Wounds

Dermatologists commonly manage a variety of wounds in the outpatient setting. Wound healing requires a multifaceted approach that often includes topical and oral therapies, adjustment of mechanical factors, and behavioral and lifestyle modifications. Physiologically, wound healing requires an inflammatory phase, a proliferative phase, and a remodeling phase. Chronic wounds undergo a prolonged inflammatory response hindered by decreased growth factors and increased wound bioburden.¹ Malnutrition has been routinely associated with wound chronicity and serves as a modifiable risk factor that may improve wound healing outcomes.²

Although the causes of wounds encountered in dermatology vary extensively, the importance of nutrition underlies all wound healing. Caloric needs in wound healing have been estimated at 30 to 40 kcal/kg dependent on baseline body weight, age, medical comorbidities, activity level, stage of wound healing, wound size, and number of wounds.^1,3,4 Nutritional supplementation is patient dependent, but this article serves to review the existing literature on macronutrient and micronutrient supplementation to clarify the potentially complementary role for nutritional support in chronic wounds. All patients should be screened with a thorough history, review of systems, and physical examination for existing nutrient deficiencies. Patients with age-related or chronic diseases are at increased risk for nutritional deficiency, and focused laboratory testing may be warranted. Supplementation for specific deficiencies with help from a registered dietician is recommended.

Macronutrients for Wound Healing

Protein—Protein is the most widely known macronutrient required for wound healing. The primary function of dietary protein is to provide amino acids to perform physiologic functions.⁵ Not only does cutaneous injury increase the metabolic needs of the wounded area, but large amounts of protein can be continually lost through wound exudates. Protein is necessary for the immune response required to transition from inflammatory to proliferative phases of wound healing.⁶ Protein energy deficiency has been reported to reduce fibroblast activity, delay angiogenesis, and decrease collagen formation.⁷ Additionally, protein is required for the formation of inflammatory cells and maintenance of oncotic pressure, specifically in venous insufficiency wounds.¹

The current recommended dietary allowance for protein in healthy adults is 0.8 g/kg daily of body weight. In patients with pressure ulcerations, a goal recommended dietary allowance of 1.25 to 2.0 g/kg daily of body weight, dependent on ulceration size, has been recommended by the National Pressure Ulcer Advisory Panel and European Pressure Ulcer Advisory Panel.⁸ This recommendation was based on a series of studies that reported enhanced healing rates in patients with pressure ulcers receiving higher-protein diets.⁹ The largest study to date was double-blinded and included 89 residents of long-term care facilities with stage II to stage IV pressure ulcers.¹⁰ Participants were randomized to receive commercial protein supplementation vs placebo. At the end of 8 weeks, a statistically significant difference was seen in mean (SD) pressure ulcer scale for healing scores (3.55 [4.66] vs 3.22 [4.11]; P<.05).¹⁰ A 2014 Cochrane review failed to identify benefit associated with nutritional interventions for either the prevention and/or treatment of pressure ulcers.¹¹ Specific recommendations on protein intake for other types of chronic wounds have not been proposed. Protein supplementation generally is provided orally, if tolerated. Liquid supplements such as Boost (Nestlé), Carnation Breakfast Essentials (Nestlé), NuBasics (SupremeMed), Resource (Nestlé Health Science), and Ensure (Abbott Laboratories) are frequently used to supplement both protein and caloric intake. Protein oversupplementation has not been associated with improved outcomes and may cause or exacerbate other medical comorbidities.

Fatty Acids for Wound Healing

Wound healing is an anabolic process that requires adequate intake of substrates such as glucose and fat. Carbohydrates serve as the major energy source required for wound healing, while fats are thought to play roles in cell membrane development and modulation of cellular signaling.¹ Fats utilize a unique pathway for energy production through beta-oxidation and the production of adenosine triphosphate, allowing available protein to be harnessed for wound healing.¹ Omega-3 and omega-6 fatty acids serve as precursors to prostaglandins, leukotrienes, and thromboxane—all key mediators of the inflammatory phase of wound healing.³ Omega-3 fatty acids are thought to downregulate genes involved in proinflammatory pathways,¹² as well as to diminish lymphocyte proliferation and levels of IL-1β, tumor necrosis factor α, and IL-6 in vitro.¹³ In vivo studies assessing the impact of omega-3 fatty acid supplementation on wound healing are minimal, and the role of dietary supplementation for this indication remains unknown. Fish oil contains the omega-3 fatty acid–rich eicosapentaenoic acid and docosahexaenoic acid, which has been compared to mineral oil supplementation for wound healing in healthy adults. When fish oil was supplemented for 4 weeks, no significant differences were identified in time to complete wound healing between groups. Interestingly, significantly higher levels of the proinflammatory cytokine IL-1β were identified in blister fluid at 24 hours after blistering vs the placebo group (t=2.52, df=25, P<.05).¹⁴ Prior studies evaluating wound healing in animal models similarly identified longer times to re-epithelialization after omega-3 polyunsaturated fatty acid supplementation orally and topically.^15,16 The fatty acid quality and composition consumed also may impact wound healing, as high-fat diets that are not rich in omega-3 fatty acids have been shown to promote inflammation and impair wound healing in rats, but this has not been thoroughly explored in human trials.¹⁷ Although adequate intake of these macronutrients is important, excessive intake may be harmful. Larger prospective trials are needed to shed light on the dose and composition of fatty acid supplementation that may optimize wound healing.

Vitamins and Micronutrients Required for Wound Healing

Vitamin A—Many vitamins serve as cofactors for the enzymatic processes required in wound healing. Vitamin A is an essential fat-soluble vitamin that serves a variety of dermatologic functions and promotes wound healing through stimulation of fibroblasts and ground substance, and it facilitates epithelial cell differentiation when applied topically.^3,18 Vitamin A works through the activation of retinoid receptors on endothelial cells, fibroblasts, keratinocytes, melanocytes, and sebocytes, and has purported anti-inflammatory effects that aid the healing of open wounds.³ Additionally, vitamin A is thought to enhance cytokine release in the inflammatory phase of wound healing.¹⁹ Supplemental vitamin A has been associated with positive effects on acute wound healing, burns, and radiation injuries.³ The utility of vitamin A supplementation in chronic wounds remains unknown; however, it has been shown to be beneficial in patients with inflammatory disease, such as rheumatoid arthritis, on corticosteroid therapy. Vitamin A supplementation in this population has been shown to counteract the negative effects of corticosteroids on wound healing via downregulation of transforming growth factor β and insulinlike growth factor 1.²⁰ Vitamin A deficiency has been associated with impaired progression through inflammatory and remodeling phases of healing due to altered B-cell and T-cell function and antibody production.¹ Some experts recommend short courses of oral vitamin A supplementation to enhance wound healing at doses between 10,000 and 25,000 IU daily.^2,3 Large, population-based studies are needed, and the safety supporting this recommendation in all patients remains unknown.

Vitamin C—Vitamin C is widely known for its role in collagen formation, immunomodulation, and antioxidant capacity.¹ Although vitamin C deficiency is associated with decreased collagen synthesis and impaired wound healing,²¹ the utility of long-term supplementation in patients who are not deficient remains unexplored. A systematic review evaluating interventional studies utilizing vitamin C supplementation on pressure ulcerations and surgical wound healing concluded that convincing evidence exists only for supplementation with at least 500 mg of vitamin C. The authors noted, “There is little evidence for improved healing of surgical wounds by high-dose single vitamin C supplementation (1–3 g/day).”²² In a prospective, randomized, controlled trial, 20 patients with pressure ulcerations were supplemented with vitamin C vs placebo with a mean reduction in pressure-sore area of 84% after 1 month in the vitamin C–supplemented group compared to 42.7% in the placebo group (P<.005). A limitation of this study is the small population.²³ One current recommendation for vitamin C supplementation in chronic wounds is for 500 mg daily in uncomplicated wounds to 2 g daily in severe wounds.³ Additional studies have suggested that the benefits of vitamin C supplementation are maximized when given in combination with zinc and arginine.²² At this time, evaluation for vitamin C deficiency and appropriate supplementation in patients with chronic wounds is needed.

Zinc—Minerals similarly play important roles in enzymatic regulation. Hundreds of zinc-containing enzymes are involved in wound healing and are required in tissue repair, growth, antioxidant capacity, and immune function.^1,24 Zinc is specifically critical to collagen, DNA, RNA, and protein synthesis, as well as cellular proliferation.⁴ Zinc deficiency has been encountered in the setting of chronic wounds with extensive drainage, decreased dietary intake, or excessive gastrointestinal losses.²⁵ Although many studies exist evaluating the utility of zinc supplementation on wound healing, many are confounded by multinutrient supplementation. No studies to date support zinc supplementation when zinc deficiency is absent. Patient assessment for medications or conditions that may impact zinc metabolism should be completed. Importantly, zinc supplementation can interfere with the absorption of other cations, so excessive supplementation should be avoided.¹

Amino Acids for Wound Healing

Arginine—Arginine is an essential amino acid that serves as a substrate for cellular proliferation, collagen deposition, and lymphocyte function.^8,26,27 Arginine serves as the biologic precursor for nitric oxide (NO), a substrate that has important wound healing properties. Nitric oxide metabolites have been shown to positively regulate wound repair while NO metabolites are reduced in wound environments in diabetic ulcerations.^28,29 Arginine also is a proline precursor, an essential building block for collagen synthesis,^6,30 and a stimulator of growth hormone and T cells.^30,31 Animal studies have suggested L-arginine supplementation may reverse impaired NO synthesis in diabetic wounds.²⁸ A single randomized trial assessing differing doses of arginine supplementation on stage II or stage IV pressure ulcers noted an almost two-fold improvement in healing time.³² However, human studies have not shown increased rates of re-epithelialization of skin graft donor sites when provided oral or parenteral arginine supplementation.³³ Inadequate data currently exist to support regular arginine supplementation for all types of wounds, and no safe dose of daily arginine intake has been established.

Glutamine—Similarly, glutamine supplementation has been proposed to accelerate wound healing due to its role as a primary metabolic fuel source for rapidly proliferating cells such as epithelial cells and fibroblasts.⁸ Glutamine is thought to induce expression of heat-shock proteins and protect against inflammatory and infectious wound complications.³⁴ Additionally, glutamine is thought to increase tissue insulin sensitivity, which may prove beneficial in wounds, as topical insulin previously has been shown in animal and human models to promote healing.³⁵ Glutamine is thought to play a role in the inflammatory phase of wound healing via superoxide production, leukocyte apoptosis, and phagocytosis.^6,34,36 Unfortunately, numerous randomized trials on glutamine supplementation have resulted in conflicting evidence confounded by multisupplementation within the same trial.^37,38 A double-blind, randomized, controlled trial of 270 participants assessed the effect of oral supplementation with arginine, glutamine, or β-hydroxy-β-methylbutyrate vs control in the healing time of diabetic foot ulcerations. Significant differences in wound closure time at week 16 were only identified in participants with low albumin levels (≤40 g/L) who were supplemented (50.8%) vs the control group (34.9%; P=.0325) and in those with poor limb perfusion (ankle-brachial index of <1.0) who were supplemented (60.3%) vs the control group (39.3%; P=.0079).³⁹ Ongoing clinical trials evaluating the effects of glutamine supplementation on differing wound types will hopefully shed light on the efficacy of supplementation.

Final Thoughts

Wound healing is multifactorial and should consider the health status and medical comorbidities of each patient treated. We propose an individualized approach to wound healing that includes exploration of specific macronutrient and micronutrient deficiencies, as malnutrition has been associated with wound chronicity and serves as a modifiable risk factor to improve healing.² The evidence backing specific nutrient supplementation in patients with deficiencies is strong and should be considered in patients with chronic wounds. Adequate caloric intake and protein content should be recommended for most wound patients; however, excessive protein intake has not been beneficial in wound healing. The data behind specific amino acid and vitamin supplementation are limited at this time. As with other therapeutics, there is likely an appropriate dose for supplementation that has not yet been elucidated. Consideration of wound type, size, depth, exudate, and underlying cause are important to optimize healing and tailor nutritional supplementation to each patient. We hope future studies will illuminate the complementary role of dietary intake and nutrient supplementation for the treatment of chronic nonhealing wounds.

Dermatologists commonly manage a variety of wounds in the outpatient setting. Wound healing requires a multifaceted approach that often includes topical and oral therapies, adjustment of mechanical factors, and behavioral and lifestyle modifications. Physiologically, wound healing requires an inflammatory phase, a proliferative phase, and a remodeling phase. Chronic wounds undergo a prolonged inflammatory response hindered by decreased growth factors and increased wound bioburden.¹ Malnutrition has been routinely associated with wound chronicity and serves as a modifiable risk factor that may improve wound healing outcomes.²

Although the causes of wounds encountered in dermatology vary extensively, the importance of nutrition underlies all wound healing. Caloric needs in wound healing have been estimated at 30 to 40 kcal/kg dependent on baseline body weight, age, medical comorbidities, activity level, stage of wound healing, wound size, and number of wounds.^1,3,4 Nutritional supplementation is patient dependent, but this article serves to review the existing literature on macronutrient and micronutrient supplementation to clarify the potentially complementary role for nutritional support in chronic wounds. All patients should be screened with a thorough history, review of systems, and physical examination for existing nutrient deficiencies. Patients with age-related or chronic diseases are at increased risk for nutritional deficiency, and focused laboratory testing may be warranted. Supplementation for specific deficiencies with help from a registered dietician is recommended.

Macronutrients for Wound Healing

Protein—Protein is the most widely known macronutrient required for wound healing. The primary function of dietary protein is to provide amino acids to perform physiologic functions.⁵ Not only does cutaneous injury increase the metabolic needs of the wounded area, but large amounts of protein can be continually lost through wound exudates. Protein is necessary for the immune response required to transition from inflammatory to proliferative phases of wound healing.⁶ Protein energy deficiency has been reported to reduce fibroblast activity, delay angiogenesis, and decrease collagen formation.⁷ Additionally, protein is required for the formation of inflammatory cells and maintenance of oncotic pressure, specifically in venous insufficiency wounds.¹

The current recommended dietary allowance for protein in healthy adults is 0.8 g/kg daily of body weight. In patients with pressure ulcerations, a goal recommended dietary allowance of 1.25 to 2.0 g/kg daily of body weight, dependent on ulceration size, has been recommended by the National Pressure Ulcer Advisory Panel and European Pressure Ulcer Advisory Panel.⁸ This recommendation was based on a series of studies that reported enhanced healing rates in patients with pressure ulcers receiving higher-protein diets.⁹ The largest study to date was double-blinded and included 89 residents of long-term care facilities with stage II to stage IV pressure ulcers.¹⁰ Participants were randomized to receive commercial protein supplementation vs placebo. At the end of 8 weeks, a statistically significant difference was seen in mean (SD) pressure ulcer scale for healing scores (3.55 [4.66] vs 3.22 [4.11]; P<.05).¹⁰ A 2014 Cochrane review failed to identify benefit associated with nutritional interventions for either the prevention and/or treatment of pressure ulcers.¹¹ Specific recommendations on protein intake for other types of chronic wounds have not been proposed. Protein supplementation generally is provided orally, if tolerated. Liquid supplements such as Boost (Nestlé), Carnation Breakfast Essentials (Nestlé), NuBasics (SupremeMed), Resource (Nestlé Health Science), and Ensure (Abbott Laboratories) are frequently used to supplement both protein and caloric intake. Protein oversupplementation has not been associated with improved outcomes and may cause or exacerbate other medical comorbidities.

Fatty Acids for Wound Healing

Wound healing is an anabolic process that requires adequate intake of substrates such as glucose and fat. Carbohydrates serve as the major energy source required for wound healing, while fats are thought to play roles in cell membrane development and modulation of cellular signaling.¹ Fats utilize a unique pathway for energy production through beta-oxidation and the production of adenosine triphosphate, allowing available protein to be harnessed for wound healing.¹ Omega-3 and omega-6 fatty acids serve as precursors to prostaglandins, leukotrienes, and thromboxane—all key mediators of the inflammatory phase of wound healing.³ Omega-3 fatty acids are thought to downregulate genes involved in proinflammatory pathways,¹² as well as to diminish lymphocyte proliferation and levels of IL-1β, tumor necrosis factor α, and IL-6 in vitro.¹³ In vivo studies assessing the impact of omega-3 fatty acid supplementation on wound healing are minimal, and the role of dietary supplementation for this indication remains unknown. Fish oil contains the omega-3 fatty acid–rich eicosapentaenoic acid and docosahexaenoic acid, which has been compared to mineral oil supplementation for wound healing in healthy adults. When fish oil was supplemented for 4 weeks, no significant differences were identified in time to complete wound healing between groups. Interestingly, significantly higher levels of the proinflammatory cytokine IL-1β were identified in blister fluid at 24 hours after blistering vs the placebo group (t=2.52, df=25, P<.05).¹⁴ Prior studies evaluating wound healing in animal models similarly identified longer times to re-epithelialization after omega-3 polyunsaturated fatty acid supplementation orally and topically.^15,16 The fatty acid quality and composition consumed also may impact wound healing, as high-fat diets that are not rich in omega-3 fatty acids have been shown to promote inflammation and impair wound healing in rats, but this has not been thoroughly explored in human trials.¹⁷ Although adequate intake of these macronutrients is important, excessive intake may be harmful. Larger prospective trials are needed to shed light on the dose and composition of fatty acid supplementation that may optimize wound healing.

Vitamins and Micronutrients Required for Wound Healing

Vitamin A—Many vitamins serve as cofactors for the enzymatic processes required in wound healing. Vitamin A is an essential fat-soluble vitamin that serves a variety of dermatologic functions and promotes wound healing through stimulation of fibroblasts and ground substance, and it facilitates epithelial cell differentiation when applied topically.^3,18 Vitamin A works through the activation of retinoid receptors on endothelial cells, fibroblasts, keratinocytes, melanocytes, and sebocytes, and has purported anti-inflammatory effects that aid the healing of open wounds.³ Additionally, vitamin A is thought to enhance cytokine release in the inflammatory phase of wound healing.¹⁹ Supplemental vitamin A has been associated with positive effects on acute wound healing, burns, and radiation injuries.³ The utility of vitamin A supplementation in chronic wounds remains unknown; however, it has been shown to be beneficial in patients with inflammatory disease, such as rheumatoid arthritis, on corticosteroid therapy. Vitamin A supplementation in this population has been shown to counteract the negative effects of corticosteroids on wound healing via downregulation of transforming growth factor β and insulinlike growth factor 1.²⁰ Vitamin A deficiency has been associated with impaired progression through inflammatory and remodeling phases of healing due to altered B-cell and T-cell function and antibody production.¹ Some experts recommend short courses of oral vitamin A supplementation to enhance wound healing at doses between 10,000 and 25,000 IU daily.^2,3 Large, population-based studies are needed, and the safety supporting this recommendation in all patients remains unknown.

Vitamin C—Vitamin C is widely known for its role in collagen formation, immunomodulation, and antioxidant capacity.¹ Although vitamin C deficiency is associated with decreased collagen synthesis and impaired wound healing,²¹ the utility of long-term supplementation in patients who are not deficient remains unexplored. A systematic review evaluating interventional studies utilizing vitamin C supplementation on pressure ulcerations and surgical wound healing concluded that convincing evidence exists only for supplementation with at least 500 mg of vitamin C. The authors noted, “There is little evidence for improved healing of surgical wounds by high-dose single vitamin C supplementation (1–3 g/day).”²² In a prospective, randomized, controlled trial, 20 patients with pressure ulcerations were supplemented with vitamin C vs placebo with a mean reduction in pressure-sore area of 84% after 1 month in the vitamin C–supplemented group compared to 42.7% in the placebo group (P<.005). A limitation of this study is the small population.²³ One current recommendation for vitamin C supplementation in chronic wounds is for 500 mg daily in uncomplicated wounds to 2 g daily in severe wounds.³ Additional studies have suggested that the benefits of vitamin C supplementation are maximized when given in combination with zinc and arginine.²² At this time, evaluation for vitamin C deficiency and appropriate supplementation in patients with chronic wounds is needed.

Zinc—Minerals similarly play important roles in enzymatic regulation. Hundreds of zinc-containing enzymes are involved in wound healing and are required in tissue repair, growth, antioxidant capacity, and immune function.^1,24 Zinc is specifically critical to collagen, DNA, RNA, and protein synthesis, as well as cellular proliferation.⁴ Zinc deficiency has been encountered in the setting of chronic wounds with extensive drainage, decreased dietary intake, or excessive gastrointestinal losses.²⁵ Although many studies exist evaluating the utility of zinc supplementation on wound healing, many are confounded by multinutrient supplementation. No studies to date support zinc supplementation when zinc deficiency is absent. Patient assessment for medications or conditions that may impact zinc metabolism should be completed. Importantly, zinc supplementation can interfere with the absorption of other cations, so excessive supplementation should be avoided.¹

Amino Acids for Wound Healing

Arginine—Arginine is an essential amino acid that serves as a substrate for cellular proliferation, collagen deposition, and lymphocyte function.^8,26,27 Arginine serves as the biologic precursor for nitric oxide (NO), a substrate that has important wound healing properties. Nitric oxide metabolites have been shown to positively regulate wound repair while NO metabolites are reduced in wound environments in diabetic ulcerations.^28,29 Arginine also is a proline precursor, an essential building block for collagen synthesis,^6,30 and a stimulator of growth hormone and T cells.^30,31 Animal studies have suggested L-arginine supplementation may reverse impaired NO synthesis in diabetic wounds.²⁸ A single randomized trial assessing differing doses of arginine supplementation on stage II or stage IV pressure ulcers noted an almost two-fold improvement in healing time.³² However, human studies have not shown increased rates of re-epithelialization of skin graft donor sites when provided oral or parenteral arginine supplementation.³³ Inadequate data currently exist to support regular arginine supplementation for all types of wounds, and no safe dose of daily arginine intake has been established.

Glutamine—Similarly, glutamine supplementation has been proposed to accelerate wound healing due to its role as a primary metabolic fuel source for rapidly proliferating cells such as epithelial cells and fibroblasts.⁸ Glutamine is thought to induce expression of heat-shock proteins and protect against inflammatory and infectious wound complications.³⁴ Additionally, glutamine is thought to increase tissue insulin sensitivity, which may prove beneficial in wounds, as topical insulin previously has been shown in animal and human models to promote healing.³⁵ Glutamine is thought to play a role in the inflammatory phase of wound healing via superoxide production, leukocyte apoptosis, and phagocytosis.^6,34,36 Unfortunately, numerous randomized trials on glutamine supplementation have resulted in conflicting evidence confounded by multisupplementation within the same trial.^37,38 A double-blind, randomized, controlled trial of 270 participants assessed the effect of oral supplementation with arginine, glutamine, or β-hydroxy-β-methylbutyrate vs control in the healing time of diabetic foot ulcerations. Significant differences in wound closure time at week 16 were only identified in participants with low albumin levels (≤40 g/L) who were supplemented (50.8%) vs the control group (34.9%; P=.0325) and in those with poor limb perfusion (ankle-brachial index of <1.0) who were supplemented (60.3%) vs the control group (39.3%; P=.0079).³⁹ Ongoing clinical trials evaluating the effects of glutamine supplementation on differing wound types will hopefully shed light on the efficacy of supplementation.

