014.

[email protected]

DENVER – Move over, gauze, bandages, and moist wound-healing techniques. Nanomaterials are making significant inroads in wound regeneration.

Dr. Adam Friedman, director of dermatologic research at the Montefiore-Einstein College of Medicine, New York, highlighted four nanotherapies in the field of wound care.

• Antimicrobial nano-based dressings. The antibacterial properties of silver have been documented since 1000 B.C., said Dr. Friedman of the departments of dermatology and of physiology and biophysics at the medical school. Silver ions are believed to directly disrupt pathogen cell walls/membranes and suppress respiratory enzymes and electron transport components. Silver has been used commercially for decades, with demonstrated antimicrobial effects (Crede’s 1% silver nitrate eyedrops were used to prevent mother to child transmission of gonococcal eye infection); anti-inflammatory properties (silver nitrate is used in pleurodesis); and infection protection (silver nanoparticle–impregnated wound dressings prevent infection and enhance wound healing).

Silver nanoparticles have an "increased likelihood of directly interacting with the target bacteria or virus," Dr. Friedman said in an interview in advance of the annual meeting of the American Academy of Dermatology. "They bind to and/or disturb bacterial cell membrane activity as well as release silver ions much more readily then their bulk counterparts." Silver dressings currently on the market include Silvercel, Aquacel, and Acticoat.

Similarly to nanometals, the biological activity of curcumin (a water-insoluble polyphenolic compound derived from tumeric) can be used in the nanoform and has been shown to both effectively clear methicillin-resistant Staphylococcus aureus in burn wound infections and accelerate the healing of thermal burn wounds.

• Immunomodulating antimicrobial nanoparticles. One of the most promising immunomodulators in wound healing is the gaseous molecule nitric oxide (NO). This potential has yet to be realized, Dr. Friedman said, as NO is highly unstable and its site of action is often microns from its source of generation. Nanotechnology can allow for controlled and sustained release of this evasive biomolecule and make therapeutic translation a reality. "At Einstein, we are utilizing NO-generating nanoparticles to accelerate wound healing and eradicate multidrug resistant pathogens," he said. "But, because NO is integral to so many biological processes, it can do so much more. This technology is also being studied for the treatment of cardiovascular disease and even the topical treatment of erectile dysfunction."

• Gene modifying/silencing technologies. RNA interference is an endogenous mechanism to control gene expression in a variety of organisms. "We can take advantage of this process using siRNA (small interfering RNA) to manipulate limitless biological processes," Dr. Friedman explained. "While a hot area, translation to the bedside has been difficult as siRNA are very unstable and have a difficult time reaching their targets inside cells. Nanoparticles have been shown to overcome these limitations." Dr. Friedman noted how siRNA encapsulate nanoparticles targeting fidgetin-like 2 (an ATPase that cleaves microtubules), can knock down this gene in vivo, resulting in accelerated epithelial cell migration and hastened wound closure in both excisional and burn wound mouse models.

• Growth factor–releasing nanoparticles. Growth factors have been found to speed the healing of acute and chronic wounds in humans, including Regranex, a analogue of platelet-derived growth factor that is FDA-approved for treating leg and foot ulcers in diabetic patients, epidermal growth factor (donor-site wounds), fibroblast growth factor (burn wounds), and growth hormone (donor sites in burned children). "Nanomaterials offer many advantages here, from allowing for temporal release depending on the wound environment to delivering multiple factors at the same or different times, to even serving as a structural foundation for wound healing while releasing factors simultaneously," Dr. Friedman said. "The possibilities are limitless."

Dr. Friedman characterized nanomedicine as "a newborn branch of science. These promising and innovative tools should help us overcome limitations of traditional wound care, improve direct intervention on phases of wound healing, and provide better solutions for wound dressing that induce favorable wound healing environments. More work – and funding – is needed."

Dr. Friedman disclosed that he is a consultant and/or a member of the scientific advisory board for SanovaWorks, Prodigy, Oakstone Institute, Liquidia Technologies, L’Oréal, Amgen, Onset, Aveeno, GSK, MicroCures, and Nano Bio-Med. He is also a speaker for Onset and Amgen.

This article was updated March 24, 2014.

[email protected]