Final Thoughts

Wound healing is multifactorial and should consider the health status and medical comorbidities of each patient treated. We propose an individualized approach to wound healing that includes exploration of specific macronutrient and micronutrient deficiencies, as malnutrition has been associated with wound chronicity and serves as a modifiable risk factor to improve healing.² The evidence backing specific nutrient supplementation in patients with deficiencies is strong and should be considered in patients with chronic wounds. Adequate caloric intake and protein content should be recommended for most wound patients; however, excessive protein intake has not been beneficial in wound healing. The data behind specific amino acid and vitamin supplementation are limited at this time. As with other therapeutics, there is likely an appropriate dose for supplementation that has not yet been elucidated. Consideration of wound type, size, depth, exudate, and underlying cause are important to optimize healing and tailor nutritional supplementation to each patient. We hope future studies will illuminate the complementary role of dietary intake and nutrient supplementation for the treatment of chronic nonhealing wounds.

Dermatologists commonly manage a variety of wounds in the outpatient setting. Wound healing requires a multifaceted approach that often includes topical and oral therapies, adjustment of mechanical factors, and behavioral and lifestyle modifications. Physiologically, wound healing requires an inflammatory phase, a proliferative phase, and a remodeling phase. Chronic wounds undergo a prolonged inflammatory response hindered by decreased growth factors and increased wound bioburden.¹ Malnutrition has been routinely associated with wound chronicity and serves as a modifiable risk factor that may improve wound healing outcomes.²

Although the causes of wounds encountered in dermatology vary extensively, the importance of nutrition underlies all wound healing. Caloric needs in wound healing have been estimated at 30 to 40 kcal/kg dependent on baseline body weight, age, medical comorbidities, activity level, stage of wound healing, wound size, and number of wounds.^1,3,4 Nutritional supplementation is patient dependent, but this article serves to review the existing literature on macronutrient and micronutrient supplementation to clarify the potentially complementary role for nutritional support in chronic wounds. All patients should be screened with a thorough history, review of systems, and physical examination for existing nutrient deficiencies. Patients with age-related or chronic diseases are at increased risk for nutritional deficiency, and focused laboratory testing may be warranted. Supplementation for specific deficiencies with help from a registered dietician is recommended.

Macronutrients for Wound Healing

Protein—Protein is the most widely known macronutrient required for wound healing. The primary function of dietary protein is to provide amino acids to perform physiologic functions.⁵ Not only does cutaneous injury increase the metabolic needs of the wounded area, but large amounts of protein can be continually lost through wound exudates. Protein is necessary for the immune response required to transition from inflammatory to proliferative phases of wound healing.⁶ Protein energy deficiency has been reported to reduce fibroblast activity, delay angiogenesis, and decrease collagen formation.⁷ Additionally, protein is required for the formation of inflammatory cells and maintenance of oncotic pressure, specifically in venous insufficiency wounds.¹

The current recommended dietary allowance for protein in healthy adults is 0.8 g/kg daily of body weight. In patients with pressure ulcerations, a goal recommended dietary allowance of 1.25 to 2.0 g/kg daily of body weight, dependent on ulceration size, has been recommended by the National Pressure Ulcer Advisory Panel and European Pressure Ulcer Advisory Panel.⁸ This recommendation was based on a series of studies that reported enhanced healing rates in patients with pressure ulcers receiving higher-protein diets.⁹ The largest study to date was double-blinded and included 89 residents of long-term care facilities with stage II to stage IV pressure ulcers.¹⁰ Participants were randomized to receive commercial protein supplementation vs placebo. At the end of 8 weeks, a statistically significant difference was seen in mean (SD) pressure ulcer scale for healing scores (3.55 [4.66] vs 3.22 [4.11]; P<.05).¹⁰ A 2014 Cochrane review failed to identify benefit associated with nutritional interventions for either the prevention and/or treatment of pressure ulcers.¹¹ Specific recommendations on protein intake for other types of chronic wounds have not been proposed. Protein supplementation generally is provided orally, if tolerated. Liquid supplements such as Boost (Nestlé), Carnation Breakfast Essentials (Nestlé), NuBasics (SupremeMed), Resource (Nestlé Health Science), and Ensure (Abbott Laboratories) are frequently used to supplement both protein and caloric intake. Protein oversupplementation has not been associated with improved outcomes and may cause or exacerbate other medical comorbidities.

Fatty Acids for Wound Healing

Wound healing is an anabolic process that requires adequate intake of substrates such as glucose and fat. Carbohydrates serve as the major energy source required for wound healing, while fats are thought to play roles in cell membrane development and modulation of cellular signaling.¹ Fats utilize a unique pathway for energy production through beta-oxidation and the production of adenosine triphosphate, allowing available protein to be harnessed for wound healing.¹ Omega-3 and omega-6 fatty acids serve as precursors to prostaglandins, leukotrienes, and thromboxane—all key mediators of the inflammatory phase of wound healing.³ Omega-3 fatty acids are thought to downregulate genes involved in proinflammatory pathways,¹² as well as to diminish lymphocyte proliferation and levels of IL-1β, tumor necrosis factor α, and IL-6 in vitro.¹³ In vivo studies assessing the impact of omega-3 fatty acid supplementation on wound healing are minimal, and the role of dietary supplementation for this indication remains unknown. Fish oil contains the omega-3 fatty acid–rich eicosapentaenoic acid and docosahexaenoic acid, which has been compared to mineral oil supplementation for wound healing in healthy adults. When fish oil was supplemented for 4 weeks, no significant differences were identified in time to complete wound healing between groups. Interestingly, significantly higher levels of the proinflammatory cytokine IL-1β were identified in blister fluid at 24 hours after blistering vs the placebo group (t=2.52, df=25, P<.05).¹⁴ Prior studies evaluating wound healing in animal models similarly identified longer times to re-epithelialization after omega-3 polyunsaturated fatty acid supplementation orally and topically.^15,16 The fatty acid quality and composition consumed also may impact wound healing, as high-fat diets that are not rich in omega-3 fatty acids have been shown to promote inflammation and impair wound healing in rats, but this has not been thoroughly explored in human trials.¹⁷ Although adequate intake of these macronutrients is important, excessive intake may be harmful. Larger prospective trials are needed to shed light on the dose and composition of fatty acid supplementation that may optimize wound healing.

Vitamins and Micronutrients Required for Wound Healing

Vitamin A—Many vitamins serve as cofactors for the enzymatic processes required in wound healing. Vitamin A is an essential fat-soluble vitamin that serves a variety of dermatologic functions and promotes wound healing through stimulation of fibroblasts and ground substance, and it facilitates epithelial cell differentiation when applied topically.^3,18 Vitamin A works through the activation of retinoid receptors on endothelial cells, fibroblasts, keratinocytes, melanocytes, and sebocytes, and has purported anti-inflammatory effects that aid the healing of open wounds.³ Additionally, vitamin A is thought to enhance cytokine release in the inflammatory phase of wound healing.¹⁹ Supplemental vitamin A has been associated with positive effects on acute wound healing, burns, and radiation injuries.³ The utility of vitamin A supplementation in chronic wounds remains unknown; however, it has been shown to be beneficial in patients with inflammatory disease, such as rheumatoid arthritis, on corticosteroid therapy. Vitamin A supplementation in this population has been shown to counteract the negative effects of corticosteroids on wound healing via downregulation of transforming growth factor β and insulinlike growth factor 1.²⁰ Vitamin A deficiency has been associated with impaired progression through inflammatory and remodeling phases of healing due to altered B-cell and T-cell function and antibody production.¹ Some experts recommend short courses of oral vitamin A supplementation to enhance wound healing at doses between 10,000 and 25,000 IU daily.^2,3 Large, population-based studies are needed, and the safety supporting this recommendation in all patients remains unknown.

Vitamin C—Vitamin C is widely known for its role in collagen formation, immunomodulation, and antioxidant capacity.¹ Although vitamin C deficiency is associated with decreased collagen synthesis and impaired wound healing,²¹ the utility of long-term supplementation in patients who are not deficient remains unexplored. A systematic review evaluating interventional studies utilizing vitamin C supplementation on pressure ulcerations and surgical wound healing concluded that convincing evidence exists only for supplementation with at least 500 mg of vitamin C. The authors noted, “There is little evidence for improved healing of surgical wounds by high-dose single vitamin C supplementation (1–3 g/day).”²² In a prospective, randomized, controlled trial, 20 patients with pressure ulcerations were supplemented with vitamin C vs placebo with a mean reduction in pressure-sore area of 84% after 1 month in the vitamin C–supplemented group compared to 42.7% in the placebo group (P<.005). A limitation of this study is the small population.²³ One current recommendation for vitamin C supplementation in chronic wounds is for 500 mg daily in uncomplicated wounds to 2 g daily in severe wounds.³ Additional studies have suggested that the benefits of vitamin C supplementation are maximized when given in combination with zinc and arginine.²² At this time, evaluation for vitamin C deficiency and appropriate supplementation in patients with chronic wounds is needed.

Zinc—Minerals similarly play important roles in enzymatic regulation. Hundreds of zinc-containing enzymes are involved in wound healing and are required in tissue repair, growth, antioxidant capacity, and immune function.^1,24 Zinc is specifically critical to collagen, DNA, RNA, and protein synthesis, as well as cellular proliferation.⁴ Zinc deficiency has been encountered in the setting of chronic wounds with extensive drainage, decreased dietary intake, or excessive gastrointestinal losses.²⁵ Although many studies exist evaluating the utility of zinc supplementation on wound healing, many are confounded by multinutrient supplementation. No studies to date support zinc supplementation when zinc deficiency is absent. Patient assessment for medications or conditions that may impact zinc metabolism should be completed. Importantly, zinc supplementation can interfere with the absorption of other cations, so excessive supplementation should be avoided.¹

Amino Acids for Wound Healing

Arginine—Arginine is an essential amino acid that serves as a substrate for cellular proliferation, collagen deposition, and lymphocyte function.^8,26,27 Arginine serves as the biologic precursor for nitric oxide (NO), a substrate that has important wound healing properties. Nitric oxide metabolites have been shown to positively regulate wound repair while NO metabolites are reduced in wound environments in diabetic ulcerations.^28,29 Arginine also is a proline precursor, an essential building block for collagen synthesis,^6,30 and a stimulator of growth hormone and T cells.^30,31 Animal studies have suggested L-arginine supplementation may reverse impaired NO synthesis in diabetic wounds.²⁸ A single randomized trial assessing differing doses of arginine supplementation on stage II or stage IV pressure ulcers noted an almost two-fold improvement in healing time.³² However, human studies have not shown increased rates of re-epithelialization of skin graft donor sites when provided oral or parenteral arginine supplementation.³³ Inadequate data currently exist to support regular arginine supplementation for all types of wounds, and no safe dose of daily arginine intake has been established.

Glutamine—Similarly, glutamine supplementation has been proposed to accelerate wound healing due to its role as a primary metabolic fuel source for rapidly proliferating cells such as epithelial cells and fibroblasts.⁸ Glutamine is thought to induce expression of heat-shock proteins and protect against inflammatory and infectious wound complications.³⁴ Additionally, glutamine is thought to increase tissue insulin sensitivity, which may prove beneficial in wounds, as topical insulin previously has been shown in animal and human models to promote healing.³⁵ Glutamine is thought to play a role in the inflammatory phase of wound healing via superoxide production, leukocyte apoptosis, and phagocytosis.^6,34,36 Unfortunately, numerous randomized trials on glutamine supplementation have resulted in conflicting evidence confounded by multisupplementation within the same trial.^37,38 A double-blind, randomized, controlled trial of 270 participants assessed the effect of oral supplementation with arginine, glutamine, or β-hydroxy-β-methylbutyrate vs control in the healing time of diabetic foot ulcerations. Significant differences in wound closure time at week 16 were only identified in participants with low albumin levels (≤40 g/L) who were supplemented (50.8%) vs the control group (34.9%; P=.0325) and in those with poor limb perfusion (ankle-brachial index of <1.0) who were supplemented (60.3%) vs the control group (39.3%; P=.0079).³⁹ Ongoing clinical trials evaluating the effects of glutamine supplementation on differing wound types will hopefully shed light on the efficacy of supplementation.

Final Thoughts

Wound healing is multifactorial and should consider the health status and medical comorbidities of each patient treated. We propose an individualized approach to wound healing that includes exploration of specific macronutrient and micronutrient deficiencies, as malnutrition has been associated with wound chronicity and serves as a modifiable risk factor to improve healing.² The evidence backing specific nutrient supplementation in patients with deficiencies is strong and should be considered in patients with chronic wounds. Adequate caloric intake and protein content should be recommended for most wound patients; however, excessive protein intake has not been beneficial in wound healing. The data behind specific amino acid and vitamin supplementation are limited at this time. As with other therapeutics, there is likely an appropriate dose for supplementation that has not yet been elucidated. Consideration of wound type, size, depth, exudate, and underlying cause are important to optimize healing and tailor nutritional supplementation to each patient. We hope future studies will illuminate the complementary role of dietary intake and nutrient supplementation for the treatment of chronic nonhealing wounds.

The Diagnosis: Vibrio vulnificus Infection

At the initial presentation, the differential diagnosis included infectious processes such as bacterial or angioinvasive fungal infections or an inflammatory process such as pyoderma gangrenosum. Blood cultures were found to be positive for pansensitive Vibrio vulnificus. He initially was treated with piperacillin-tazobactam and received surgical debridement of the affected tissues. Pathologic interpretation of the wound tissues revealed a diagnosis of necrotizing softtissue infection and positive Candida albicans growth. He received topical bacitracin on discharge as well as a 7-day course of amoxicillin-clavulanate and fluconazole. He continued to receive debridement procedures and skin grafts, followed by topical mupirocin treatment and silver sulfadiazine. He was seen 6 weeks after discharge with healing wounds and healthy-appearing granulation tissue at the base.

Our patient’s presentation of retiform purpura with stellate necrosis was consistent with a wide range of serious pathologies ranging from medium-vessel vasculitis to thromboembolic phenomena and angioinvasive fungal infections.¹ Although Vibrio infection rarely is the first explanation that comes to mind when observing necrotic retiform purpura, the chronic nonhealing injury on the leg combined with the recent history of ocean swimming made V vulnificus stand out as a likely culprit. Although V vulnificus infection traditionally presents with cellulitis, edema, and hemorrhagic bulla,² necrosis also has been observed.³Vibrio vulnificus produces multiple virulence factors, and it is believed that these severe cutaneous symptoms are attributable to the production of a specific metalloprotease that enhances vascular permeability, thereby inducing hemorrhage within the vascular basement membrane zone.²

Vibrio vulnificus is an opportunistic bacterial pathogen associated with consumption of contaminated seafood or swimming in ocean waters with open wounds. Infections are rare, with only approximately 100 cases reported annually in the United States.4 However, V vulnificus infections have demonstrated increasing incidence in recent years, especially infections of pre-existing wounds.^4,5 Risk factors for their development include age over 40 years and underlying conditions including liver disease, diabetes mellitus, and immune dysfunction.⁴Vibrio vulnificus infections also demonstrate a strong male predilection, with almost 90% of infections occurring in males.⁴ Although the precise etiology of this sex discrepancy remains unknown, estrogen has been suggested to be a protective factor.⁶ Alternatively, behavioral differences also have been proposed as possible explanations for this discrepancy, with women less likely to consume seafood or go swimming. However, epidemiologic data reveal strong correlations between male sex and liver cirrhosis, a primary risk factor for V vulnificus infections, suggesting that male sex may simply be a confounding variable.⁷

Infections with V vulnificus are notable for their short incubation periods, with onset of symptoms occurring within 24 hours of exposure, making prompt diagnosis and treatment of high importance.⁸ Although rare, V vulnificus infections are associated with high mortality rates. From 1988 to 2010, nearly 600 deaths were reported secondary to V vulnificus infections.⁴ Wound infections carry a 17.6% fatality rate,⁴ while bloodborne V vulnificus infections exceed 50% fatality.⁸ Although sepsis secondary to V vulnificus usually is caused by ingestion of raw or undercooked shellfish, primarily oysters,⁴ our case highlights a rarer instance of both sepsis and localized infection stemming from ocean water exposure.

Vibrio vulnificus is an obligate halophile and therefore is found in marine environments rather than freshwater bodies. However, it rarely is isolated from bodies of water with salinities over 25 parts per thousand, such as the Mediterranean Sea; it usually is found in warmer waters, making it more common in the summer months from May to October.⁴ Given this proclivity for warmer environments, climate change has contributed to both a greater incidence and global distribution of V vulnificus. ^9,10

Treatment of V vulnificus infections centers on antibiotic treatment, with Vibrio species generally demonstrating susceptibility to most antibiotics of human significance.¹¹ However, some Vibrio isolates within the United States have demonstrated antibiotic resistance; 45% of a variety of clinical and environmental samples from South Carolina and Georgia demonstrated resistance to at least 3 antibiotic classes, and 17.3% resisted 8 or more classes of antibiotics.¹² These included medications such as doxycycline, tetracycline, aminoglycosides, and cephalosporins—agents that normally are prescribed for V vulnificus infections. Although tetracyclines have long been touted as the preferred treatment of V vulnificus infections, the spread of antibiotic resistance may require greater reliance on alternative regimens such as combinations of cephalosporins and doxycycline or a single fluoroquinolone.¹³ Although rare, Vibrio infections can have rapidly fatal consequences and should be given serious consideration when evaluating patients with relevant risk factors.

The differential diagnosis included angioinvasive mucormycosis, calciphylaxis, pyoderma gangrenosum, and Stevens-Johnson syndrome/toxic epidermal necrolysis. Mucormycosis is a fungal infection caused by Mucorales fungi that most commonly is seen in patients with diabetes mellitus, hematologic malignancies, neutropenia, and immunocompromise.¹⁴ Calciphylaxis is a condition involving microvascular occlusion due to diffuse calcium deposition in cutaneous blood vessels. It typically presents as violaceous retiform patches and plaques commonly seen on areas such as the thighs, buttocks, or abdomen and usually is associated with chronic renal failure, hemodialysis, and/or secondary hyperparathyroidism.¹⁵ Pyoderma gangrenosum is an inflammatory condition involving neutrophilic ulceration of the skin that typically presents as ulceration with a classically undermined border. It frequently is considered a diagnosis of exclusion and therefore requires that providers rule out other causes of ulceration prior to diagnosis.¹⁶ Stevens-Johnson syndrome/toxic epidermal necrolysis is a rare drug reaction involving mucosal erosions and cutaneous detachment.¹⁷ This diagnosis is less likely given that our patient lacked mucosal involvement and did not have any notable medication exposures prior to symptom onset.

The Diagnosis: Vibrio vulnificus Infection

At the initial presentation, the differential diagnosis included infectious processes such as bacterial or angioinvasive fungal infections or an inflammatory process such as pyoderma gangrenosum. Blood cultures were found to be positive for pansensitive Vibrio vulnificus. He initially was treated with piperacillin-tazobactam and received surgical debridement of the affected tissues. Pathologic interpretation of the wound tissues revealed a diagnosis of necrotizing softtissue infection and positive Candida albicans growth. He received topical bacitracin on discharge as well as a 7-day course of amoxicillin-clavulanate and fluconazole. He continued to receive debridement procedures and skin grafts, followed by topical mupirocin treatment and silver sulfadiazine. He was seen 6 weeks after discharge with healing wounds and healthy-appearing granulation tissue at the base.

Our patient’s presentation of retiform purpura with stellate necrosis was consistent with a wide range of serious pathologies ranging from medium-vessel vasculitis to thromboembolic phenomena and angioinvasive fungal infections.¹ Although Vibrio infection rarely is the first explanation that comes to mind when observing necrotic retiform purpura, the chronic nonhealing injury on the leg combined with the recent history of ocean swimming made V vulnificus stand out as a likely culprit. Although V vulnificus infection traditionally presents with cellulitis, edema, and hemorrhagic bulla,² necrosis also has been observed.³Vibrio vulnificus produces multiple virulence factors, and it is believed that these severe cutaneous symptoms are attributable to the production of a specific metalloprotease that enhances vascular permeability, thereby inducing hemorrhage within the vascular basement membrane zone.²

Vibrio vulnificus is an opportunistic bacterial pathogen associated with consumption of contaminated seafood or swimming in ocean waters with open wounds. Infections are rare, with only approximately 100 cases reported annually in the United States.4 However, V vulnificus infections have demonstrated increasing incidence in recent years, especially infections of pre-existing wounds.^4,5 Risk factors for their development include age over 40 years and underlying conditions including liver disease, diabetes mellitus, and immune dysfunction.⁴Vibrio vulnificus infections also demonstrate a strong male predilection, with almost 90% of infections occurring in males.⁴ Although the precise etiology of this sex discrepancy remains unknown, estrogen has been suggested to be a protective factor.⁶ Alternatively, behavioral differences also have been proposed as possible explanations for this discrepancy, with women less likely to consume seafood or go swimming. However, epidemiologic data reveal strong correlations between male sex and liver cirrhosis, a primary risk factor for V vulnificus infections, suggesting that male sex may simply be a confounding variable.⁷

Infections with V vulnificus are notable for their short incubation periods, with onset of symptoms occurring within 24 hours of exposure, making prompt diagnosis and treatment of high importance.⁸ Although rare, V vulnificus infections are associated with high mortality rates. From 1988 to 2010, nearly 600 deaths were reported secondary to V vulnificus infections.⁴ Wound infections carry a 17.6% fatality rate,⁴ while bloodborne V vulnificus infections exceed 50% fatality.⁸ Although sepsis secondary to V vulnificus usually is caused by ingestion of raw or undercooked shellfish, primarily oysters,⁴ our case highlights a rarer instance of both sepsis and localized infection stemming from ocean water exposure.

Vibrio vulnificus is an obligate halophile and therefore is found in marine environments rather than freshwater bodies. However, it rarely is isolated from bodies of water with salinities over 25 parts per thousand, such as the Mediterranean Sea; it usually is found in warmer waters, making it more common in the summer months from May to October.⁴ Given this proclivity for warmer environments, climate change has contributed to both a greater incidence and global distribution of V vulnificus. ^9,10

Treatment of V vulnificus infections centers on antibiotic treatment, with Vibrio species generally demonstrating susceptibility to most antibiotics of human significance.¹¹ However, some Vibrio isolates within the United States have demonstrated antibiotic resistance; 45% of a variety of clinical and environmental samples from South Carolina and Georgia demonstrated resistance to at least 3 antibiotic classes, and 17.3% resisted 8 or more classes of antibiotics.¹² These included medications such as doxycycline, tetracycline, aminoglycosides, and cephalosporins—agents that normally are prescribed for V vulnificus infections. Although tetracyclines have long been touted as the preferred treatment of V vulnificus infections, the spread of antibiotic resistance may require greater reliance on alternative regimens such as combinations of cephalosporins and doxycycline or a single fluoroquinolone.¹³ Although rare, Vibrio infections can have rapidly fatal consequences and should be given serious consideration when evaluating patients with relevant risk factors.

The differential diagnosis included angioinvasive mucormycosis, calciphylaxis, pyoderma gangrenosum, and Stevens-Johnson syndrome/toxic epidermal necrolysis. Mucormycosis is a fungal infection caused by Mucorales fungi that most commonly is seen in patients with diabetes mellitus, hematologic malignancies, neutropenia, and immunocompromise.¹⁴ Calciphylaxis is a condition involving microvascular occlusion due to diffuse calcium deposition in cutaneous blood vessels. It typically presents as violaceous retiform patches and plaques commonly seen on areas such as the thighs, buttocks, or abdomen and usually is associated with chronic renal failure, hemodialysis, and/or secondary hyperparathyroidism.¹⁵ Pyoderma gangrenosum is an inflammatory condition involving neutrophilic ulceration of the skin that typically presents as ulceration with a classically undermined border. It frequently is considered a diagnosis of exclusion and therefore requires that providers rule out other causes of ulceration prior to diagnosis.¹⁶ Stevens-Johnson syndrome/toxic epidermal necrolysis is a rare drug reaction involving mucosal erosions and cutaneous detachment.¹⁷ This diagnosis is less likely given that our patient lacked mucosal involvement and did not have any notable medication exposures prior to symptom onset.

The Diagnosis: Vibrio vulnificus Infection

At the initial presentation, the differential diagnosis included infectious processes such as bacterial or angioinvasive fungal infections or an inflammatory process such as pyoderma gangrenosum. Blood cultures were found to be positive for pansensitive Vibrio vulnificus. He initially was treated with piperacillin-tazobactam and received surgical debridement of the affected tissues. Pathologic interpretation of the wound tissues revealed a diagnosis of necrotizing softtissue infection and positive Candida albicans growth. He received topical bacitracin on discharge as well as a 7-day course of amoxicillin-clavulanate and fluconazole. He continued to receive debridement procedures and skin grafts, followed by topical mupirocin treatment and silver sulfadiazine. He was seen 6 weeks after discharge with healing wounds and healthy-appearing granulation tissue at the base.

Our patient’s presentation of retiform purpura with stellate necrosis was consistent with a wide range of serious pathologies ranging from medium-vessel vasculitis to thromboembolic phenomena and angioinvasive fungal infections.¹ Although Vibrio infection rarely is the first explanation that comes to mind when observing necrotic retiform purpura, the chronic nonhealing injury on the leg combined with the recent history of ocean swimming made V vulnificus stand out as a likely culprit. Although V vulnificus infection traditionally presents with cellulitis, edema, and hemorrhagic bulla,² necrosis also has been observed.³Vibrio vulnificus produces multiple virulence factors, and it is believed that these severe cutaneous symptoms are attributable to the production of a specific metalloprotease that enhances vascular permeability, thereby inducing hemorrhage within the vascular basement membrane zone.²

Vibrio vulnificus is an opportunistic bacterial pathogen associated with consumption of contaminated seafood or swimming in ocean waters with open wounds. Infections are rare, with only approximately 100 cases reported annually in the United States.4 However, V vulnificus infections have demonstrated increasing incidence in recent years, especially infections of pre-existing wounds.^4,5 Risk factors for their development include age over 40 years and underlying conditions including liver disease, diabetes mellitus, and immune dysfunction.⁴Vibrio vulnificus infections also demonstrate a strong male predilection, with almost 90% of infections occurring in males.⁴ Although the precise etiology of this sex discrepancy remains unknown, estrogen has been suggested to be a protective factor.⁶ Alternatively, behavioral differences also have been proposed as possible explanations for this discrepancy, with women less likely to consume seafood or go swimming. However, epidemiologic data reveal strong correlations between male sex and liver cirrhosis, a primary risk factor for V vulnificus infections, suggesting that male sex may simply be a confounding variable.⁷

Infections with V vulnificus are notable for their short incubation periods, with onset of symptoms occurring within 24 hours of exposure, making prompt diagnosis and treatment of high importance.⁸ Although rare, V vulnificus infections are associated with high mortality rates. From 1988 to 2010, nearly 600 deaths were reported secondary to V vulnificus infections.⁴ Wound infections carry a 17.6% fatality rate,⁴ while bloodborne V vulnificus infections exceed 50% fatality.⁸ Although sepsis secondary to V vulnificus usually is caused by ingestion of raw or undercooked shellfish, primarily oysters,⁴ our case highlights a rarer instance of both sepsis and localized infection stemming from ocean water exposure.

Vibrio vulnificus is an obligate halophile and therefore is found in marine environments rather than freshwater bodies. However, it rarely is isolated from bodies of water with salinities over 25 parts per thousand, such as the Mediterranean Sea; it usually is found in warmer waters, making it more common in the summer months from May to October.⁴ Given this proclivity for warmer environments, climate change has contributed to both a greater incidence and global distribution of V vulnificus. ^9,10

Treatment of V vulnificus infections centers on antibiotic treatment, with Vibrio species generally demonstrating susceptibility to most antibiotics of human significance.¹¹ However, some Vibrio isolates within the United States have demonstrated antibiotic resistance; 45% of a variety of clinical and environmental samples from South Carolina and Georgia demonstrated resistance to at least 3 antibiotic classes, and 17.3% resisted 8 or more classes of antibiotics.¹² These included medications such as doxycycline, tetracycline, aminoglycosides, and cephalosporins—agents that normally are prescribed for V vulnificus infections. Although tetracyclines have long been touted as the preferred treatment of V vulnificus infections, the spread of antibiotic resistance may require greater reliance on alternative regimens such as combinations of cephalosporins and doxycycline or a single fluoroquinolone.¹³ Although rare, Vibrio infections can have rapidly fatal consequences and should be given serious consideration when evaluating patients with relevant risk factors.

The differential diagnosis included angioinvasive mucormycosis, calciphylaxis, pyoderma gangrenosum, and Stevens-Johnson syndrome/toxic epidermal necrolysis. Mucormycosis is a fungal infection caused by Mucorales fungi that most commonly is seen in patients with diabetes mellitus, hematologic malignancies, neutropenia, and immunocompromise.¹⁴ Calciphylaxis is a condition involving microvascular occlusion due to diffuse calcium deposition in cutaneous blood vessels. It typically presents as violaceous retiform patches and plaques commonly seen on areas such as the thighs, buttocks, or abdomen and usually is associated with chronic renal failure, hemodialysis, and/or secondary hyperparathyroidism.¹⁵ Pyoderma gangrenosum is an inflammatory condition involving neutrophilic ulceration of the skin that typically presents as ulceration with a classically undermined border. It frequently is considered a diagnosis of exclusion and therefore requires that providers rule out other causes of ulceration prior to diagnosis.¹⁶ Stevens-Johnson syndrome/toxic epidermal necrolysis is a rare drug reaction involving mucosal erosions and cutaneous detachment.¹⁷ This diagnosis is less likely given that our patient lacked mucosal involvement and did not have any notable medication exposures prior to symptom onset.

To the Editor:

Bullous pemphigoid (BP) is an autoimmune bullous dermatosis characterized by tense subepidermal blisters. It primarily affects older individuals who typically report pruritus in the affected area. Subepidermal blisters are caused by a humoral and cellular autoimmune attack directed against 2 BP antigens—BP180 and BP230—which are 2 critical components of the hemidesmosome whose primary function is to anchor the epidermis to the underlying dermis. Although tense bullae typically prompt immediate consideration of BP in the differential diagnosis, early disease often is characterized by urticarial plaques that require a high degree of suspicion to make the appropriate diagnosis. Locus minoris resistentiae is a term used to describe the phenomenon of skin disease occurring at the point of least resistance.¹

A 79-year-old woman with type 2 diabetes mellitus, peptic ulcer disease, and hypertension was referred to the dermatology clinic due to concern for allergic contact dermatitis limited to the area of and adjacent to a well-healed surgical wound. History and examination revealed that the patient had sustained a left femoral neck fracture 10 months prior to presentation that required closed reduction and surgical pinning. The surgical site healed well postoperatively; however, 7 months after surgery, she began to develop edema and erythema within and immediately adjacent to the surgical scar. She subsequently developed areas of superficial erosion within the erythema and was evaluated by her surgeon who was concerned for suture granuloma. Superficial wound debridement of the area was performed without improvement. Approximately 9 months after surgery, the patient developed bullae along the old surgical site, which raised concern for an allergic reaction to the implanted screws. Orthopedics elected to remove the hardware but also sent intraoperative tissue for pathologic examination, which revealed subepidermal bullae containing eosinophils and neutrophils, most consistent with a bullous drug eruption. During the ensuing weeks after hardware removal, the plaque spread along the old surgical wound, and several bullous lesions began to appear. The patient’s primary care physician became concerned for allergic contact dermatitis, possibly to the surgical scrub employed during hardware removal. He prescribed triamcinolone ointment 0.1% and referred the patient to dermatology.

Upon presentation to dermatology, the patient noted stinging pain and intense pruritus of the affected area. Examination revealed a pink edematous plaque distributed along a well-healed surgical wound (Figure). Numerous fluid-filled tense bullae were superimposed on this plaque as well as areas of superficial erosion with serum crust. An expanded examination revealed similar smaller lesions on the upper arms, inner thighs, and lateral breasts. A 4-mm punch biopsy of lesional and perilesional skin was sent for hematoxylin and eosin staining and direct immunofluorescence, which demonstrated a subepidermal bullous dermatosis with a predominance of neutrophilic inflammation as well as a band of linear IgG deposition at the dermal-epidermal junction. The patient was diagnosed with BP exhibiting a locus minoris resistentiae phenomenon within the surgical site. She was started on prednisone 1 mg/kg daily and doxycycline 100 mg twice daily and demonstrated rapid improvement.

Although the tense bullae seen in well-developed BP are fairly characteristic, the prodromal phase of this disease can present with urticarial plaques that are nonspecific. This progression is well described, but our case demonstrates the difficulty of considering BP when a patient presents with an urticarial plaque. As lesions progress to the bullous phase, they may be inappropriately diagnosed as allergic contact dermatitis, an error that may lead to unnecessary interventions (eg, removal of an implicated prosthesis). This case is a reminder that not all cutaneous eruptions in and around postsurgical scars are allergic in nature.

This case also depicts BP appearing in the locus minoris resistentiae, a well-healed surgical wound in our patient. Although many diseases have been shown to exhibit this type of isomorphic response, this phenomenon may pose diagnostic and management conundrums. Locus minoris resistentiae has been reported in many different diseases, both cutaneous and otherwise, but there likely are distinct disease- and case-specific mechanisms via which this occurs. Local phenomena reported to trigger BP include contact dermatitis, vaccination, radiation therapy, phototherapy, infection, and surgery.² We suspect that the mechanism of locus minoris resistentiae in our patient was disruption of the architecture of the dermal-epidermal basement membrane zone due to surgical trauma. Disruption of this architecture may have resulted in exposure of previously occult antigens, recognition by T cells, T-cell stimulation of autoantibody production by B cells, binding of autoantibodies to BP180, complement deposition, recruitment of inflammatory cells, release of proteinases, and degradation of BP180 and extracellular matrix proteins.²

To the Editor:

Bullous pemphigoid (BP) is an autoimmune bullous dermatosis characterized by tense subepidermal blisters. It primarily affects older individuals who typically report pruritus in the affected area. Subepidermal blisters are caused by a humoral and cellular autoimmune attack directed against 2 BP antigens—BP180 and BP230—which are 2 critical components of the hemidesmosome whose primary function is to anchor the epidermis to the underlying dermis. Although tense bullae typically prompt immediate consideration of BP in the differential diagnosis, early disease often is characterized by urticarial plaques that require a high degree of suspicion to make the appropriate diagnosis. Locus minoris resistentiae is a term used to describe the phenomenon of skin disease occurring at the point of least resistance.¹

A 79-year-old woman with type 2 diabetes mellitus, peptic ulcer disease, and hypertension was referred to the dermatology clinic due to concern for allergic contact dermatitis limited to the area of and adjacent to a well-healed surgical wound. History and examination revealed that the patient had sustained a left femoral neck fracture 10 months prior to presentation that required closed reduction and surgical pinning. The surgical site healed well postoperatively; however, 7 months after surgery, she began to develop edema and erythema within and immediately adjacent to the surgical scar. She subsequently developed areas of superficial erosion within the erythema and was evaluated by her surgeon who was concerned for suture granuloma. Superficial wound debridement of the area was performed without improvement. Approximately 9 months after surgery, the patient developed bullae along the old surgical site, which raised concern for an allergic reaction to the implanted screws. Orthopedics elected to remove the hardware but also sent intraoperative tissue for pathologic examination, which revealed subepidermal bullae containing eosinophils and neutrophils, most consistent with a bullous drug eruption. During the ensuing weeks after hardware removal, the plaque spread along the old surgical wound, and several bullous lesions began to appear. The patient’s primary care physician became concerned for allergic contact dermatitis, possibly to the surgical scrub employed during hardware removal. He prescribed triamcinolone ointment 0.1% and referred the patient to dermatology.

Upon presentation to dermatology, the patient noted stinging pain and intense pruritus of the affected area. Examination revealed a pink edematous plaque distributed along a well-healed surgical wound (Figure). Numerous fluid-filled tense bullae were superimposed on this plaque as well as areas of superficial erosion with serum crust. An expanded examination revealed similar smaller lesions on the upper arms, inner thighs, and lateral breasts. A 4-mm punch biopsy of lesional and perilesional skin was sent for hematoxylin and eosin staining and direct immunofluorescence, which demonstrated a subepidermal bullous dermatosis with a predominance of neutrophilic inflammation as well as a band of linear IgG deposition at the dermal-epidermal junction. The patient was diagnosed with BP exhibiting a locus minoris resistentiae phenomenon within the surgical site. She was started on prednisone 1 mg/kg daily and doxycycline 100 mg twice daily and demonstrated rapid improvement.

Although the tense bullae seen in well-developed BP are fairly characteristic, the prodromal phase of this disease can present with urticarial plaques that are nonspecific. This progression is well described, but our case demonstrates the difficulty of considering BP when a patient presents with an urticarial plaque. As lesions progress to the bullous phase, they may be inappropriately diagnosed as allergic contact dermatitis, an error that may lead to unnecessary interventions (eg, removal of an implicated prosthesis). This case is a reminder that not all cutaneous eruptions in and around postsurgical scars are allergic in nature.

This case also depicts BP appearing in the locus minoris resistentiae, a well-healed surgical wound in our patient. Although many diseases have been shown to exhibit this type of isomorphic response, this phenomenon may pose diagnostic and management conundrums. Locus minoris resistentiae has been reported in many different diseases, both cutaneous and otherwise, but there likely are distinct disease- and case-specific mechanisms via which this occurs. Local phenomena reported to trigger BP include contact dermatitis, vaccination, radiation therapy, phototherapy, infection, and surgery.² We suspect that the mechanism of locus minoris resistentiae in our patient was disruption of the architecture of the dermal-epidermal basement membrane zone due to surgical trauma. Disruption of this architecture may have resulted in exposure of previously occult antigens, recognition by T cells, T-cell stimulation of autoantibody production by B cells, binding of autoantibodies to BP180, complement deposition, recruitment of inflammatory cells, release of proteinases, and degradation of BP180 and extracellular matrix proteins.²

To the Editor:

Bullous pemphigoid (BP) is an autoimmune bullous dermatosis characterized by tense subepidermal blisters. It primarily affects older individuals who typically report pruritus in the affected area. Subepidermal blisters are caused by a humoral and cellular autoimmune attack directed against 2 BP antigens—BP180 and BP230—which are 2 critical components of the hemidesmosome whose primary function is to anchor the epidermis to the underlying dermis. Although tense bullae typically prompt immediate consideration of BP in the differential diagnosis, early disease often is characterized by urticarial plaques that require a high degree of suspicion to make the appropriate diagnosis. Locus minoris resistentiae is a term used to describe the phenomenon of skin disease occurring at the point of least resistance.¹

A 79-year-old woman with type 2 diabetes mellitus, peptic ulcer disease, and hypertension was referred to the dermatology clinic due to concern for allergic contact dermatitis limited to the area of and adjacent to a well-healed surgical wound. History and examination revealed that the patient had sustained a left femoral neck fracture 10 months prior to presentation that required closed reduction and surgical pinning. The surgical site healed well postoperatively; however, 7 months after surgery, she began to develop edema and erythema within and immediately adjacent to the surgical scar. She subsequently developed areas of superficial erosion within the erythema and was evaluated by her surgeon who was concerned for suture granuloma. Superficial wound debridement of the area was performed without improvement. Approximately 9 months after surgery, the patient developed bullae along the old surgical site, which raised concern for an allergic reaction to the implanted screws. Orthopedics elected to remove the hardware but also sent intraoperative tissue for pathologic examination, which revealed subepidermal bullae containing eosinophils and neutrophils, most consistent with a bullous drug eruption. During the ensuing weeks after hardware removal, the plaque spread along the old surgical wound, and several bullous lesions began to appear. The patient’s primary care physician became concerned for allergic contact dermatitis, possibly to the surgical scrub employed during hardware removal. He prescribed triamcinolone ointment 0.1% and referred the patient to dermatology.

Upon presentation to dermatology, the patient noted stinging pain and intense pruritus of the affected area. Examination revealed a pink edematous plaque distributed along a well-healed surgical wound (Figure). Numerous fluid-filled tense bullae were superimposed on this plaque as well as areas of superficial erosion with serum crust. An expanded examination revealed similar smaller lesions on the upper arms, inner thighs, and lateral breasts. A 4-mm punch biopsy of lesional and perilesional skin was sent for hematoxylin and eosin staining and direct immunofluorescence, which demonstrated a subepidermal bullous dermatosis with a predominance of neutrophilic inflammation as well as a band of linear IgG deposition at the dermal-epidermal junction. The patient was diagnosed with BP exhibiting a locus minoris resistentiae phenomenon within the surgical site. She was started on prednisone 1 mg/kg daily and doxycycline 100 mg twice daily and demonstrated rapid improvement.

Although the tense bullae seen in well-developed BP are fairly characteristic, the prodromal phase of this disease can present with urticarial plaques that are nonspecific. This progression is well described, but our case demonstrates the difficulty of considering BP when a patient presents with an urticarial plaque. As lesions progress to the bullous phase, they may be inappropriately diagnosed as allergic contact dermatitis, an error that may lead to unnecessary interventions (eg, removal of an implicated prosthesis). This case is a reminder that not all cutaneous eruptions in and around postsurgical scars are allergic in nature.

This case also depicts BP appearing in the locus minoris resistentiae, a well-healed surgical wound in our patient. Although many diseases have been shown to exhibit this type of isomorphic response, this phenomenon may pose diagnostic and management conundrums. Locus minoris resistentiae has been reported in many different diseases, both cutaneous and otherwise, but there likely are distinct disease- and case-specific mechanisms via which this occurs. Local phenomena reported to trigger BP include contact dermatitis, vaccination, radiation therapy, phototherapy, infection, and surgery.² We suspect that the mechanism of locus minoris resistentiae in our patient was disruption of the architecture of the dermal-epidermal basement membrane zone due to surgical trauma. Disruption of this architecture may have resulted in exposure of previously occult antigens, recognition by T cells, T-cell stimulation of autoantibody production by B cells, binding of autoantibodies to BP180, complement deposition, recruitment of inflammatory cells, release of proteinases, and degradation of BP180 and extracellular matrix proteins.²

To the Editor:

A 56-year-old man with a history of opioid abuse and splenectomy decades prior due to a motor vehicle accident was brought to an outside emergency department with confusion, slurred speech, and difficulty breathing. Over the next few days, he became febrile and hypotensive, requiring vasopressors. Clinical laboratory testing revealed a urine drug screen positive for opioids and a low platelet count in the setting of a rapidly evolving retiform purpuric rash.

The patient was transferred to our institution 6 days after initial presentation with primary diagnoses of septic shock with multiorgan failure and disseminated intravascular coagulation (DIC). Blood cultures were positive for gram-negative rods. After several days of broad-spectrum antibiotics and supportive care, cultures were reported as positive for Capnocytophaga canimorsus. Upon further questioning, the patient’s wife reported that the couple had a new puppy and that the patient often allowed the dog to bite him playfully and lick abrasions on his hands and legs. He had not received medical treatment for any of the dog’s bites.

On initial examination at the time of transfer, the patient’s skin was remarkable for diffuse areas of stellate and retiform purpura with dusky centers and necrosis of the nasal tip and earlobes. Both hands were purpuric, with necrosis of the fingertips (Figure 1A). The flank was marked by large areas of full-thickness sloughing of the skin (Figure 1B). The lower extremities were edematous, with some areas of stellate purpura and numerous large bullae that drained straw-colored fluid (Figure 1C). Lower extremity pulses were found with Doppler ultrasonography.

Given the presence of rapidly developing retiform purpura in the clinical context of severe sepsis, purpura fulminans (PF) was the primary consideration in the differential diagnosis. Levamisole-induced necrosis syndrome also was considered because of necrosis of the ears and nose as well as the history of substance use; however, the patient was not known to have a history of cocaine abuse, and a test of antineutrophil cytoplasmic antibody was negative.

A punch biopsy of the abdomen revealed intravascular thrombi with epidermal and sweat gland necrosis, consistent with PF (Figure 2). Gram, Giemsa, and Gomori methenamine-silver stains were negative for organisms. Tissue culture remained negative. Repeat blood cultures demonstrated Candida parapsilosis fungemia. Respiratory culture was positive for budding yeast.

The patient was treated with antimicrobials, intravenous argatroban, and subcutaneous heparin. Purpura and bullae on the trunk slowly resolved with systemic therapy and wound care with petrolatum and nonadherent dressings. However, lesions on the nasal tip, all fingers of both hands, and several toes evolved into dry gangrene. The hospital course was complicated by renal failure requiring continuous renal replacement therapy; respiratory failure requiring ventilator support; and elevated levels of liver enzymes, consistent with involvement of the hepatic microvasculature.

The patient was in the medical intensive care unit at our institution for 2 weeks and was transferred to a burn center for specialized wound care. At transfer, he was still on a ventilator and receiving continuous renal replacement therapy. Subsequently, the patient required a left above-the-knee amputation, right below-the-knee amputation, and amputation of several digits of the upper extremities. In the months after the amputations, he required multiple stump revisions and experienced surgical site infections that complicated healing.

Purpura fulminans is an uncommon syndrome characterized by intravascular thrombosis and hemorrhagic infarction of the skin. The condition commonly is associated with septic shock, causing vascular collapse and DIC. It often develops rapidly.

Because of associated high mortality, it is important to differentiate PF from other causes of cutaneous retiform purpura, including other causes of thrombosis and large vessel vasculitis. Leading causes of PF include infection and hereditary or acquired deficiency of protein C, protein S, or antithrombin III. Regardless of cause, biopsy results demonstrate vascular thrombosis out of proportion to vasculitis. The mortality rate is 42% to 50%. The incidence of postinfectious sepsis sequelae in PF is higher than in survivors of sepsis only, especially amputation.^1-3 Most patients do not die from complications of sepsis but from sequelae of the hypercoagulable and prothrombotic state associated with PF.⁴ Hemorrhagic infarction can affect the kidneys, brain, lungs, heart, eyes, and adrenal glands (ie, necrosis, namely Waterhouse-Friderichsen syndrome).⁵

The most common infectious cause of PF is sepsis secondary to Neisseria meningitidis, with as many as 25% of infected patients developing PF.⁶Streptococcus pneumoniae is another common cause. Other important causative organisms include Streptococcus pyogenes; Staphylococcus aureus (in the setting of intravenous substance use); Klebsiella oxytoca; Klebsiella aerogenes; rickettsial organisms; and viruses, including cytomegalovirus and varicella-zoster virus.^2,7-13 Two earlier cases associated with Capnocytophaga were characterized by concomitant renal failure, metabolic acidosis, hemolytic anemia, and DIC.¹⁴

It is estimated that Capnocytophaga causes 11% to 46% of all cases of sepsis¹⁵; sepsis resulting from Capnocytophaga has extremely poor outcomes, with mortality reaching as high as 60%. The organism is part of the normal oral flora of cats and dogs, and a bite (less often, a scratch) is the cause of most Capnocytophaga infections. The clinical spectrum of C canimorsus infection associated with dog saliva exposure more commonly includes cellulitis at or around the site of inoculation, meningitis, and endocarditis.¹⁶

Although patients affected by PF can be young and healthy, several risk factors for PF have been identified^2,6,16: asplenia, an immunocompromised state, systemic corticosteroid use, cirrhosis, and alcoholism. Asplenic patients have been shown to be particularly susceptible to systemic Capnocytophaga infection; when bitten by a dog, they should be treated with prophylactic antibiotics to cover Capnocytophaga.¹⁷ Immunocompetent patients rarely develop severe infection with Capnocytophaga.^16,18,19 The complement system in particular is critically important in defending against C canimorsus.²⁰

The underlying pathophysiology of acute infectious PF is multifactorial, encompassing increased expression of procoagulant tissue factor by monocytes and endothelial cells in the presence of bacterial pathogens. Dysfunction of protein C, an anticoagulant component of the coagulation cascade, often is cited as a crucial derangement leading to the development of a prothrombotic state in acute infectious PF.²¹ Serum protein S and antithrombin deficiency also can play a role.²² Specific in vitro examination of C canimorsus has revealed a protease that catalyzes N-terminal cleavage of procoagulant factor X, resulting in loss of function.¹⁵

Retiform purpura is a hallmark feature of PF, often beginning as nonblanching erythema with localized edema and petechiae before evolving into the characteristic stellate lesions with hemorrhagic bullae and subsequent necrosis.²³ Pathologic examination reveals microthrombi involving arterioles and smaller vessels.²⁴ There typically is laboratory evidence of DIC in PF, including elevated prothrombin time and partial thromboplastin time, thrombocytopenia, elevated D-dimer, and a decreased fibrinogen level.^6,23

Capnocytophaga bacteria are challenging to grow on standard culture media. Optimal media for growth include 5% sheep’s blood and chocolate agar.¹⁶ Polymerase chain reaction can identify Capnocytophaga; in cases in which blood culture does not produce growth, 16S ribosomal RNA gene sequencing of tissue from skin biopsy has identified the pathogen.²⁵

Some Capnocytophaga isolates have been shown to produce beta-lactamase; individual strains can be resistant to penicillins, cephalosporins, and imipenem.²⁶ Factors associated with an increased risk for death include decreased leukocyte and platelet counts and an increased level of arterial lactate.²⁷

Empiric antibiotic therapy for Capnocytophaga sepsis should include a beta-lactam and beta-lactamase inhibitor, such as piperacillin-tazobactam. Management of DIC can include therapeutic heparin or low-molecular-weight heparin and prophylactic platelet transfusion to maintain a pre-established value.^28-30 Debridement should be conservative; it is important to wait for definite delineation between viable and necrotic tissue,³¹ which might take several months.³² Human skin allografts, in addition to artificial skin, are utilized as supplemental therapy for more rapid wound closure after removal of necrotic tissue.^33,34 Hyperoxygenated fatty acids have been noted to aid in more rapid wound healing in infants with PF.³⁵

Fresh frozen plasma is one method to replace missing factors, but it contains little protein C.³⁶ Outcomes with recombinant human activated protein C (drotrecogin alfa) are mixed, and studies have shown no benefit in reducing the risk for death.^37,38 Protein C concentrate has shown therapeutic benefit in some case reports and small retrospective studies.⁴ In one case report, protein C concentrate and heparin were utilized in combination with antithrombin III.²¹

Hyperbaric O₂ might be of benefit when initiated within 5 days after onset of PF. However, hyperbaric O₂ does carry risk; O₂ toxicity, barotrauma, and barriers to timely resuscitation when the patient is inside the pressurized chamber can occur.²

There is a single report of successful use of the vasodilator iloprost for meningococcal PF without need for surgical intervention; the team also utilized topical nitroglycerin patches on the fingers to avoid digital amputation.³⁹ Epoprostenol, tissue plasminogen activator, and antithrombin have been utilized in cases of extensive PF. Fibrinolytic therapy might have some utility, but only in a setting of malignancy-associated DIC.⁴⁰

Treatment of acute infectious PF lacks a high level of evidence. Options include replacement of anticoagulant factors, anticoagulant therapy, hyperbaric O₂, topical and systemic vasodilators, and, in the setting of underlying cancer, fibrinolytics. Even with therapy, prognosis is guarded.

To the Editor:

A 56-year-old man with a history of opioid abuse and splenectomy decades prior due to a motor vehicle accident was brought to an outside emergency department with confusion, slurred speech, and difficulty breathing. Over the next few days, he became febrile and hypotensive, requiring vasopressors. Clinical laboratory testing revealed a urine drug screen positive for opioids and a low platelet count in the setting of a rapidly evolving retiform purpuric rash.

The patient was transferred to our institution 6 days after initial presentation with primary diagnoses of septic shock with multiorgan failure and disseminated intravascular coagulation (DIC). Blood cultures were positive for gram-negative rods. After several days of broad-spectrum antibiotics and supportive care, cultures were reported as positive for Capnocytophaga canimorsus. Upon further questioning, the patient’s wife reported that the couple had a new puppy and that the patient often allowed the dog to bite him playfully and lick abrasions on his hands and legs. He had not received medical treatment for any of the dog’s bites.

On initial examination at the time of transfer, the patient’s skin was remarkable for diffuse areas of stellate and retiform purpura with dusky centers and necrosis of the nasal tip and earlobes. Both hands were purpuric, with necrosis of the fingertips (Figure 1A). The flank was marked by large areas of full-thickness sloughing of the skin (Figure 1B). The lower extremities were edematous, with some areas of stellate purpura and numerous large bullae that drained straw-colored fluid (Figure 1C). Lower extremity pulses were found with Doppler ultrasonography.

Given the presence of rapidly developing retiform purpura in the clinical context of severe sepsis, purpura fulminans (PF) was the primary consideration in the differential diagnosis. Levamisole-induced necrosis syndrome also was considered because of necrosis of the ears and nose as well as the history of substance use; however, the patient was not known to have a history of cocaine abuse, and a test of antineutrophil cytoplasmic antibody was negative.

A punch biopsy of the abdomen revealed intravascular thrombi with epidermal and sweat gland necrosis, consistent with PF (Figure 2). Gram, Giemsa, and Gomori methenamine-silver stains were negative for organisms. Tissue culture remained negative. Repeat blood cultures demonstrated Candida parapsilosis fungemia. Respiratory culture was positive for budding yeast.

The patient was treated with antimicrobials, intravenous argatroban, and subcutaneous heparin. Purpura and bullae on the trunk slowly resolved with systemic therapy and wound care with petrolatum and nonadherent dressings. However, lesions on the nasal tip, all fingers of both hands, and several toes evolved into dry gangrene. The hospital course was complicated by renal failure requiring continuous renal replacement therapy; respiratory failure requiring ventilator support; and elevated levels of liver enzymes, consistent with involvement of the hepatic microvasculature.

The patient was in the medical intensive care unit at our institution for 2 weeks and was transferred to a burn center for specialized wound care. At transfer, he was still on a ventilator and receiving continuous renal replacement therapy. Subsequently, the patient required a left above-the-knee amputation, right below-the-knee amputation, and amputation of several digits of the upper extremities. In the months after the amputations, he required multiple stump revisions and experienced surgical site infections that complicated healing.

Purpura fulminans is an uncommon syndrome characterized by intravascular thrombosis and hemorrhagic infarction of the skin. The condition commonly is associated with septic shock, causing vascular collapse and DIC. It often develops rapidly.

Because of associated high mortality, it is important to differentiate PF from other causes of cutaneous retiform purpura, including other causes of thrombosis and large vessel vasculitis. Leading causes of PF include infection and hereditary or acquired deficiency of protein C, protein S, or antithrombin III. Regardless of cause, biopsy results demonstrate vascular thrombosis out of proportion to vasculitis. The mortality rate is 42% to 50%. The incidence of postinfectious sepsis sequelae in PF is higher than in survivors of sepsis only, especially amputation.^1-3 Most patients do not die from complications of sepsis but from sequelae of the hypercoagulable and prothrombotic state associated with PF.⁴ Hemorrhagic infarction can affect the kidneys, brain, lungs, heart, eyes, and adrenal glands (ie, necrosis, namely Waterhouse-Friderichsen syndrome).⁵

The most common infectious cause of PF is sepsis secondary to Neisseria meningitidis, with as many as 25% of infected patients developing PF.⁶Streptococcus pneumoniae is another common cause. Other important causative organisms include Streptococcus pyogenes; Staphylococcus aureus (in the setting of intravenous substance use); Klebsiella oxytoca; Klebsiella aerogenes; rickettsial organisms; and viruses, including cytomegalovirus and varicella-zoster virus.^2,7-13 Two earlier cases associated with Capnocytophaga were characterized by concomitant renal failure, metabolic acidosis, hemolytic anemia, and DIC.¹⁴

It is estimated that Capnocytophaga causes 11% to 46% of all cases of sepsis¹⁵; sepsis resulting from Capnocytophaga has extremely poor outcomes, with mortality reaching as high as 60%. The organism is part of the normal oral flora of cats and dogs, and a bite (less often, a scratch) is the cause of most Capnocytophaga infections. The clinical spectrum of C canimorsus infection associated with dog saliva exposure more commonly includes cellulitis at or around the site of inoculation, meningitis, and endocarditis.¹⁶

Although patients affected by PF can be young and healthy, several risk factors for PF have been identified^2,6,16: asplenia, an immunocompromised state, systemic corticosteroid use, cirrhosis, and alcoholism. Asplenic patients have been shown to be particularly susceptible to systemic Capnocytophaga infection; when bitten by a dog, they should be treated with prophylactic antibiotics to cover Capnocytophaga.¹⁷ Immunocompetent patients rarely develop severe infection with Capnocytophaga.^16,18,19 The complement system in particular is critically important in defending against C canimorsus.²⁰

The underlying pathophysiology of acute infectious PF is multifactorial, encompassing increased expression of procoagulant tissue factor by monocytes and endothelial cells in the presence of bacterial pathogens. Dysfunction of protein C, an anticoagulant component of the coagulation cascade, often is cited as a crucial derangement leading to the development of a prothrombotic state in acute infectious PF.²¹ Serum protein S and antithrombin deficiency also can play a role.²² Specific in vitro examination of C canimorsus has revealed a protease that catalyzes N-terminal cleavage of procoagulant factor X, resulting in loss of function.¹⁵

Retiform purpura is a hallmark feature of PF, often beginning as nonblanching erythema with localized edema and petechiae before evolving into the characteristic stellate lesions with hemorrhagic bullae and subsequent necrosis.²³ Pathologic examination reveals microthrombi involving arterioles and smaller vessels.²⁴ There typically is laboratory evidence of DIC in PF, including elevated prothrombin time and partial thromboplastin time, thrombocytopenia, elevated D-dimer, and a decreased fibrinogen level.^6,23

Capnocytophaga bacteria are challenging to grow on standard culture media. Optimal media for growth include 5% sheep’s blood and chocolate agar.¹⁶ Polymerase chain reaction can identify Capnocytophaga; in cases in which blood culture does not produce growth, 16S ribosomal RNA gene sequencing of tissue from skin biopsy has identified the pathogen.²⁵

Some Capnocytophaga isolates have been shown to produce beta-lactamase; individual strains can be resistant to penicillins, cephalosporins, and imipenem.²⁶ Factors associated with an increased risk for death include decreased leukocyte and platelet counts and an increased level of arterial lactate.²⁷

Empiric antibiotic therapy for Capnocytophaga sepsis should include a beta-lactam and beta-lactamase inhibitor, such as piperacillin-tazobactam. Management of DIC can include therapeutic heparin or low-molecular-weight heparin and prophylactic platelet transfusion to maintain a pre-established value.^28-30 Debridement should be conservative; it is important to wait for definite delineation between viable and necrotic tissue,³¹ which might take several months.³² Human skin allografts, in addition to artificial skin, are utilized as supplemental therapy for more rapid wound closure after removal of necrotic tissue.^33,34 Hyperoxygenated fatty acids have been noted to aid in more rapid wound healing in infants with PF.³⁵

Fresh frozen plasma is one method to replace missing factors, but it contains little protein C.³⁶ Outcomes with recombinant human activated protein C (drotrecogin alfa) are mixed, and studies have shown no benefit in reducing the risk for death.^37,38 Protein C concentrate has shown therapeutic benefit in some case reports and small retrospective studies.⁴ In one case report, protein C concentrate and heparin were utilized in combination with antithrombin III.²¹

Hyperbaric O₂ might be of benefit when initiated within 5 days after onset of PF. However, hyperbaric O₂ does carry risk; O₂ toxicity, barotrauma, and barriers to timely resuscitation when the patient is inside the pressurized chamber can occur.²

There is a single report of successful use of the vasodilator iloprost for meningococcal PF without need for surgical intervention; the team also utilized topical nitroglycerin patches on the fingers to avoid digital amputation.³⁹ Epoprostenol, tissue plasminogen activator, and antithrombin have been utilized in cases of extensive PF. Fibrinolytic therapy might have some utility, but only in a setting of malignancy-associated DIC.⁴⁰

Treatment of acute infectious PF lacks a high level of evidence. Options include replacement of anticoagulant factors, anticoagulant therapy, hyperbaric O₂, topical and systemic vasodilators, and, in the setting of underlying cancer, fibrinolytics. Even with therapy, prognosis is guarded.

To the Editor:

A 56-year-old man with a history of opioid abuse and splenectomy decades prior due to a motor vehicle accident was brought to an outside emergency department with confusion, slurred speech, and difficulty breathing. Over the next few days, he became febrile and hypotensive, requiring vasopressors. Clinical laboratory testing revealed a urine drug screen positive for opioids and a low platelet count in the setting of a rapidly evolving retiform purpuric rash.

The patient was transferred to our institution 6 days after initial presentation with primary diagnoses of septic shock with multiorgan failure and disseminated intravascular coagulation (DIC). Blood cultures were positive for gram-negative rods. After several days of broad-spectrum antibiotics and supportive care, cultures were reported as positive for Capnocytophaga canimorsus. Upon further questioning, the patient’s wife reported that the couple had a new puppy and that the patient often allowed the dog to bite him playfully and lick abrasions on his hands and legs. He had not received medical treatment for any of the dog’s bites.

On initial examination at the time of transfer, the patient’s skin was remarkable for diffuse areas of stellate and retiform purpura with dusky centers and necrosis of the nasal tip and earlobes. Both hands were purpuric, with necrosis of the fingertips (Figure 1A). The flank was marked by large areas of full-thickness sloughing of the skin (Figure 1B). The lower extremities were edematous, with some areas of stellate purpura and numerous large bullae that drained straw-colored fluid (Figure 1C). Lower extremity pulses were found with Doppler ultrasonography.

Given the presence of rapidly developing retiform purpura in the clinical context of severe sepsis, purpura fulminans (PF) was the primary consideration in the differential diagnosis. Levamisole-induced necrosis syndrome also was considered because of necrosis of the ears and nose as well as the history of substance use; however, the patient was not known to have a history of cocaine abuse, and a test of antineutrophil cytoplasmic antibody was negative.

A punch biopsy of the abdomen revealed intravascular thrombi with epidermal and sweat gland necrosis, consistent with PF (Figure 2). Gram, Giemsa, and Gomori methenamine-silver stains were negative for organisms. Tissue culture remained negative. Repeat blood cultures demonstrated Candida parapsilosis fungemia. Respiratory culture was positive for budding yeast.

The patient was treated with antimicrobials, intravenous argatroban, and subcutaneous heparin. Purpura and bullae on the trunk slowly resolved with systemic therapy and wound care with petrolatum and nonadherent dressings. However, lesions on the nasal tip, all fingers of both hands, and several toes evolved into dry gangrene. The hospital course was complicated by renal failure requiring continuous renal replacement therapy; respiratory failure requiring ventilator support; and elevated levels of liver enzymes, consistent with involvement of the hepatic microvasculature.

The patient was in the medical intensive care unit at our institution for 2 weeks and was transferred to a burn center for specialized wound care. At transfer, he was still on a ventilator and receiving continuous renal replacement therapy. Subsequently, the patient required a left above-the-knee amputation, right below-the-knee amputation, and amputation of several digits of the upper extremities. In the months after the amputations, he required multiple stump revisions and experienced surgical site infections that complicated healing.

Purpura fulminans is an uncommon syndrome characterized by intravascular thrombosis and hemorrhagic infarction of the skin. The condition commonly is associated with septic shock, causing vascular collapse and DIC. It often develops rapidly.

Because of associated high mortality, it is important to differentiate PF from other causes of cutaneous retiform purpura, including other causes of thrombosis and large vessel vasculitis. Leading causes of PF include infection and hereditary or acquired deficiency of protein C, protein S, or antithrombin III. Regardless of cause, biopsy results demonstrate vascular thrombosis out of proportion to vasculitis. The mortality rate is 42% to 50%. The incidence of postinfectious sepsis sequelae in PF is higher than in survivors of sepsis only, especially amputation.^1-3 Most patients do not die from complications of sepsis but from sequelae of the hypercoagulable and prothrombotic state associated with PF.⁴ Hemorrhagic infarction can affect the kidneys, brain, lungs, heart, eyes, and adrenal glands (ie, necrosis, namely Waterhouse-Friderichsen syndrome).⁵

The most common infectious cause of PF is sepsis secondary to Neisseria meningitidis, with as many as 25% of infected patients developing PF.⁶Streptococcus pneumoniae is another common cause. Other important causative organisms include Streptococcus pyogenes; Staphylococcus aureus (in the setting of intravenous substance use); Klebsiella oxytoca; Klebsiella aerogenes; rickettsial organisms; and viruses, including cytomegalovirus and varicella-zoster virus.^2,7-13 Two earlier cases associated with Capnocytophaga were characterized by concomitant renal failure, metabolic acidosis, hemolytic anemia, and DIC.¹⁴

It is estimated that Capnocytophaga causes 11% to 46% of all cases of sepsis¹⁵; sepsis resulting from Capnocytophaga has extremely poor outcomes, with mortality reaching as high as 60%. The organism is part of the normal oral flora of cats and dogs, and a bite (less often, a scratch) is the cause of most Capnocytophaga infections. The clinical spectrum of C canimorsus infection associated with dog saliva exposure more commonly includes cellulitis at or around the site of inoculation, meningitis, and endocarditis.¹⁶

Although patients affected by PF can be young and healthy, several risk factors for PF have been identified^2,6,16: asplenia, an immunocompromised state, systemic corticosteroid use, cirrhosis, and alcoholism. Asplenic patients have been shown to be particularly susceptible to systemic Capnocytophaga infection; when bitten by a dog, they should be treated with prophylactic antibiotics to cover Capnocytophaga.¹⁷ Immunocompetent patients rarely develop severe infection with Capnocytophaga.^16,18,19 The complement system in particular is critically important in defending against C canimorsus.²⁰

The underlying pathophysiology of acute infectious PF is multifactorial, encompassing increased expression of procoagulant tissue factor by monocytes and endothelial cells in the presence of bacterial pathogens. Dysfunction of protein C, an anticoagulant component of the coagulation cascade, often is cited as a crucial derangement leading to the development of a prothrombotic state in acute infectious PF.²¹ Serum protein S and antithrombin deficiency also can play a role.²² Specific in vitro examination of C canimorsus has revealed a protease that catalyzes N-terminal cleavage of procoagulant factor X, resulting in loss of function.¹⁵

Retiform purpura is a hallmark feature of PF, often beginning as nonblanching erythema with localized edema and petechiae before evolving into the characteristic stellate lesions with hemorrhagic bullae and subsequent necrosis.²³ Pathologic examination reveals microthrombi involving arterioles and smaller vessels.²⁴ There typically is laboratory evidence of DIC in PF, including elevated prothrombin time and partial thromboplastin time, thrombocytopenia, elevated D-dimer, and a decreased fibrinogen level.^6,23

Capnocytophaga bacteria are challenging to grow on standard culture media. Optimal media for growth include 5% sheep’s blood and chocolate agar.¹⁶ Polymerase chain reaction can identify Capnocytophaga; in cases in which blood culture does not produce growth, 16S ribosomal RNA gene sequencing of tissue from skin biopsy has identified the pathogen.²⁵

Some Capnocytophaga isolates have been shown to produce beta-lactamase; individual strains can be resistant to penicillins, cephalosporins, and imipenem.²⁶ Factors associated with an increased risk for death include decreased leukocyte and platelet counts and an increased level of arterial lactate.²⁷

Empiric antibiotic therapy for Capnocytophaga sepsis should include a beta-lactam and beta-lactamase inhibitor, such as piperacillin-tazobactam. Management of DIC can include therapeutic heparin or low-molecular-weight heparin and prophylactic platelet transfusion to maintain a pre-established value.^28-30 Debridement should be conservative; it is important to wait for definite delineation between viable and necrotic tissue,³¹ which might take several months.³² Human skin allografts, in addition to artificial skin, are utilized as supplemental therapy for more rapid wound closure after removal of necrotic tissue.^33,34 Hyperoxygenated fatty acids have been noted to aid in more rapid wound healing in infants with PF.³⁵

Fresh frozen plasma is one method to replace missing factors, but it contains little protein C.³⁶ Outcomes with recombinant human activated protein C (drotrecogin alfa) are mixed, and studies have shown no benefit in reducing the risk for death.^37,38 Protein C concentrate has shown therapeutic benefit in some case reports and small retrospective studies.⁴ In one case report, protein C concentrate and heparin were utilized in combination with antithrombin III.²¹

Hyperbaric O₂ might be of benefit when initiated within 5 days after onset of PF. However, hyperbaric O₂ does carry risk; O₂ toxicity, barotrauma, and barriers to timely resuscitation when the patient is inside the pressurized chamber can occur.²

There is a single report of successful use of the vasodilator iloprost for meningococcal PF without need for surgical intervention; the team also utilized topical nitroglycerin patches on the fingers to avoid digital amputation.³⁹ Epoprostenol, tissue plasminogen activator, and antithrombin have been utilized in cases of extensive PF. Fibrinolytic therapy might have some utility, but only in a setting of malignancy-associated DIC.⁴⁰

Treatment of acute infectious PF lacks a high level of evidence. Options include replacement of anticoagulant factors, anticoagulant therapy, hyperbaric O₂, topical and systemic vasodilators, and, in the setting of underlying cancer, fibrinolytics. Even with therapy, prognosis is guarded.

The Boswellia serrata exudate or gum (known in India as “guggulu”) that forms an aromatic resin traditionally used as incense – and known as frankincense (especially when retrieved from Boswellia species found in Eritrea and Somalia but also from the Indian variety) – has been considered for thousands of years to possess therapeutic properties. It is used in Ayurvedic medicine, as well as in traditional medicine in China and the Middle East, particularly for its anti-inflammatory effects to treat chronic conditions.^1-8 In fact, such essential oils have been used since 2800 BC to treat various inflammatory conditions, including skin sores and wounds, as well as in perfumes and incense.^2,9 In the West, use of frankincense dates back to thousands of years as well, more often found in the form of incense for religious and cultural ceremonies.⁷ Over the past 2 decades, evidence supporting the use of frankincense for therapeutic medical purposes has increased, particularly because of its purported anti-inflammatory and anticancer properties.³ This column focuses on some of the emerging data on this ancient botanical agent.

Madeleine_Steinbach / iStock / Getty Images Plus

Chemical constituents

Terpenoids and essential oils are the primary components of frankincense and are known to impart anti-inflammatory and anticancer activity. The same is true for myrrh, which has been combined with frankincense in traditional Chinese medicine as a single medication for millennia, with the two acting synergistically and considered still to be a potent combination in conferring various biological benefits.⁷

In 2010, in a systematic review of the anti-inflammatory and anticancer activities of Boswellia species and their chemical ingredients, Efferth and Oesch found that frankincense blocks the production of leukotrienes, cyclooxygenase (COX) 1 and 2, as well as 5-lipoxygenase; and oxidative stress. It also contributes to regulation of immune cells from the innate and acquired immune systems and exerts anticancer activity by influencing signaling transduction responsible for cell cycle arrest, as well as inhibition of proliferation, angiogenesis, invasion, and metastasis. The investigators also reported on clinical trial results that have found efficacy of frankincense and its constituents in ameliorating symptoms of psoriasis and erythematous eczema, among other disorders.³

Anti-inflammatory activity

Li et al. completed a study in 2016 to identify the active ingredients responsible for the anti-inflammatory and analgesic effects of frankincense. They found that alpha-pinene, linalool, and 1-octanol were key contributors. These constituents were noted for suppressing COX-2 overexpression in mice, as well as nociceptive stimulus-induced inflammatory infiltrates.¹⁰

Noting the increasing popularity of frankincense essential oil in skin care, despite a paucity of data, in 2017, Han et al. evaluated the biological activities of the essential oil in pre-inflamed human dermal fibroblasts using 17 key protein biomarkers. Frankincense essential oil displayed significant antiproliferative activity and suppressed collagen III, interferon gamma-induced protein 10, and intracellular adhesion molecule 1. The investigators referred to the overall encouraging potential of frankincense essential oil to exert influence over inflammation and tissue remodeling in human skin and called for additional research into its mechanisms of action and active constituents.¹¹

Anticancer activity

The main active ingredient in frankincense, boswellic acid, has been shown to promote apoptosis, suppress matrix metalloproteinase secretion, and hinder migration in metastatic melanoma cell lines in mice.^6,12

In 2019, Hakkim et al. demonstrated that frankincense essential oil yielded substantial antimelanoma activity in vitro and in vivo and ameliorated hepatotoxicity caused by acetaminophen.¹³

There is one case report in the literature on the use of frankincense as a treatment for skin cancer. A 56-year-old man received frankincense oil multiple times a day for 4 months to treat a nodular basal cell carcinoma on one arm (which resolved) and an infiltrative BCC on the chest (some focal residual tumor remained).^6,14 Topical frankincense or boswellic acid has been given a grade D recommendation for treating skin cancer, however, because of only one level-of-evidence-5 study.⁶

Antimicrobial activity

In 2012, de Rapper et al. collected samples of three essential oils of frankincense (Boswellia rivae, Boswellia neglecta, and Boswellia papyrifera) and two essential oil samples of myrrh and sweet myrrh from different regions of Ethiopia to study their anti-infective properties alone and in combination. The investigators observed synergistic and additive effects, particularly between B. papyrifera and Commiphora myrrha. While noting the long history of the combined use of frankincense and myrrh essential oils since 1500 BC, the investigators highlighted their study as the first antimicrobial work to verify the effectiveness of this combination, validating the use of this combination to thwart particular pathogens.¹⁵

Just 2 years ago, Ljaljević Grbić et al. evaluated the in vitro antimicrobial potential of the liquid and vapor phases of B. carteri and C. myrrha (frankincense and myrrh, respectively) essential oils, finding that frankincense demonstrated marked capacity to act as a natural antimicrobial agent.⁹

Transdermal delivery

In 2017, Zhu et al. showed that frankincense and myrrh essential oils promoted the permeability of the Chinese herb Chuanxiong and may facilitate drug elimination from the epidermis via dermal capillaries by dint of improved cutaneous blood flow, thereby augmenting transdermal drug delivery.¹⁶ The same team also showed that frankincense and myrrh essential oils, by fostering permeation by enhancing drug delivery across the stratum corneum, can also alter the structure of the stratum corneum.¹⁷

Conclusion

The use of frankincense in traditional medicine has a long and impressive track record. Recent research provides reason for optimism, and further investigating the possible incorporation of this botanical agent into modern dermatologic therapies appears warranted. Clearly, however, much more research is needed.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Kimmatkar N et al. Phytomedicine. 2003 Jan;10(1):3-7.

2. Ammon HP. Wien Med Wochenschr. 2002;152(15-16):373-8.

3. Efferth T & Oesch F. Semin Cancer Biol. 2020 Feb 4;S1044-579X(20)30034-1.

4. Banno N et al. J Ethnopharmacol. 2006 Sep 19;107(2):249-53.

5. Poeckel D & Werz O. Curr Med Chem. 2006;13(28):3359-69.

6. Li JY, Kampp JT. Dermatol Surg. 2019 Jan;45(1):58-67.

7. Cao B et al. Molecules. 2019 Aug 24;24(17): 3076.

8. Mertens M et al. Flavour Fragr J. 2009;24:279-300.

9. Ljaljević Grbić M et al. J Ethnopharmacol. 2018 Jun 12;219:1-14.

10. Li XJ et al. J Ethnopharmacol. 2016 Feb 17;179:22-6.

11. Han X et al. Biochim Open. 2017 Feb 3;4:31-5.

12. Zhao W et al. Cancer Detect Prev. 2003;27:67-75.

13. Hakkim FL et al. Oncotarget. 2019 May 28;10(37):3472-90.

14. Fung K et al. OA Altern Med 2013;1:14.

15. de Rapper S et al. Lett Appl Microbiol. 2012 Apr;54(4):352-8.

16. Zhu XF et al. Zhongguo Zhong Yao Za Zhi. 2017 Feb;42(4):680-5.

17. Guan YM et al. Zhongguo Zhong Yao Za Zhi. 2017 Sep;42(17):3350-5.

The Boswellia serrata exudate or gum (known in India as “guggulu”) that forms an aromatic resin traditionally used as incense – and known as frankincense (especially when retrieved from Boswellia species found in Eritrea and Somalia but also from the Indian variety) – has been considered for thousands of years to possess therapeutic properties. It is used in Ayurvedic medicine, as well as in traditional medicine in China and the Middle East, particularly for its anti-inflammatory effects to treat chronic conditions.^1-8 In fact, such essential oils have been used since 2800 BC to treat various inflammatory conditions, including skin sores and wounds, as well as in perfumes and incense.^2,9 In the West, use of frankincense dates back to thousands of years as well, more often found in the form of incense for religious and cultural ceremonies.⁷ Over the past 2 decades, evidence supporting the use of frankincense for therapeutic medical purposes has increased, particularly because of its purported anti-inflammatory and anticancer properties.³ This column focuses on some of the emerging data on this ancient botanical agent.

Madeleine_Steinbach / iStock / Getty Images Plus

Chemical constituents

Terpenoids and essential oils are the primary components of frankincense and are known to impart anti-inflammatory and anticancer activity. The same is true for myrrh, which has been combined with frankincense in traditional Chinese medicine as a single medication for millennia, with the two acting synergistically and considered still to be a potent combination in conferring various biological benefits.⁷

In 2010, in a systematic review of the anti-inflammatory and anticancer activities of Boswellia species and their chemical ingredients, Efferth and Oesch found that frankincense blocks the production of leukotrienes, cyclooxygenase (COX) 1 and 2, as well as 5-lipoxygenase; and oxidative stress. It also contributes to regulation of immune cells from the innate and acquired immune systems and exerts anticancer activity by influencing signaling transduction responsible for cell cycle arrest, as well as inhibition of proliferation, angiogenesis, invasion, and metastasis. The investigators also reported on clinical trial results that have found efficacy of frankincense and its constituents in ameliorating symptoms of psoriasis and erythematous eczema, among other disorders.³

Anti-inflammatory activity

Li et al. completed a study in 2016 to identify the active ingredients responsible for the anti-inflammatory and analgesic effects of frankincense. They found that alpha-pinene, linalool, and 1-octanol were key contributors. These constituents were noted for suppressing COX-2 overexpression in mice, as well as nociceptive stimulus-induced inflammatory infiltrates.¹⁰

Noting the increasing popularity of frankincense essential oil in skin care, despite a paucity of data, in 2017, Han et al. evaluated the biological activities of the essential oil in pre-inflamed human dermal fibroblasts using 17 key protein biomarkers. Frankincense essential oil displayed significant antiproliferative activity and suppressed collagen III, interferon gamma-induced protein 10, and intracellular adhesion molecule 1. The investigators referred to the overall encouraging potential of frankincense essential oil to exert influence over inflammation and tissue remodeling in human skin and called for additional research into its mechanisms of action and active constituents.¹¹

Anticancer activity

The main active ingredient in frankincense, boswellic acid, has been shown to promote apoptosis, suppress matrix metalloproteinase secretion, and hinder migration in metastatic melanoma cell lines in mice.^6,12

In 2019, Hakkim et al. demonstrated that frankincense essential oil yielded substantial antimelanoma activity in vitro and in vivo and ameliorated hepatotoxicity caused by acetaminophen.¹³

There is one case report in the literature on the use of frankincense as a treatment for skin cancer. A 56-year-old man received frankincense oil multiple times a day for 4 months to treat a nodular basal cell carcinoma on one arm (which resolved) and an infiltrative BCC on the chest (some focal residual tumor remained).^6,14 Topical frankincense or boswellic acid has been given a grade D recommendation for treating skin cancer, however, because of only one level-of-evidence-5 study.⁶

Antimicrobial activity

In 2012, de Rapper et al. collected samples of three essential oils of frankincense (Boswellia rivae, Boswellia neglecta, and Boswellia papyrifera) and two essential oil samples of myrrh and sweet myrrh from different regions of Ethiopia to study their anti-infective properties alone and in combination. The investigators observed synergistic and additive effects, particularly between B. papyrifera and Commiphora myrrha. While noting the long history of the combined use of frankincense and myrrh essential oils since 1500 BC, the investigators highlighted their study as the first antimicrobial work to verify the effectiveness of this combination, validating the use of this combination to thwart particular pathogens.¹⁵

Just 2 years ago, Ljaljević Grbić et al. evaluated the in vitro antimicrobial potential of the liquid and vapor phases of B. carteri and C. myrrha (frankincense and myrrh, respectively) essential oils, finding that frankincense demonstrated marked capacity to act as a natural antimicrobial agent.⁹

Transdermal delivery

In 2017, Zhu et al. showed that frankincense and myrrh essential oils promoted the permeability of the Chinese herb Chuanxiong and may facilitate drug elimination from the epidermis via dermal capillaries by dint of improved cutaneous blood flow, thereby augmenting transdermal drug delivery.¹⁶ The same team also showed that frankincense and myrrh essential oils, by fostering permeation by enhancing drug delivery across the stratum corneum, can also alter the structure of the stratum corneum.¹⁷

Conclusion

The use of frankincense in traditional medicine has a long and impressive track record. Recent research provides reason for optimism, and further investigating the possible incorporation of this botanical agent into modern dermatologic therapies appears warranted. Clearly, however, much more research is needed.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Kimmatkar N et al. Phytomedicine. 2003 Jan;10(1):3-7.

2. Ammon HP. Wien Med Wochenschr. 2002;152(15-16):373-8.

3. Efferth T & Oesch F. Semin Cancer Biol. 2020 Feb 4;S1044-579X(20)30034-1.

4. Banno N et al. J Ethnopharmacol. 2006 Sep 19;107(2):249-53.

5. Poeckel D & Werz O. Curr Med Chem. 2006;13(28):3359-69.

6. Li JY, Kampp JT. Dermatol Surg. 2019 Jan;45(1):58-67.

7. Cao B et al. Molecules. 2019 Aug 24;24(17): 3076.

8. Mertens M et al. Flavour Fragr J. 2009;24:279-300.

9. Ljaljević Grbić M et al. J Ethnopharmacol. 2018 Jun 12;219:1-14.

10. Li XJ et al. J Ethnopharmacol. 2016 Feb 17;179:22-6.

11. Han X et al. Biochim Open. 2017 Feb 3;4:31-5.

12. Zhao W et al. Cancer Detect Prev. 2003;27:67-75.

13. Hakkim FL et al. Oncotarget. 2019 May 28;10(37):3472-90.

14. Fung K et al. OA Altern Med 2013;1:14.

15. de Rapper S et al. Lett Appl Microbiol. 2012 Apr;54(4):352-8.

16. Zhu XF et al. Zhongguo Zhong Yao Za Zhi. 2017 Feb;42(4):680-5.

17. Guan YM et al. Zhongguo Zhong Yao Za Zhi. 2017 Sep;42(17):3350-5.

The Boswellia serrata exudate or gum (known in India as “guggulu”) that forms an aromatic resin traditionally used as incense – and known as frankincense (especially when retrieved from Boswellia species found in Eritrea and Somalia but also from the Indian variety) – has been considered for thousands of years to possess therapeutic properties. It is used in Ayurvedic medicine, as well as in traditional medicine in China and the Middle East, particularly for its anti-inflammatory effects to treat chronic conditions.^1-8 In fact, such essential oils have been used since 2800 BC to treat various inflammatory conditions, including skin sores and wounds, as well as in perfumes and incense.^2,9 In the West, use of frankincense dates back to thousands of years as well, more often found in the form of incense for religious and cultural ceremonies.⁷ Over the past 2 decades, evidence supporting the use of frankincense for therapeutic medical purposes has increased, particularly because of its purported anti-inflammatory and anticancer properties.³ This column focuses on some of the emerging data on this ancient botanical agent.

Madeleine_Steinbach / iStock / Getty Images Plus

Chemical constituents

Terpenoids and essential oils are the primary components of frankincense and are known to impart anti-inflammatory and anticancer activity. The same is true for myrrh, which has been combined with frankincense in traditional Chinese medicine as a single medication for millennia, with the two acting synergistically and considered still to be a potent combination in conferring various biological benefits.⁷

In 2010, in a systematic review of the anti-inflammatory and anticancer activities of Boswellia species and their chemical ingredients, Efferth and Oesch found that frankincense blocks the production of leukotrienes, cyclooxygenase (COX) 1 and 2, as well as 5-lipoxygenase; and oxidative stress. It also contributes to regulation of immune cells from the innate and acquired immune systems and exerts anticancer activity by influencing signaling transduction responsible for cell cycle arrest, as well as inhibition of proliferation, angiogenesis, invasion, and metastasis. The investigators also reported on clinical trial results that have found efficacy of frankincense and its constituents in ameliorating symptoms of psoriasis and erythematous eczema, among other disorders.³

Anti-inflammatory activity

Li et al. completed a study in 2016 to identify the active ingredients responsible for the anti-inflammatory and analgesic effects of frankincense. They found that alpha-pinene, linalool, and 1-octanol were key contributors. These constituents were noted for suppressing COX-2 overexpression in mice, as well as nociceptive stimulus-induced inflammatory infiltrates.¹⁰

Noting the increasing popularity of frankincense essential oil in skin care, despite a paucity of data, in 2017, Han et al. evaluated the biological activities of the essential oil in pre-inflamed human dermal fibroblasts using 17 key protein biomarkers. Frankincense essential oil displayed significant antiproliferative activity and suppressed collagen III, interferon gamma-induced protein 10, and intracellular adhesion molecule 1. The investigators referred to the overall encouraging potential of frankincense essential oil to exert influence over inflammation and tissue remodeling in human skin and called for additional research into its mechanisms of action and active constituents.¹¹

Anticancer activity

The main active ingredient in frankincense, boswellic acid, has been shown to promote apoptosis, suppress matrix metalloproteinase secretion, and hinder migration in metastatic melanoma cell lines in mice.^6,12

In 2019, Hakkim et al. demonstrated that frankincense essential oil yielded substantial antimelanoma activity in vitro and in vivo and ameliorated hepatotoxicity caused by acetaminophen.¹³

There is one case report in the literature on the use of frankincense as a treatment for skin cancer. A 56-year-old man received frankincense oil multiple times a day for 4 months to treat a nodular basal cell carcinoma on one arm (which resolved) and an infiltrative BCC on the chest (some focal residual tumor remained).^6,14 Topical frankincense or boswellic acid has been given a grade D recommendation for treating skin cancer, however, because of only one level-of-evidence-5 study.⁶

Antimicrobial activity

In 2012, de Rapper et al. collected samples of three essential oils of frankincense (Boswellia rivae, Boswellia neglecta, and Boswellia papyrifera) and two essential oil samples of myrrh and sweet myrrh from different regions of Ethiopia to study their anti-infective properties alone and in combination. The investigators observed synergistic and additive effects, particularly between B. papyrifera and Commiphora myrrha. While noting the long history of the combined use of frankincense and myrrh essential oils since 1500 BC, the investigators highlighted their study as the first antimicrobial work to verify the effectiveness of this combination, validating the use of this combination to thwart particular pathogens.¹⁵

Just 2 years ago, Ljaljević Grbić et al. evaluated the in vitro antimicrobial potential of the liquid and vapor phases of B. carteri and C. myrrha (frankincense and myrrh, respectively) essential oils, finding that frankincense demonstrated marked capacity to act as a natural antimicrobial agent.⁹

Transdermal delivery

In 2017, Zhu et al. showed that frankincense and myrrh essential oils promoted the permeability of the Chinese herb Chuanxiong and may facilitate drug elimination from the epidermis via dermal capillaries by dint of improved cutaneous blood flow, thereby augmenting transdermal drug delivery.¹⁶ The same team also showed that frankincense and myrrh essential oils, by fostering permeation by enhancing drug delivery across the stratum corneum, can also alter the structure of the stratum corneum.¹⁷

Conclusion

The use of frankincense in traditional medicine has a long and impressive track record. Recent research provides reason for optimism, and further investigating the possible incorporation of this botanical agent into modern dermatologic therapies appears warranted. Clearly, however, much more research is needed.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Kimmatkar N et al. Phytomedicine. 2003 Jan;10(1):3-7.

2. Ammon HP. Wien Med Wochenschr. 2002;152(15-16):373-8.

3. Efferth T & Oesch F. Semin Cancer Biol. 2020 Feb 4;S1044-579X(20)30034-1.

4. Banno N et al. J Ethnopharmacol. 2006 Sep 19;107(2):249-53.

5. Poeckel D & Werz O. Curr Med Chem. 2006;13(28):3359-69.

6. Li JY, Kampp JT. Dermatol Surg. 2019 Jan;45(1):58-67.

7. Cao B et al. Molecules. 2019 Aug 24;24(17): 3076.

8. Mertens M et al. Flavour Fragr J. 2009;24:279-300.

9. Ljaljević Grbić M et al. J Ethnopharmacol. 2018 Jun 12;219:1-14.

10. Li XJ et al. J Ethnopharmacol. 2016 Feb 17;179:22-6.

11. Han X et al. Biochim Open. 2017 Feb 3;4:31-5.

12. Zhao W et al. Cancer Detect Prev. 2003;27:67-75.

13. Hakkim FL et al. Oncotarget. 2019 May 28;10(37):3472-90.

14. Fung K et al. OA Altern Med 2013;1:14.

15. de Rapper S et al. Lett Appl Microbiol. 2012 Apr;54(4):352-8.

16. Zhu XF et al. Zhongguo Zhong Yao Za Zhi. 2017 Feb;42(4):680-5.

17. Guan YM et al. Zhongguo Zhong Yao Za Zhi. 2017 Sep;42(17):3350-5.

To the Editor:

A 67-year-old man with diabetes mellitus was admitted to the hospital for exacerbation of congestive heart failure and atrial flutter with rapid ventricular response. He subsequently developed a non-ST segment elevation myocardial infarction and was started on subcutaneous enoxaparin 110 mg twice daily. On day 9 of hospitalization, small “blood blisters” on the legs were noted by the nurse, and dermatology was consulted.

Physical examination revealed tense hemorrhagic bullae with erythematous haloes scattered over the arms and legs and to a lesser extent on the trunk. The bullae were most concentrated at the surrounding subcutaneous injection sites of insulin and enoxaparin with secondary bruising (Figure 1). The lesions also were present on the legs, where pitting edema and capillaritis also were appreciated (Figure 2).

Laboratory workup for heparin-induced thrombocytopenia was negative. A diagnosis of enoxaparin-associated hemorrhagic bullae was made. Biopsy was recommended, but the patient declined based on anecdotal reports that the bullae typically self-resolve.

The enoxaparin was discontinued 7 days after the dermatology consultation, and the patient was transitioned to apixaban. A review of the medical record during the dermatology consultation revealed he had been on aspirin (81–385 mg/d) for 13 years prior to admission and had received prophylactic enoxaparin (40 mg/d) while hospitalized 2 and 7 years prior to the current episode of hemorrhagic bullae.

The patient declined outpatient dermatology follow-up; however, his cardiologist noted that the skin lesions had resolved at a 3-week postdischarge appointment. Approximately 5 months after discharge, the patient was re-treated by the cardiologist with enoxaparin 110 mg twice daily for 3 days to bridge to warfarin after he developed a deep vein thrombosis while taking apixaban. He did not develop hemorrhagic bullae upon retreatment with enoxaparin.

Heparin-induced hemorrhagic bullous dermatosis (HBD) has been associated with administration of both unfractionated and low-molecular-weight heparin.¹ The condition typically develops 5 to 21 days after initiation of heparin as asymptomatic, purple-to-black bullae, sometimes with an erythematous halo.^2,3 The arms and legs are the most common location, but the exact pathogenesis of the lesions remains unknown.^3,4 Most cases resolve within weeks of discontinuing heparin, although some reports have suggested that discontinuation is unnecessary.^3,4

Histopathologic analysis shows intraepidermal or subepidermal bullae with red blood cells and fibrin in the absence of vasculitis and intravascular thrombi.^1,4 Immunofluorescence studies are negative.³ In a comprehensive review of HBD, the investigators hypothesized that the pathogenesis may be related to noninflammatory to pauci-inflammatory activation of basement membrane zone proteases or possibly epithelial or endothelial fragility in conjunction with trauma that causes disruption of the vascular endothelium (eg, subcutaneous injections, vasculitis).⁴

Our case is of particular interest because the bullae were strikingly limited to sites of subcutaneous injection and surrounding areas along with coexistent endothelial pathology on the lower legs (capillaritis and pitting edema). These clinical observations support trauma from the injections and altered endothelia as pathogenetic factors in HBD.

Of interest, our patient had 2 prior hospitalizations during which he received prophylactic enoxaparin and did not develop hemorrhagic bullae. Furthermore, repeat exposure to therapeutic dosing of enoxaparin with a shorter duration did not result in recurrence of HBD. This suggests that heparin dosing and duration of therapy also might be involved in the development of HBD.

Our hope is that future reports of HBD will address the presence or absence of coexistent cutaneous pathology, such as edema, stasis dermatitis, bruising, and capillaritis, along with heparin dosing, duration, and prior exposure to heparin treatment so that risk factors and pathogenesis can be further investigated. We also agree with Snow et al⁴ that HBD should be included as an outcome in future trials of heparin therapy.

To the Editor:

A 67-year-old man with diabetes mellitus was admitted to the hospital for exacerbation of congestive heart failure and atrial flutter with rapid ventricular response. He subsequently developed a non-ST segment elevation myocardial infarction and was started on subcutaneous enoxaparin 110 mg twice daily. On day 9 of hospitalization, small “blood blisters” on the legs were noted by the nurse, and dermatology was consulted.

Physical examination revealed tense hemorrhagic bullae with erythematous haloes scattered over the arms and legs and to a lesser extent on the trunk. The bullae were most concentrated at the surrounding subcutaneous injection sites of insulin and enoxaparin with secondary bruising (Figure 1). The lesions also were present on the legs, where pitting edema and capillaritis also were appreciated (Figure 2).

Laboratory workup for heparin-induced thrombocytopenia was negative. A diagnosis of enoxaparin-associated hemorrhagic bullae was made. Biopsy was recommended, but the patient declined based on anecdotal reports that the bullae typically self-resolve.

The enoxaparin was discontinued 7 days after the dermatology consultation, and the patient was transitioned to apixaban. A review of the medical record during the dermatology consultation revealed he had been on aspirin (81–385 mg/d) for 13 years prior to admission and had received prophylactic enoxaparin (40 mg/d) while hospitalized 2 and 7 years prior to the current episode of hemorrhagic bullae.

The patient declined outpatient dermatology follow-up; however, his cardiologist noted that the skin lesions had resolved at a 3-week postdischarge appointment. Approximately 5 months after discharge, the patient was re-treated by the cardiologist with enoxaparin 110 mg twice daily for 3 days to bridge to warfarin after he developed a deep vein thrombosis while taking apixaban. He did not develop hemorrhagic bullae upon retreatment with enoxaparin.

Heparin-induced hemorrhagic bullous dermatosis (HBD) has been associated with administration of both unfractionated and low-molecular-weight heparin.¹ The condition typically develops 5 to 21 days after initiation of heparin as asymptomatic, purple-to-black bullae, sometimes with an erythematous halo.^2,3 The arms and legs are the most common location, but the exact pathogenesis of the lesions remains unknown.^3,4 Most cases resolve within weeks of discontinuing heparin, although some reports have suggested that discontinuation is unnecessary.^3,4

Histopathologic analysis shows intraepidermal or subepidermal bullae with red blood cells and fibrin in the absence of vasculitis and intravascular thrombi.^1,4 Immunofluorescence studies are negative.³ In a comprehensive review of HBD, the investigators hypothesized that the pathogenesis may be related to noninflammatory to pauci-inflammatory activation of basement membrane zone proteases or possibly epithelial or endothelial fragility in conjunction with trauma that causes disruption of the vascular endothelium (eg, subcutaneous injections, vasculitis).⁴

Our case is of particular interest because the bullae were strikingly limited to sites of subcutaneous injection and surrounding areas along with coexistent endothelial pathology on the lower legs (capillaritis and pitting edema). These clinical observations support trauma from the injections and altered endothelia as pathogenetic factors in HBD.

Of interest, our patient had 2 prior hospitalizations during which he received prophylactic enoxaparin and did not develop hemorrhagic bullae. Furthermore, repeat exposure to therapeutic dosing of enoxaparin with a shorter duration did not result in recurrence of HBD. This suggests that heparin dosing and duration of therapy also might be involved in the development of HBD.

Our hope is that future reports of HBD will address the presence or absence of coexistent cutaneous pathology, such as edema, stasis dermatitis, bruising, and capillaritis, along with heparin dosing, duration, and prior exposure to heparin treatment so that risk factors and pathogenesis can be further investigated. We also agree with Snow et al⁴ that HBD should be included as an outcome in future trials of heparin therapy.

To the Editor:

A 67-year-old man with diabetes mellitus was admitted to the hospital for exacerbation of congestive heart failure and atrial flutter with rapid ventricular response. He subsequently developed a non-ST segment elevation myocardial infarction and was started on subcutaneous enoxaparin 110 mg twice daily. On day 9 of hospitalization, small “blood blisters” on the legs were noted by the nurse, and dermatology was consulted.

Physical examination revealed tense hemorrhagic bullae with erythematous haloes scattered over the arms and legs and to a lesser extent on the trunk. The bullae were most concentrated at the surrounding subcutaneous injection sites of insulin and enoxaparin with secondary bruising (Figure 1). The lesions also were present on the legs, where pitting edema and capillaritis also were appreciated (Figure 2).

Laboratory workup for heparin-induced thrombocytopenia was negative. A diagnosis of enoxaparin-associated hemorrhagic bullae was made. Biopsy was recommended, but the patient declined based on anecdotal reports that the bullae typically self-resolve.

The enoxaparin was discontinued 7 days after the dermatology consultation, and the patient was transitioned to apixaban. A review of the medical record during the dermatology consultation revealed he had been on aspirin (81–385 mg/d) for 13 years prior to admission and had received prophylactic enoxaparin (40 mg/d) while hospitalized 2 and 7 years prior to the current episode of hemorrhagic bullae.

The patient declined outpatient dermatology follow-up; however, his cardiologist noted that the skin lesions had resolved at a 3-week postdischarge appointment. Approximately 5 months after discharge, the patient was re-treated by the cardiologist with enoxaparin 110 mg twice daily for 3 days to bridge to warfarin after he developed a deep vein thrombosis while taking apixaban. He did not develop hemorrhagic bullae upon retreatment with enoxaparin.

Heparin-induced hemorrhagic bullous dermatosis (HBD) has been associated with administration of both unfractionated and low-molecular-weight heparin.¹ The condition typically develops 5 to 21 days after initiation of heparin as asymptomatic, purple-to-black bullae, sometimes with an erythematous halo.^2,3 The arms and legs are the most common location, but the exact pathogenesis of the lesions remains unknown.^3,4 Most cases resolve within weeks of discontinuing heparin, although some reports have suggested that discontinuation is unnecessary.^3,4

Histopathologic analysis shows intraepidermal or subepidermal bullae with red blood cells and fibrin in the absence of vasculitis and intravascular thrombi.^1,4 Immunofluorescence studies are negative.³ In a comprehensive review of HBD, the investigators hypothesized that the pathogenesis may be related to noninflammatory to pauci-inflammatory activation of basement membrane zone proteases or possibly epithelial or endothelial fragility in conjunction with trauma that causes disruption of the vascular endothelium (eg, subcutaneous injections, vasculitis).⁴

Our case is of particular interest because the bullae were strikingly limited to sites of subcutaneous injection and surrounding areas along with coexistent endothelial pathology on the lower legs (capillaritis and pitting edema). These clinical observations support trauma from the injections and altered endothelia as pathogenetic factors in HBD.

Of interest, our patient had 2 prior hospitalizations during which he received prophylactic enoxaparin and did not develop hemorrhagic bullae. Furthermore, repeat exposure to therapeutic dosing of enoxaparin with a shorter duration did not result in recurrence of HBD. This suggests that heparin dosing and duration of therapy also might be involved in the development of HBD.

Our hope is that future reports of HBD will address the presence or absence of coexistent cutaneous pathology, such as edema, stasis dermatitis, bruising, and capillaritis, along with heparin dosing, duration, and prior exposure to heparin treatment so that risk factors and pathogenesis can be further investigated. We also agree with Snow et al⁴ that HBD should be included as an outcome in future trials of heparin therapy.

An important ingredient in the contemporary perfume and cosmetics industries, vetiver, is the only grass cultivated throughout the world to retain its essential oil, which contains sesquiterpene alcohols and hydrocarbons.^1-3 Field and glasshouse studies have revealed that vetiver grass can tolerate extreme variations in climate well, including protracted drought, floods, submergence, temperature, and soils high in acidity, alkalinity, and various heavy metals. Its heartiness may explain its continuing or even increasing use in fragrances and other products pertinent to skin health as humanity strives to adapt to climate change.⁴ In a 2017 review of various commercial essential oils as antimicrobial therapy for cutaneous disorders, Orchard and van Vuuren identified vetiver as warranting particular attention for its capacity to confer broad benefits to the skin in addressing acne, cuts, eczema, oiliness, sores, wounds, and aging skin.⁵ The focus of this column will be the dermatologic potential of vetiver.

Naomi Morris/EyeEm/EyeEm

Chemical constituents

Vetiver is thought to be one of the most complex of the essential oils owing to the hundreds of sesquiterpene derivatives with large structural diversity that contribute to its composition. ³

In a 2012 analysis of the components of South Indian vetiver oils, Mallavarapu et al. found an abundance of sesquiterpenes and oxygenated sesquiterpenes with cedrane, bisabolane, eudesmane, eremophilane, and zizaane skeletons. The primary constituents identified in the four oils evaluated included eudesma-4,6-diene (delta-selinene) + beta-vetispirene (3.9%-6.1%), beta-vetivenene (0.9%-9.4%), 13-nor-trans-eudesma-4(15),7-dien-11-one + amorph-4-en-10-ol (5.0%-6.4%), trans-eudesma-4(15),7-dien-12-ol (vetiselinenol) + (E)-opposita-4(15),7(11)-dien-12-ol (3.7%-5.9%), eremophila-1 (10),11-dien-2alpha-ol (nootkatol) + ziza-6(13)-en-12-ol (khusimol) (16.1%-19.2%), and eremophila-1(10),7(11)-dien-2alpha-ol (isonootkatol) + (E)-eremophila-1(10),7(11)-12-ol (isovalencenol) (5.6%-6.9%).⁶

Antimicrobial activity

In 2012, Saikia et al. assessed the antimycobacterial activity of Vetiveria zizanioides against Mycobacterium tuberculosis H(37)Rv and H(37)Ra strains. Their results showed that ethanolic extracts and hexane fractions displayed robust antimycobacterial properties, buttressing the traditional medical uses of the plant, as well as consideration of this agent as a modern antituberculosis agent.⁷

Two years later, Dos Santos et al. showed that Vetiveria zizanioides roots grown in Brazil exhibited notable antimicrobial effects against various pathogenic organisms.⁸In 2017, Burger et al. showed that vetiver essential oil primarily contributes its scent to cosmetic formulations but also displayed antimicrobial activity against Gram-positive bacterial strains, as well as one strain of Candida glabrata. They suggest that vetiver should be considered for its antimicrobial capacity as an added bonus to cosmetic formulations.²

In a 2018 study to ascertain the antimicrobial activity of 247 essential oil combinations against five reference strains of wound pathogens, Orchard et al. found that 26 combinations exhibited extensive antimicrobial activity. Sandalwood and vetiver were found to contribute most to antimicrobial function when used in combination. The investigators concluded that such combinations warrant consideration for wound therapy.⁹

Antiacne activity

In 2018, Orchard et al. conducted another study of the efficacy of commercial essential oil combinations against the two pathogens responsible for acne, Propionibacterium acnes and Staphlyococcus epidermidis. They investigated 408 combinations, of which 167 exhibited notable antimicrobial activity. They observed that the combination with the lowest minimum inhibitory concentration value against P. acnes and S. epidermidis was vetiver and cinnamon bark.¹⁰ This usage points to the potential of vetiver use as an antiacne ingredient.
 

Safety

The Scientific Committee on Consumer Safety (SCCS) offered a final opinion on the safety of the fragrance ingredient acetylated vetiver oil in 2019, declaring its use with 1% alpha-tocopherol in cosmetic leave-on and rinse-off products safe at proposed concentration levels. They noted that acetylated vetiver oil has been used for several years without provoking contact allergies.¹1
 

Conclusion

Vetiver is an important ingredient in modern perfumery. It also has potential to impart benefits to the skin in topical formulations. Much more research is necessary to determine just what kind of a role this perfumery powerhouse can play in dermatology.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Del Giudice L et al. Environ Microbiol. 2008 Oct;10(10):2824-41.

2. Burger P et al. Medicines (Basel). 2017 Jun 16;4(2):41.

3. Belhassen E et al. Chem Biodivers. 2014 Nov;11(11):1821–42.

4. Danh LT et al. Int J Phytoremediation. 2009 Oct-Dec;11(8):664–91.

5. Orchard A and van Vuuren S. Evid Based Complement Alternat Med. 2017;2017:4517971.

6. Mallavarapu GR et al. Nat Prod Commun. 2012 Feb;7(2):223–5.

7. Saikia D et al. Complement Ther Med. 2012 Dec;20(6):434–6.

8. Dos Santos DS et al. Acta Pharm. 2014 Dec;64(4):495-501.

9. Orchard A et al. Chem Biodivers. 2018 Dec;15(12):e1800405.

10. Orchard A et al. Int J Cosmet Sci. 2018 Mar 24. [Epub ahead of print].

11. SCCS members & External experts. Regul Toxicol Pharmacol. 2019 Oct;107:104389.

An important ingredient in the contemporary perfume and cosmetics industries, vetiver, is the only grass cultivated throughout the world to retain its essential oil, which contains sesquiterpene alcohols and hydrocarbons.^1-3 Field and glasshouse studies have revealed that vetiver grass can tolerate extreme variations in climate well, including protracted drought, floods, submergence, temperature, and soils high in acidity, alkalinity, and various heavy metals. Its heartiness may explain its continuing or even increasing use in fragrances and other products pertinent to skin health as humanity strives to adapt to climate change.⁴ In a 2017 review of various commercial essential oils as antimicrobial therapy for cutaneous disorders, Orchard and van Vuuren identified vetiver as warranting particular attention for its capacity to confer broad benefits to the skin in addressing acne, cuts, eczema, oiliness, sores, wounds, and aging skin.⁵ The focus of this column will be the dermatologic potential of vetiver.

Naomi Morris/EyeEm/EyeEm

Chemical constituents

Vetiver is thought to be one of the most complex of the essential oils owing to the hundreds of sesquiterpene derivatives with large structural diversity that contribute to its composition. ³

In a 2012 analysis of the components of South Indian vetiver oils, Mallavarapu et al. found an abundance of sesquiterpenes and oxygenated sesquiterpenes with cedrane, bisabolane, eudesmane, eremophilane, and zizaane skeletons. The primary constituents identified in the four oils evaluated included eudesma-4,6-diene (delta-selinene) + beta-vetispirene (3.9%-6.1%), beta-vetivenene (0.9%-9.4%), 13-nor-trans-eudesma-4(15),7-dien-11-one + amorph-4-en-10-ol (5.0%-6.4%), trans-eudesma-4(15),7-dien-12-ol (vetiselinenol) + (E)-opposita-4(15),7(11)-dien-12-ol (3.7%-5.9%), eremophila-1 (10),11-dien-2alpha-ol (nootkatol) + ziza-6(13)-en-12-ol (khusimol) (16.1%-19.2%), and eremophila-1(10),7(11)-dien-2alpha-ol (isonootkatol) + (E)-eremophila-1(10),7(11)-12-ol (isovalencenol) (5.6%-6.9%).⁶

Antimicrobial activity

In 2012, Saikia et al. assessed the antimycobacterial activity of Vetiveria zizanioides against Mycobacterium tuberculosis H(37)Rv and H(37)Ra strains. Their results showed that ethanolic extracts and hexane fractions displayed robust antimycobacterial properties, buttressing the traditional medical uses of the plant, as well as consideration of this agent as a modern antituberculosis agent.⁷

Two years later, Dos Santos et al. showed that Vetiveria zizanioides roots grown in Brazil exhibited notable antimicrobial effects against various pathogenic organisms.⁸In 2017, Burger et al. showed that vetiver essential oil primarily contributes its scent to cosmetic formulations but also displayed antimicrobial activity against Gram-positive bacterial strains, as well as one strain of Candida glabrata. They suggest that vetiver should be considered for its antimicrobial capacity as an added bonus to cosmetic formulations.²

In a 2018 study to ascertain the antimicrobial activity of 247 essential oil combinations against five reference strains of wound pathogens, Orchard et al. found that 26 combinations exhibited extensive antimicrobial activity. Sandalwood and vetiver were found to contribute most to antimicrobial function when used in combination. The investigators concluded that such combinations warrant consideration for wound therapy.⁹

Antiacne activity

In 2018, Orchard et al. conducted another study of the efficacy of commercial essential oil combinations against the two pathogens responsible for acne, Propionibacterium acnes and Staphlyococcus epidermidis. They investigated 408 combinations, of which 167 exhibited notable antimicrobial activity. They observed that the combination with the lowest minimum inhibitory concentration value against P. acnes and S. epidermidis was vetiver and cinnamon bark.¹⁰ This usage points to the potential of vetiver use as an antiacne ingredient.
 

Safety

The Scientific Committee on Consumer Safety (SCCS) offered a final opinion on the safety of the fragrance ingredient acetylated vetiver oil in 2019, declaring its use with 1% alpha-tocopherol in cosmetic leave-on and rinse-off products safe at proposed concentration levels. They noted that acetylated vetiver oil has been used for several years without provoking contact allergies.¹1
 

Conclusion

Vetiver is an important ingredient in modern perfumery. It also has potential to impart benefits to the skin in topical formulations. Much more research is necessary to determine just what kind of a role this perfumery powerhouse can play in dermatology.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Del Giudice L et al. Environ Microbiol. 2008 Oct;10(10):2824-41.

2. Burger P et al. Medicines (Basel). 2017 Jun 16;4(2):41.

3. Belhassen E et al. Chem Biodivers. 2014 Nov;11(11):1821–42.

4. Danh LT et al. Int J Phytoremediation. 2009 Oct-Dec;11(8):664–91.

5. Orchard A and van Vuuren S. Evid Based Complement Alternat Med. 2017;2017:4517971.

6. Mallavarapu GR et al. Nat Prod Commun. 2012 Feb;7(2):223–5.

7. Saikia D et al. Complement Ther Med. 2012 Dec;20(6):434–6.

8. Dos Santos DS et al. Acta Pharm. 2014 Dec;64(4):495-501.

9. Orchard A et al. Chem Biodivers. 2018 Dec;15(12):e1800405.

10. Orchard A et al. Int J Cosmet Sci. 2018 Mar 24. [Epub ahead of print].

11. SCCS members & External experts. Regul Toxicol Pharmacol. 2019 Oct;107:104389.

An important ingredient in the contemporary perfume and cosmetics industries, vetiver, is the only grass cultivated throughout the world to retain its essential oil, which contains sesquiterpene alcohols and hydrocarbons.^1-3 Field and glasshouse studies have revealed that vetiver grass can tolerate extreme variations in climate well, including protracted drought, floods, submergence, temperature, and soils high in acidity, alkalinity, and various heavy metals. Its heartiness may explain its continuing or even increasing use in fragrances and other products pertinent to skin health as humanity strives to adapt to climate change.⁴ In a 2017 review of various commercial essential oils as antimicrobial therapy for cutaneous disorders, Orchard and van Vuuren identified vetiver as warranting particular attention for its capacity to confer broad benefits to the skin in addressing acne, cuts, eczema, oiliness, sores, wounds, and aging skin.⁵ The focus of this column will be the dermatologic potential of vetiver.

Naomi Morris/EyeEm/EyeEm

Chemical constituents

Vetiver is thought to be one of the most complex of the essential oils owing to the hundreds of sesquiterpene derivatives with large structural diversity that contribute to its composition. ³

In a 2012 analysis of the components of South Indian vetiver oils, Mallavarapu et al. found an abundance of sesquiterpenes and oxygenated sesquiterpenes with cedrane, bisabolane, eudesmane, eremophilane, and zizaane skeletons. The primary constituents identified in the four oils evaluated included eudesma-4,6-diene (delta-selinene) + beta-vetispirene (3.9%-6.1%), beta-vetivenene (0.9%-9.4%), 13-nor-trans-eudesma-4(15),7-dien-11-one + amorph-4-en-10-ol (5.0%-6.4%), trans-eudesma-4(15),7-dien-12-ol (vetiselinenol) + (E)-opposita-4(15),7(11)-dien-12-ol (3.7%-5.9%), eremophila-1 (10),11-dien-2alpha-ol (nootkatol) + ziza-6(13)-en-12-ol (khusimol) (16.1%-19.2%), and eremophila-1(10),7(11)-dien-2alpha-ol (isonootkatol) + (E)-eremophila-1(10),7(11)-12-ol (isovalencenol) (5.6%-6.9%).⁶

Antimicrobial activity

In 2012, Saikia et al. assessed the antimycobacterial activity of Vetiveria zizanioides against Mycobacterium tuberculosis H(37)Rv and H(37)Ra strains. Their results showed that ethanolic extracts and hexane fractions displayed robust antimycobacterial properties, buttressing the traditional medical uses of the plant, as well as consideration of this agent as a modern antituberculosis agent.⁷

Two years later, Dos Santos et al. showed that Vetiveria zizanioides roots grown in Brazil exhibited notable antimicrobial effects against various pathogenic organisms.⁸In 2017, Burger et al. showed that vetiver essential oil primarily contributes its scent to cosmetic formulations but also displayed antimicrobial activity against Gram-positive bacterial strains, as well as one strain of Candida glabrata. They suggest that vetiver should be considered for its antimicrobial capacity as an added bonus to cosmetic formulations.²

In a 2018 study to ascertain the antimicrobial activity of 247 essential oil combinations against five reference strains of wound pathogens, Orchard et al. found that 26 combinations exhibited extensive antimicrobial activity. Sandalwood and vetiver were found to contribute most to antimicrobial function when used in combination. The investigators concluded that such combinations warrant consideration for wound therapy.⁹

Antiacne activity

In 2018, Orchard et al. conducted another study of the efficacy of commercial essential oil combinations against the two pathogens responsible for acne, Propionibacterium acnes and Staphlyococcus epidermidis. They investigated 408 combinations, of which 167 exhibited notable antimicrobial activity. They observed that the combination with the lowest minimum inhibitory concentration value against P. acnes and S. epidermidis was vetiver and cinnamon bark.¹⁰ This usage points to the potential of vetiver use as an antiacne ingredient.
 

Safety

The Scientific Committee on Consumer Safety (SCCS) offered a final opinion on the safety of the fragrance ingredient acetylated vetiver oil in 2019, declaring its use with 1% alpha-tocopherol in cosmetic leave-on and rinse-off products safe at proposed concentration levels. They noted that acetylated vetiver oil has been used for several years without provoking contact allergies.¹1
 

Conclusion

Vetiver is an important ingredient in modern perfumery. It also has potential to impart benefits to the skin in topical formulations. Much more research is necessary to determine just what kind of a role this perfumery powerhouse can play in dermatology.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Del Giudice L et al. Environ Microbiol. 2008 Oct;10(10):2824-41.

2. Burger P et al. Medicines (Basel). 2017 Jun 16;4(2):41.

3. Belhassen E et al. Chem Biodivers. 2014 Nov;11(11):1821–42.

4. Danh LT et al. Int J Phytoremediation. 2009 Oct-Dec;11(8):664–91.

5. Orchard A and van Vuuren S. Evid Based Complement Alternat Med. 2017;2017:4517971.

6. Mallavarapu GR et al. Nat Prod Commun. 2012 Feb;7(2):223–5.

7. Saikia D et al. Complement Ther Med. 2012 Dec;20(6):434–6.

8. Dos Santos DS et al. Acta Pharm. 2014 Dec;64(4):495-501.

9. Orchard A et al. Chem Biodivers. 2018 Dec;15(12):e1800405.

10. Orchard A et al. Int J Cosmet Sci. 2018 Mar 24. [Epub ahead of print].

11. SCCS members & External experts. Regul Toxicol Pharmacol. 2019 Oct;107:104389.

In the clinical opinion of Alex G. Ortega-Loayza, MD, MCR, few absolutes drive the initial assessment of patients who present with skin ulcers.

While lower-extremity ulcers stem from vascular, neuropathic, or pressure-related causes in about 70% of cases, an estimated 20% of cases are atypical, and another 10% are inconclusive. The causes can be neoplastic, infectious, inflammatory, vasculopathic, external, and genetic. “Sometimes they can be of mixed etiology, which make them even more complicated to heal,” Dr. Ortega-Loayza, of the department of dermatology at Oregon Health & Science University, Portland, said during the annual meeting of the Pacific Dermatologic Association.

In a study published in 2019, he and his colleagues at four academic hospitals evaluated characteristics and diagnoses of ulcers in 274 patients with skin ulcers in inpatient dermatology consultation services between July 2015 and July 2018. Most primary teams requesting the consultation (93%) were from nonsurgical specialties. The median age of these patients was 54 years, 45% were male, and 50% had lower-extremity ulcers. Nearly two-thirds of the ulcers (62%) were chronic in nature, while the remaining 38% were acute. The skin ulcer was the chief reason for admission in 49% of cases and 66% were admitted through the ED. In addition, 11% had a superinfected skin ulcer.

The top three etiologies rendered by dermatologists after assessing these patients were pyoderma gangrenosum (17%), infection (13%), and exogenous causes (12%); another 12% remained diagnostically inconclusive after consultation. Diagnostic agreements between the primary team requesting the consultation and the dermatologist were poor to modest.

These data highlights the role of the dermatologists in the workup of skin ulcers of unknown etiology.

“The diagnosis of skin ulcers can be challenging,” Dr. Ortega-Loayza said. “Subjective factors playing a role in the diagnosis of skin ulcers include the type of level of training/experience you’ve had and general awareness and education about skin ulcers.” In addition, there is also a lack of gold-standard diagnostic criteria for atypical/inflammatory ulcers and a lack of specificity of ancillary testing, such as for pyoderma gangrenosum.

Dr. Ortega-Loayza’s basic workup is based on the review of systems and the patient’s comorbidities. Blood work may include CBC, comprehensive metabolic panel, erythrocyte sedimentation rate/C-reactive protein, glucose-6-phosphate dehydrogenase, albumin/prealbumin, autoimmune panels, and hypercoagulable panels. He may order a skin biopsy with H&E staining and microbiological studies, superficial bacterial wound cultures, and vascular studies, such as ankle brachial index (ABI) and chronic venous reflux tests, and Doppler ultrasound, and he might consider an angiogram for certain type of ulcers. Additional imaging studies may include x-ray, CT scan, and/or MRI.

The four key factors to control in patients with skin ulcers, he continued, include effective management of edema (such as compression garments depending on the results of the vascular studies); infection (with topical/oral antibiotics and debridement); the wound microenvironment (with wound dressings), and pain (mainly with nonopioids). “In my practice, we tend to do multilayered compression,” he said. “This can be two- or four-layer. I do light compression if the patient has peripheral arterial disease. I always bring in the patient 2 days later to check on them, or do a telehealth visit, to make sure they are not developing any worsening of the ulcers.”

Infections can be managed with topical antimicrobials such as metronidazole 1% gel and cadexomer iodine. “Iodine can also help dry the wound when you need to do so,” said Dr. Ortega-Loayza, who directs a pyoderma gangrenosum clinic at OHSU. “Debridement can be done with a curette or with commercially available enzymatic products such as Collagenase, PluroGel, and MediHoney.”

When the ulcer is in an active phase (characterized by significant amount of drainage and erythema), he uses one or more of the following products to control the wound microenvironment: zinc oxide, an antimicrobial dressing, a hyperabsorbent dressing, an abdominal pad, and compression.

During the healing phase, with evidence of re-epithelization, he tends to use more foam dressings and continues with compression. His preferred options for managing pain associated with ulcers are medications to control neuropathic pain including initially gabapentin (100 mg-300 mg at bedtime), pregabalin (75 mg twice a day), or duloxetine (extended release, 30 mg once a day). All of these medications can be titrated up based on patients’ needs. Foam dressings with ibuprofen can also provide comfort, he said.

Dr. Ortega-Loayza also provided a few clinical pearls highlighting the role and utility of interleukin-23 inhibitors in the management of patients with pyoderma gangrenosum, oral vitamin K in patients with calciphylaxis, and stanozolol for lipodermatosclerosis. He is also leading the first open-label trial testing a Janus kinase inhibitor – baricitinib – as a treatment for patients with pyoderma gangrenosum.

Dr. Ortega-Loayza disclosed that he is a consultant to Genentech and Guidepoint and is a member of the advisory board for Bristol-Myers Squibb, Boehringer Ingelheim, and Janssen. He also has received research support from Lilly.

[email protected]

In the clinical opinion of Alex G. Ortega-Loayza, MD, MCR, few absolutes drive the initial assessment of patients who present with skin ulcers.

While lower-extremity ulcers stem from vascular, neuropathic, or pressure-related causes in about 70% of cases, an estimated 20% of cases are atypical, and another 10% are inconclusive. The causes can be neoplastic, infectious, inflammatory, vasculopathic, external, and genetic. “Sometimes they can be of mixed etiology, which make them even more complicated to heal,” Dr. Ortega-Loayza, of the department of dermatology at Oregon Health & Science University, Portland, said during the annual meeting of the Pacific Dermatologic Association.

In a study published in 2019, he and his colleagues at four academic hospitals evaluated characteristics and diagnoses of ulcers in 274 patients with skin ulcers in inpatient dermatology consultation services between July 2015 and July 2018. Most primary teams requesting the consultation (93%) were from nonsurgical specialties. The median age of these patients was 54 years, 45% were male, and 50% had lower-extremity ulcers. Nearly two-thirds of the ulcers (62%) were chronic in nature, while the remaining 38% were acute. The skin ulcer was the chief reason for admission in 49% of cases and 66% were admitted through the ED. In addition, 11% had a superinfected skin ulcer.

The top three etiologies rendered by dermatologists after assessing these patients were pyoderma gangrenosum (17%), infection (13%), and exogenous causes (12%); another 12% remained diagnostically inconclusive after consultation. Diagnostic agreements between the primary team requesting the consultation and the dermatologist were poor to modest.

These data highlights the role of the dermatologists in the workup of skin ulcers of unknown etiology.

“The diagnosis of skin ulcers can be challenging,” Dr. Ortega-Loayza said. “Subjective factors playing a role in the diagnosis of skin ulcers include the type of level of training/experience you’ve had and general awareness and education about skin ulcers.” In addition, there is also a lack of gold-standard diagnostic criteria for atypical/inflammatory ulcers and a lack of specificity of ancillary testing, such as for pyoderma gangrenosum.

Dr. Ortega-Loayza’s basic workup is based on the review of systems and the patient’s comorbidities. Blood work may include CBC, comprehensive metabolic panel, erythrocyte sedimentation rate/C-reactive protein, glucose-6-phosphate dehydrogenase, albumin/prealbumin, autoimmune panels, and hypercoagulable panels. He may order a skin biopsy with H&E staining and microbiological studies, superficial bacterial wound cultures, and vascular studies, such as ankle brachial index (ABI) and chronic venous reflux tests, and Doppler ultrasound, and he might consider an angiogram for certain type of ulcers. Additional imaging studies may include x-ray, CT scan, and/or MRI.

The four key factors to control in patients with skin ulcers, he continued, include effective management of edema (such as compression garments depending on the results of the vascular studies); infection (with topical/oral antibiotics and debridement); the wound microenvironment (with wound dressings), and pain (mainly with nonopioids). “In my practice, we tend to do multilayered compression,” he said. “This can be two- or four-layer. I do light compression if the patient has peripheral arterial disease. I always bring in the patient 2 days later to check on them, or do a telehealth visit, to make sure they are not developing any worsening of the ulcers.”

Infections can be managed with topical antimicrobials such as metronidazole 1% gel and cadexomer iodine. “Iodine can also help dry the wound when you need to do so,” said Dr. Ortega-Loayza, who directs a pyoderma gangrenosum clinic at OHSU. “Debridement can be done with a curette or with commercially available enzymatic products such as Collagenase, PluroGel, and MediHoney.”

When the ulcer is in an active phase (characterized by significant amount of drainage and erythema), he uses one or more of the following products to control the wound microenvironment: zinc oxide, an antimicrobial dressing, a hyperabsorbent dressing, an abdominal pad, and compression.

During the healing phase, with evidence of re-epithelization, he tends to use more foam dressings and continues with compression. His preferred options for managing pain associated with ulcers are medications to control neuropathic pain including initially gabapentin (100 mg-300 mg at bedtime), pregabalin (75 mg twice a day), or duloxetine (extended release, 30 mg once a day). All of these medications can be titrated up based on patients’ needs. Foam dressings with ibuprofen can also provide comfort, he said.

Dr. Ortega-Loayza also provided a few clinical pearls highlighting the role and utility of interleukin-23 inhibitors in the management of patients with pyoderma gangrenosum, oral vitamin K in patients with calciphylaxis, and stanozolol for lipodermatosclerosis. He is also leading the first open-label trial testing a Janus kinase inhibitor – baricitinib – as a treatment for patients with pyoderma gangrenosum.

Dr. Ortega-Loayza disclosed that he is a consultant to Genentech and Guidepoint and is a member of the advisory board for Bristol-Myers Squibb, Boehringer Ingelheim, and Janssen. He also has received research support from Lilly.

[email protected]

In the clinical opinion of Alex G. Ortega-Loayza, MD, MCR, few absolutes drive the initial assessment of patients who present with skin ulcers.

While lower-extremity ulcers stem from vascular, neuropathic, or pressure-related causes in about 70% of cases, an estimated 20% of cases are atypical, and another 10% are inconclusive. The causes can be neoplastic, infectious, inflammatory, vasculopathic, external, and genetic. “Sometimes they can be of mixed etiology, which make them even more complicated to heal,” Dr. Ortega-Loayza, of the department of dermatology at Oregon Health & Science University, Portland, said during the annual meeting of the Pacific Dermatologic Association.

In a study published in 2019, he and his colleagues at four academic hospitals evaluated characteristics and diagnoses of ulcers in 274 patients with skin ulcers in inpatient dermatology consultation services between July 2015 and July 2018. Most primary teams requesting the consultation (93%) were from nonsurgical specialties. The median age of these patients was 54 years, 45% were male, and 50% had lower-extremity ulcers. Nearly two-thirds of the ulcers (62%) were chronic in nature, while the remaining 38% were acute. The skin ulcer was the chief reason for admission in 49% of cases and 66% were admitted through the ED. In addition, 11% had a superinfected skin ulcer.

The top three etiologies rendered by dermatologists after assessing these patients were pyoderma gangrenosum (17%), infection (13%), and exogenous causes (12%); another 12% remained diagnostically inconclusive after consultation. Diagnostic agreements between the primary team requesting the consultation and the dermatologist were poor to modest.

These data highlights the role of the dermatologists in the workup of skin ulcers of unknown etiology.

“The diagnosis of skin ulcers can be challenging,” Dr. Ortega-Loayza said. “Subjective factors playing a role in the diagnosis of skin ulcers include the type of level of training/experience you’ve had and general awareness and education about skin ulcers.” In addition, there is also a lack of gold-standard diagnostic criteria for atypical/inflammatory ulcers and a lack of specificity of ancillary testing, such as for pyoderma gangrenosum.

Dr. Ortega-Loayza’s basic workup is based on the review of systems and the patient’s comorbidities. Blood work may include CBC, comprehensive metabolic panel, erythrocyte sedimentation rate/C-reactive protein, glucose-6-phosphate dehydrogenase, albumin/prealbumin, autoimmune panels, and hypercoagulable panels. He may order a skin biopsy with H&E staining and microbiological studies, superficial bacterial wound cultures, and vascular studies, such as ankle brachial index (ABI) and chronic venous reflux tests, and Doppler ultrasound, and he might consider an angiogram for certain type of ulcers. Additional imaging studies may include x-ray, CT scan, and/or MRI.

The four key factors to control in patients with skin ulcers, he continued, include effective management of edema (such as compression garments depending on the results of the vascular studies); infection (with topical/oral antibiotics and debridement); the wound microenvironment (with wound dressings), and pain (mainly with nonopioids). “In my practice, we tend to do multilayered compression,” he said. “This can be two- or four-layer. I do light compression if the patient has peripheral arterial disease. I always bring in the patient 2 days later to check on them, or do a telehealth visit, to make sure they are not developing any worsening of the ulcers.”

Infections can be managed with topical antimicrobials such as metronidazole 1% gel and cadexomer iodine. “Iodine can also help dry the wound when you need to do so,” said Dr. Ortega-Loayza, who directs a pyoderma gangrenosum clinic at OHSU. “Debridement can be done with a curette or with commercially available enzymatic products such as Collagenase, PluroGel, and MediHoney.”

When the ulcer is in an active phase (characterized by significant amount of drainage and erythema), he uses one or more of the following products to control the wound microenvironment: zinc oxide, an antimicrobial dressing, a hyperabsorbent dressing, an abdominal pad, and compression.

During the healing phase, with evidence of re-epithelization, he tends to use more foam dressings and continues with compression. His preferred options for managing pain associated with ulcers are medications to control neuropathic pain including initially gabapentin (100 mg-300 mg at bedtime), pregabalin (75 mg twice a day), or duloxetine (extended release, 30 mg once a day). All of these medications can be titrated up based on patients’ needs. Foam dressings with ibuprofen can also provide comfort, he said.

Dr. Ortega-Loayza also provided a few clinical pearls highlighting the role and utility of interleukin-23 inhibitors in the management of patients with pyoderma gangrenosum, oral vitamin K in patients with calciphylaxis, and stanozolol for lipodermatosclerosis. He is also leading the first open-label trial testing a Janus kinase inhibitor – baricitinib – as a treatment for patients with pyoderma gangrenosum.

Dr. Ortega-Loayza disclosed that he is a consultant to Genentech and Guidepoint and is a member of the advisory board for Bristol-Myers Squibb, Boehringer Ingelheim, and Janssen. He also has received research support from Lilly.

[email protected]

ON101 (Fespixon, Oneness Biotech), a first-in-class, macrophage-regulating, wound-healing cream for diabetic foot ulcers has shown benefit over absorbent dressings in a phase 3 trial, with another trial ongoing.

The product became available in Taiwan on July 4, 2021, after receiving regulatory approval from the Taiwan Food and Drug Administration based on efficacy and safety findings in a three-country phase 3 clinical trial.  

Oneness Biotech has also just started a second phase 3 trial in the United States, with a planned enrollment of 208 patients with diabetic foot ulcers, which will compare ON101 cream versus placebo cream, in addition to standard care, over 20 weeks.

The company expects to complete that trial and file a new drug application with the U.S. Food and Drug Administration in 2023, and a global launch is planned for 2025, said Oneness Biotech founder and CEO William Lu.
 

Current and upcoming trials

The Taiwan FDA approval of ON101 was based on a 236-patient clinical trial conducted in Taiwan, China, and the United States by Yu-Yao Huang MD, PhD, Chang Gung Memorial Hospital, Taoyuan City, Taiwan, and colleagues, which was published online Sept. 3, 2021, in JAMA Network Open.

The study results will also be presented during an oral session at the European Association for the Study of Diabetes meeting on Sept. 30.

The published trial showed that foot ulcers treated with ON101 cream were almost three times more likely to be completely healed at 16 weeks than those treated with standard care with an absorbent dressing (Aquacel Hydrofiber, ConvaTec) (odds ratio, 2.84; P < .001).

“The findings of this study suggest that ON101, a macrophage regulator that behaves differently from moisture-retaining dressings, represents an active-healing alternative for home and primary care of patients with chronic [diabetic foot ulcers],” the researchers concluded.

“ON101 was also granted a fast track designation by the U.S. FDA in March this year,” senior author Shun-Chen Chang, MD, Taipei Medical University–Shuang Ho Hospital, New Taipei City, Taiwan, said in an interview.

“Patients in the United States can access this new drug via the expanded access program or by participating in the second phase 3 trial in the United States,” added coauthor Shawn M. Cazzell, DPM, chief medical officer, Limb Preservation Platform, Fresno, Calif., who is involved with both trials.

It is “exciting” to have a new therapy for diabetic foot ulcers, said Dr. Cazzell, because they are serious and life-threatening.
 

Could cream with plant extracts surpass current care?

Current standard clinical care for diabetic foot ulcer consists of debridement, off-loading, infection control, and maintaining a moist environment with dressings, Huang and colleagues explain. If the foot ulcer does not respond, growth factors, tissue-engineering products, hyperbaric oxygen, or negative pressure wound therapies may be used.

However, the number of amputations from chronic diabetic foot ulcers that do not heal is increasing, pointing to a need for better treatment options.  

Hyperglycemia increases the ratio of M1 proinflammatory macrophages to M2 proregenerative macrophages, and accumulating evidence suggests this might be a potential treatment target.  

Researchers at Oneness Biotech showed that ON101, which is comprised of extracts from two plants, Plectranthus amboinicus and Centella asiatica, exerts a wound-healing effect by regulating the balance between M1 and M2 macrophages.

An extract of one plant suppresses inflammation, while an extract of the other increases collagen synthesis.

In preclinical studies, these two plant extracts had a synergistic effect on balancing the ratio of M1 to M2 macrophages and accelerating wound healing in a mouse model. This was followed by promising efficacy and safety results in two trials of 24 patients and 30 patients.
 

Significantly better healing with ON101 than standard care

For the current phase 3, randomized clinical trial, researchers enrolled patients in 21 clinics from November 2012 to May 2020.

To be eligible for the study, patients had to be 20-80 years old, with a hemoglobin A1c less than 12%. They also had to have a Wagner grade 1 or 2 foot ulcer that was 1-25 cm² after debridement, had been treated with standard care, and was present for at least 4 weeks.

Patients were a mean age of 57 years and 74% were men. They had a mean A1c of 8.1%, and 61% had had diabetes for more than 10 years.

Most (78%) of the diabetic foot ulcers were Wagner grade 2. The wounds had a mean area of 4.8 cm² and had been present for a mean of 7 months.

Patients were instructed on how to self-administer ON101 cream twice a day (treatment group, n = 122) or how to apply an absorbent dressing and change it daily or two or three times a week (standard care group, n = 114). All patients were allowed to apply a sterile gauze dressing.  

They visited the clinic every 2 weeks during the 16-week treatment phase and 12-week observation phase.

In the full analysis set, 74 patients (61%) in the ON101 group and 40 patients (35%) in the standard care group had complete wound healing after 16 weeks of treatment.

The subgroup of patients at higher risk of poor wound healing (A1c >9%, ulcer area >5 cm², and diabetic foot ulcer duration >6 months) also had significantly better healing with the ON101 cream than standard care.

There were seven (5.7%) treatment-emergent adverse events in the ON101 group versus five (4.4%) in the standard care group.

There were no treatment-related serious adverse events in the ON101 group versus one (0.9%) in the comparator group.

The study was funded by Oneness Biotech, Microbio Group, and Shanghai Haihe Pharmaceutical. One author has reported receiving fees from Oneness Biotech, and Dr. Chang has reported receiving a speakers fee from Oneness Biotech. The other authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ON101 (Fespixon, Oneness Biotech), a first-in-class, macrophage-regulating, wound-healing cream for diabetic foot ulcers has shown benefit over absorbent dressings in a phase 3 trial, with another trial ongoing.

The product became available in Taiwan on July 4, 2021, after receiving regulatory approval from the Taiwan Food and Drug Administration based on efficacy and safety findings in a three-country phase 3 clinical trial.  

Oneness Biotech has also just started a second phase 3 trial in the United States, with a planned enrollment of 208 patients with diabetic foot ulcers, which will compare ON101 cream versus placebo cream, in addition to standard care, over 20 weeks.

The company expects to complete that trial and file a new drug application with the U.S. Food and Drug Administration in 2023, and a global launch is planned for 2025, said Oneness Biotech founder and CEO William Lu.
 

Current and upcoming trials

The Taiwan FDA approval of ON101 was based on a 236-patient clinical trial conducted in Taiwan, China, and the United States by Yu-Yao Huang MD, PhD, Chang Gung Memorial Hospital, Taoyuan City, Taiwan, and colleagues, which was published online Sept. 3, 2021, in JAMA Network Open.

The study results will also be presented during an oral session at the European Association for the Study of Diabetes meeting on Sept. 30.

The published trial showed that foot ulcers treated with ON101 cream were almost three times more likely to be completely healed at 16 weeks than those treated with standard care with an absorbent dressing (Aquacel Hydrofiber, ConvaTec) (odds ratio, 2.84; P < .001).

“The findings of this study suggest that ON101, a macrophage regulator that behaves differently from moisture-retaining dressings, represents an active-healing alternative for home and primary care of patients with chronic [diabetic foot ulcers],” the researchers concluded.

“ON101 was also granted a fast track designation by the U.S. FDA in March this year,” senior author Shun-Chen Chang, MD, Taipei Medical University–Shuang Ho Hospital, New Taipei City, Taiwan, said in an interview.

“Patients in the United States can access this new drug via the expanded access program or by participating in the second phase 3 trial in the United States,” added coauthor Shawn M. Cazzell, DPM, chief medical officer, Limb Preservation Platform, Fresno, Calif., who is involved with both trials.

It is “exciting” to have a new therapy for diabetic foot ulcers, said Dr. Cazzell, because they are serious and life-threatening.
 

Could cream with plant extracts surpass current care?

Current standard clinical care for diabetic foot ulcer consists of debridement, off-loading, infection control, and maintaining a moist environment with dressings, Huang and colleagues explain. If the foot ulcer does not respond, growth factors, tissue-engineering products, hyperbaric oxygen, or negative pressure wound therapies may be used.

However, the number of amputations from chronic diabetic foot ulcers that do not heal is increasing, pointing to a need for better treatment options.  

Hyperglycemia increases the ratio of M1 proinflammatory macrophages to M2 proregenerative macrophages, and accumulating evidence suggests this might be a potential treatment target.  

Researchers at Oneness Biotech showed that ON101, which is comprised of extracts from two plants, Plectranthus amboinicus and Centella asiatica, exerts a wound-healing effect by regulating the balance between M1 and M2 macrophages.

An extract of one plant suppresses inflammation, while an extract of the other increases collagen synthesis.

In preclinical studies, these two plant extracts had a synergistic effect on balancing the ratio of M1 to M2 macrophages and accelerating wound healing in a mouse model. This was followed by promising efficacy and safety results in two trials of 24 patients and 30 patients.
 

Significantly better healing with ON101 than standard care

For the current phase 3, randomized clinical trial, researchers enrolled patients in 21 clinics from November 2012 to May 2020.

To be eligible for the study, patients had to be 20-80 years old, with a hemoglobin A1c less than 12%. They also had to have a Wagner grade 1 or 2 foot ulcer that was 1-25 cm² after debridement, had been treated with standard care, and was present for at least 4 weeks.

Patients were a mean age of 57 years and 74% were men. They had a mean A1c of 8.1%, and 61% had had diabetes for more than 10 years.

Most (78%) of the diabetic foot ulcers were Wagner grade 2. The wounds had a mean area of 4.8 cm² and had been present for a mean of 7 months.

Patients were instructed on how to self-administer ON101 cream twice a day (treatment group, n = 122) or how to apply an absorbent dressing and change it daily or two or three times a week (standard care group, n = 114). All patients were allowed to apply a sterile gauze dressing.  

They visited the clinic every 2 weeks during the 16-week treatment phase and 12-week observation phase.

In the full analysis set, 74 patients (61%) in the ON101 group and 40 patients (35%) in the standard care group had complete wound healing after 16 weeks of treatment.

The subgroup of patients at higher risk of poor wound healing (A1c >9%, ulcer area >5 cm², and diabetic foot ulcer duration >6 months) also had significantly better healing with the ON101 cream than standard care.

There were seven (5.7%) treatment-emergent adverse events in the ON101 group versus five (4.4%) in the standard care group.

There were no treatment-related serious adverse events in the ON101 group versus one (0.9%) in the comparator group.

The study was funded by Oneness Biotech, Microbio Group, and Shanghai Haihe Pharmaceutical. One author has reported receiving fees from Oneness Biotech, and Dr. Chang has reported receiving a speakers fee from Oneness Biotech. The other authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ON101 (Fespixon, Oneness Biotech), a first-in-class, macrophage-regulating, wound-healing cream for diabetic foot ulcers has shown benefit over absorbent dressings in a phase 3 trial, with another trial ongoing.

The product became available in Taiwan on July 4, 2021, after receiving regulatory approval from the Taiwan Food and Drug Administration based on efficacy and safety findings in a three-country phase 3 clinical trial.  

Oneness Biotech has also just started a second phase 3 trial in the United States, with a planned enrollment of 208 patients with diabetic foot ulcers, which will compare ON101 cream versus placebo cream, in addition to standard care, over 20 weeks.

The company expects to complete that trial and file a new drug application with the U.S. Food and Drug Administration in 2023, and a global launch is planned for 2025, said Oneness Biotech founder and CEO William Lu.
 

Current and upcoming trials

The Taiwan FDA approval of ON101 was based on a 236-patient clinical trial conducted in Taiwan, China, and the United States by Yu-Yao Huang MD, PhD, Chang Gung Memorial Hospital, Taoyuan City, Taiwan, and colleagues, which was published online Sept. 3, 2021, in JAMA Network Open.

The study results will also be presented during an oral session at the European Association for the Study of Diabetes meeting on Sept. 30.

The published trial showed that foot ulcers treated with ON101 cream were almost three times more likely to be completely healed at 16 weeks than those treated with standard care with an absorbent dressing (Aquacel Hydrofiber, ConvaTec) (odds ratio, 2.84; P < .001).

“The findings of this study suggest that ON101, a macrophage regulator that behaves differently from moisture-retaining dressings, represents an active-healing alternative for home and primary care of patients with chronic [diabetic foot ulcers],” the researchers concluded.

“ON101 was also granted a fast track designation by the U.S. FDA in March this year,” senior author Shun-Chen Chang, MD, Taipei Medical University–Shuang Ho Hospital, New Taipei City, Taiwan, said in an interview.

“Patients in the United States can access this new drug via the expanded access program or by participating in the second phase 3 trial in the United States,” added coauthor Shawn M. Cazzell, DPM, chief medical officer, Limb Preservation Platform, Fresno, Calif., who is involved with both trials.

It is “exciting” to have a new therapy for diabetic foot ulcers, said Dr. Cazzell, because they are serious and life-threatening.
 

Could cream with plant extracts surpass current care?

Current standard clinical care for diabetic foot ulcer consists of debridement, off-loading, infection control, and maintaining a moist environment with dressings, Huang and colleagues explain. If the foot ulcer does not respond, growth factors, tissue-engineering products, hyperbaric oxygen, or negative pressure wound therapies may be used.

However, the number of amputations from chronic diabetic foot ulcers that do not heal is increasing, pointing to a need for better treatment options.  

Hyperglycemia increases the ratio of M1 proinflammatory macrophages to M2 proregenerative macrophages, and accumulating evidence suggests this might be a potential treatment target.  

Researchers at Oneness Biotech showed that ON101, which is comprised of extracts from two plants, Plectranthus amboinicus and Centella asiatica, exerts a wound-healing effect by regulating the balance between M1 and M2 macrophages.

An extract of one plant suppresses inflammation, while an extract of the other increases collagen synthesis.

In preclinical studies, these two plant extracts had a synergistic effect on balancing the ratio of M1 to M2 macrophages and accelerating wound healing in a mouse model. This was followed by promising efficacy and safety results in two trials of 24 patients and 30 patients.
 

Significantly better healing with ON101 than standard care

For the current phase 3, randomized clinical trial, researchers enrolled patients in 21 clinics from November 2012 to May 2020.

To be eligible for the study, patients had to be 20-80 years old, with a hemoglobin A1c less than 12%. They also had to have a Wagner grade 1 or 2 foot ulcer that was 1-25 cm² after debridement, had been treated with standard care, and was present for at least 4 weeks.

Patients were a mean age of 57 years and 74% were men. They had a mean A1c of 8.1%, and 61% had had diabetes for more than 10 years.

Most (78%) of the diabetic foot ulcers were Wagner grade 2. The wounds had a mean area of 4.8 cm² and had been present for a mean of 7 months.

Patients were instructed on how to self-administer ON101 cream twice a day (treatment group, n = 122) or how to apply an absorbent dressing and change it daily or two or three times a week (standard care group, n = 114). All patients were allowed to apply a sterile gauze dressing.  

They visited the clinic every 2 weeks during the 16-week treatment phase and 12-week observation phase.

In the full analysis set, 74 patients (61%) in the ON101 group and 40 patients (35%) in the standard care group had complete wound healing after 16 weeks of treatment.

The subgroup of patients at higher risk of poor wound healing (A1c >9%, ulcer area >5 cm², and diabetic foot ulcer duration >6 months) also had significantly better healing with the ON101 cream than standard care.

There were seven (5.7%) treatment-emergent adverse events in the ON101 group versus five (4.4%) in the standard care group.

There were no treatment-related serious adverse events in the ON101 group versus one (0.9%) in the comparator group.

The study was funded by Oneness Biotech, Microbio Group, and Shanghai Haihe Pharmaceutical. One author has reported receiving fees from Oneness Biotech, and Dr. Chang has reported receiving a speakers fee from Oneness Biotech. The other authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The use of dragon’s blood is renowned among various medical traditions around the world.^1,2 It is known to confer anti-inflammatory, antioxidant, antitumor, antimicrobial, and wound healing benefits, among others. Dragon’s blood and its characteristic red sap has also been used in folk magic and as a coloring substance and varnish.¹ In addition, dragon’s blood resin is one of the many botanical agents with roots in traditional medicine that are among the bioactive ingredients used in the booming contemporary Korean cosmeceutical agent market.³This column will address some of the recent research on the cutaneous benefits of dragon’s blood resin obtained from several species of plants.

Rod/Moment

Many plants, only some have dermatologic properties

Essentially, the moniker “dragon’s blood” describes the deep red resin or sap that has been derived from multiple plant sources – primarily from the genera Daemonorops, Dracaena, Croton, and Pterocarpus – over multiple centuries.^2,4 In traditional Chinese medicine (TCM), various plants have been used as dragon’s blood, including Butea monosperma, Liquidambar formosana, Daemonorops draco, and, more commonly now, Dracaena cochinchinensis.⁵

Chemical constituents and activity

Dragon’s blood represents the red exudate culled from 27 species of plants from four families. Among the six Dracaena plants (D. cochinchinensis, D. cambodiana, D. cinnabari, D. draco, D. loureiroi, and D. schizantha) from which dragon’s blood is derived, flavonoids and their oligomers are considered the main active constituents. Analgesic, anti-inflammatory, antibacterial, hypolipidemic, hypoglycemic, and cytotoxic activities have been associated with these botanicals.⁶

D. cochinchinensis is one source of the ethnomedicine “dragon’s blood” that has long been used in TCM. Contemporary studies have shown that the resin of D. cochinchinensis – key constituents of which include loureirin A, loureirin B, loureirin C, cochinchinenin, socotrin-4’-ol, 4’,7-dihydroxyflavan, 4-methylcholest-7-ene-3-ol, ethylparaben, resveratrol, and hydroxyphenol – exhibits antibacterial, anti-inflammatory, analgesic, antidiabetic, and antitumor activities. It has also been shown to support skin repair.4

In 2017, Wang et al. reported that flavonoids from artificially induced dragon’s blood of D. cambodiana showed antibacterial properties.⁷ The next year, Al Fatimi reported that the dragon’s blood derived from D. cinnabari is a key plant on Yemen’s Socotra Island, where it is used for its antifungal and antioxidant properties to treat various dermal, dental, eye, and gastrointestinal diseases in humans.⁸Croton lechleri (also one of the plants known as dragon’s blood), a medicinal plant found in the Amazon rainforest and characterized by its red sap, has been shown in preclinical studies to display anti-inflammatory, antioxidant, antimicrobial, antifungal, and antineoplastic activity. Pona et al. note that, while clinical studies of C. lechleri suggest wound healing and antiviral effects, the current use of this plant has limited cutaneous applications.⁹

Wound healing activity

In 1995, Pieters et al. performed an in vivo study on rats to assess the wound healing activity of dragon’s blood (Croton spp.) from South America. In comparing the effects with those of synthetic proanthocyanidins, the researchers verified the beneficial impact of dragon’s blood in stimulating wound contraction, crust formation, new collagen development, and epithelial layer regeneration. The dragon’s blood component 3’,4-O-dimethylcedrusin was also found to enhance healing by promoting fibroblast and collagen formation, though it was not as effective as crude dragon’s blood. The authors ascribed this effect to the proanthocyanidins in the plant.¹⁰

Late in 2003, Jones published a literature review on the evidence related to Croton lechleri (known in South America as “sangre de drago” or dragon’s blood) in support of various biological effects, particularly anti-inflammatory and wound healing capability. The results from multiple in vitro and in vivo investigations buttressed previous ethnomedical justifications for the use of dragon’s blood to treat herpes, insect bites, stomach ulcers, tumors, wounds, and diarrhea, as well as other conditions. Jones added that the sap of the plant has exhibited low toxicity and has been well tolerated in clinical studies.¹¹

In 2012, Hu et al. investigated the impact of dragon’s blood powder with varying grain size on the transdermal absorption and adhesion of ZJHX paste, finding that, with decreasing grain size, penetration of dracorhodin increased, thus promoting transdermal permeability and adhesion.¹²

Lieu et al. assessed the wound healing potential of Resina Draconis, derived from D. cochinchinensis, which has long been used in traditional medicines by various cultures. In this 2013 evaluation, the investigators substantiated the traditional uses of this herb for wound healing, using excision and incision models in rats. Animals treated with D. cochinchinensis resin displayed significantly superior wound contraction and tensile strength as compared with controls, with histopathological results revealing better microvessel density and growth factor expression levels.¹³

In 2017, Jiang et al. showed that dracorhodin percolate, derived from dragon’s blood and used extensively to treat wound healing in TCM, accelerated wound healing in Wistar rats.¹⁴ A year later, they found that the use of dracorhodin perchlorate was effective in regulating fibroblast proliferation in vitro and in vivo to promote wound healing in rats. In addition, they noted that phosphorylated–extracellular signal-regulated kinase (ERK) in the wound tissue significantly increased with treatment of dracorhodin perchlorate ointment. The researchers called for clinical trials testing this compound in humans as the next step.¹⁵

In 2015, Namjoyan et al. conducted a randomized, double-blind, placebo-controlled clinical trial in 60 patients (between 14 and 65 years old) to assess the wound healing effect of a dragon’s blood cream on skin tag removal. Patients were visited every third day during this 3-week study, after which a significant difference in mean wound healing duration was identified. The investigators attributed the accelerated wound healing action to the phenolic constituents and alkaloid taspine in the resin. They also concluded that dragon’s blood warrants inclusion in the wound healing arsenal, while calling for studies in larger populations.¹⁶

Conclusion

The red resin extracts of multiple species of plants have and continue to be identified as “dragon’s blood.” This exudate has been used for various medical indications in traditional medicine for several centuries. Despite this lengthy history, modern research is hardly robust. Nevertheless, there are many credible reports of significant salutary activities associated with these resins and some evidence of cutaneous benefits. Much more research is necessary to determine how useful these ingredients are, despite their present use in a number of marketed cosmeceutical agents.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Gupta D et al. J Ethnopharmacol. 2008 Feb 12;115(3):361-80.

2. Jura-Morawiec J & Tulik. Chemoecology. 2016;26:101-5.

3. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):155-69.

4. Fan JY et al. Molecules. 2014 Jul 22;19(7):10650-69.

5. Zhang W et al. Zhongguo Zhong Yao Za Zhi. 2016 Apr;41(7):1354-7.

6. Sun J et al. J Ethnopharmacol. 2019 Nov 15;244:112138.

7. Wang H et al. Fitoterapia. 2017 Sep;121:1-5.

8. Al-Fatimi M. Plants (Basel). 2018 Oct 26;7(4):91.

9. Pona A et al. Dermatol Ther. 2019 Mar;32(2):e12786.10. Pieters L et al. Phytomedicine. 1995 Jul;2(1):17-22.

11. Jones K. J Altern Complement Med. 2003 Dec;9(6):877-96.

12. Hu Q et al. Zhongguo Zhong Yao Za Zhi. 2012 Dec;37(23):3549-53.

13. Liu H et al. Evid Based Complement Alternat Med. 2013;2013:709865.

14. Jiang XW et al. Evid Based Complement Alternat Med. 2017:8950516.

15. Jiang X et al. J Pharmacol Sci. 2018 Feb;136(2):66-72.

16. Namjoyan F et al. J Tradit Complement Med. 2015 Jan 22;6(1):37-40.

The use of dragon’s blood is renowned among various medical traditions around the world.^1,2 It is known to confer anti-inflammatory, antioxidant, antitumor, antimicrobial, and wound healing benefits, among others. Dragon’s blood and its characteristic red sap has also been used in folk magic and as a coloring substance and varnish.¹ In addition, dragon’s blood resin is one of the many botanical agents with roots in traditional medicine that are among the bioactive ingredients used in the booming contemporary Korean cosmeceutical agent market.³This column will address some of the recent research on the cutaneous benefits of dragon’s blood resin obtained from several species of plants.

Rod/Moment

Many plants, only some have dermatologic properties

Essentially, the moniker “dragon’s blood” describes the deep red resin or sap that has been derived from multiple plant sources – primarily from the genera Daemonorops, Dracaena, Croton, and Pterocarpus – over multiple centuries.^2,4 In traditional Chinese medicine (TCM), various plants have been used as dragon’s blood, including Butea monosperma, Liquidambar formosana, Daemonorops draco, and, more commonly now, Dracaena cochinchinensis.⁵

Chemical constituents and activity

Dragon’s blood represents the red exudate culled from 27 species of plants from four families. Among the six Dracaena plants (D. cochinchinensis, D. cambodiana, D. cinnabari, D. draco, D. loureiroi, and D. schizantha) from which dragon’s blood is derived, flavonoids and their oligomers are considered the main active constituents. Analgesic, anti-inflammatory, antibacterial, hypolipidemic, hypoglycemic, and cytotoxic activities have been associated with these botanicals.⁶

D. cochinchinensis is one source of the ethnomedicine “dragon’s blood” that has long been used in TCM. Contemporary studies have shown that the resin of D. cochinchinensis – key constituents of which include loureirin A, loureirin B, loureirin C, cochinchinenin, socotrin-4’-ol, 4’,7-dihydroxyflavan, 4-methylcholest-7-ene-3-ol, ethylparaben, resveratrol, and hydroxyphenol – exhibits antibacterial, anti-inflammatory, analgesic, antidiabetic, and antitumor activities. It has also been shown to support skin repair.4

In 2017, Wang et al. reported that flavonoids from artificially induced dragon’s blood of D. cambodiana showed antibacterial properties.⁷ The next year, Al Fatimi reported that the dragon’s blood derived from D. cinnabari is a key plant on Yemen’s Socotra Island, where it is used for its antifungal and antioxidant properties to treat various dermal, dental, eye, and gastrointestinal diseases in humans.⁸Croton lechleri (also one of the plants known as dragon’s blood), a medicinal plant found in the Amazon rainforest and characterized by its red sap, has been shown in preclinical studies to display anti-inflammatory, antioxidant, antimicrobial, antifungal, and antineoplastic activity. Pona et al. note that, while clinical studies of C. lechleri suggest wound healing and antiviral effects, the current use of this plant has limited cutaneous applications.⁹

Wound healing activity

In 1995, Pieters et al. performed an in vivo study on rats to assess the wound healing activity of dragon’s blood (Croton spp.) from South America. In comparing the effects with those of synthetic proanthocyanidins, the researchers verified the beneficial impact of dragon’s blood in stimulating wound contraction, crust formation, new collagen development, and epithelial layer regeneration. The dragon’s blood component 3’,4-O-dimethylcedrusin was also found to enhance healing by promoting fibroblast and collagen formation, though it was not as effective as crude dragon’s blood. The authors ascribed this effect to the proanthocyanidins in the plant.¹⁰

Late in 2003, Jones published a literature review on the evidence related to Croton lechleri (known in South America as “sangre de drago” or dragon’s blood) in support of various biological effects, particularly anti-inflammatory and wound healing capability. The results from multiple in vitro and in vivo investigations buttressed previous ethnomedical justifications for the use of dragon’s blood to treat herpes, insect bites, stomach ulcers, tumors, wounds, and diarrhea, as well as other conditions. Jones added that the sap of the plant has exhibited low toxicity and has been well tolerated in clinical studies.¹¹

In 2012, Hu et al. investigated the impact of dragon’s blood powder with varying grain size on the transdermal absorption and adhesion of ZJHX paste, finding that, with decreasing grain size, penetration of dracorhodin increased, thus promoting transdermal permeability and adhesion.¹²

Lieu et al. assessed the wound healing potential of Resina Draconis, derived from D. cochinchinensis, which has long been used in traditional medicines by various cultures. In this 2013 evaluation, the investigators substantiated the traditional uses of this herb for wound healing, using excision and incision models in rats. Animals treated with D. cochinchinensis resin displayed significantly superior wound contraction and tensile strength as compared with controls, with histopathological results revealing better microvessel density and growth factor expression levels.¹³

In 2017, Jiang et al. showed that dracorhodin percolate, derived from dragon’s blood and used extensively to treat wound healing in TCM, accelerated wound healing in Wistar rats.¹⁴ A year later, they found that the use of dracorhodin perchlorate was effective in regulating fibroblast proliferation in vitro and in vivo to promote wound healing in rats. In addition, they noted that phosphorylated–extracellular signal-regulated kinase (ERK) in the wound tissue significantly increased with treatment of dracorhodin perchlorate ointment. The researchers called for clinical trials testing this compound in humans as the next step.¹⁵

In 2015, Namjoyan et al. conducted a randomized, double-blind, placebo-controlled clinical trial in 60 patients (between 14 and 65 years old) to assess the wound healing effect of a dragon’s blood cream on skin tag removal. Patients were visited every third day during this 3-week study, after which a significant difference in mean wound healing duration was identified. The investigators attributed the accelerated wound healing action to the phenolic constituents and alkaloid taspine in the resin. They also concluded that dragon’s blood warrants inclusion in the wound healing arsenal, while calling for studies in larger populations.¹⁶

Conclusion

The red resin extracts of multiple species of plants have and continue to be identified as “dragon’s blood.” This exudate has been used for various medical indications in traditional medicine for several centuries. Despite this lengthy history, modern research is hardly robust. Nevertheless, there are many credible reports of significant salutary activities associated with these resins and some evidence of cutaneous benefits. Much more research is necessary to determine how useful these ingredients are, despite their present use in a number of marketed cosmeceutical agents.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Gupta D et al. J Ethnopharmacol. 2008 Feb 12;115(3):361-80.

2. Jura-Morawiec J & Tulik. Chemoecology. 2016;26:101-5.

3. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):155-69.

4. Fan JY et al. Molecules. 2014 Jul 22;19(7):10650-69.

5. Zhang W et al. Zhongguo Zhong Yao Za Zhi. 2016 Apr;41(7):1354-7.

6. Sun J et al. J Ethnopharmacol. 2019 Nov 15;244:112138.

7. Wang H et al. Fitoterapia. 2017 Sep;121:1-5.

8. Al-Fatimi M. Plants (Basel). 2018 Oct 26;7(4):91.

9. Pona A et al. Dermatol Ther. 2019 Mar;32(2):e12786.10. Pieters L et al. Phytomedicine. 1995 Jul;2(1):17-22.

11. Jones K. J Altern Complement Med. 2003 Dec;9(6):877-96.

12. Hu Q et al. Zhongguo Zhong Yao Za Zhi. 2012 Dec;37(23):3549-53.

13. Liu H et al. Evid Based Complement Alternat Med. 2013;2013:709865.

14. Jiang XW et al. Evid Based Complement Alternat Med. 2017:8950516.

15. Jiang X et al. J Pharmacol Sci. 2018 Feb;136(2):66-72.

16. Namjoyan F et al. J Tradit Complement Med. 2015 Jan 22;6(1):37-40.

The use of dragon’s blood is renowned among various medical traditions around the world.^1,2 It is known to confer anti-inflammatory, antioxidant, antitumor, antimicrobial, and wound healing benefits, among others. Dragon’s blood and its characteristic red sap has also been used in folk magic and as a coloring substance and varnish.¹ In addition, dragon’s blood resin is one of the many botanical agents with roots in traditional medicine that are among the bioactive ingredients used in the booming contemporary Korean cosmeceutical agent market.³This column will address some of the recent research on the cutaneous benefits of dragon’s blood resin obtained from several species of plants.

Rod/Moment

Many plants, only some have dermatologic properties

Essentially, the moniker “dragon’s blood” describes the deep red resin or sap that has been derived from multiple plant sources – primarily from the genera Daemonorops, Dracaena, Croton, and Pterocarpus – over multiple centuries.^2,4 In traditional Chinese medicine (TCM), various plants have been used as dragon’s blood, including Butea monosperma, Liquidambar formosana, Daemonorops draco, and, more commonly now, Dracaena cochinchinensis.⁵

Chemical constituents and activity

Dragon’s blood represents the red exudate culled from 27 species of plants from four families. Among the six Dracaena plants (D. cochinchinensis, D. cambodiana, D. cinnabari, D. draco, D. loureiroi, and D. schizantha) from which dragon’s blood is derived, flavonoids and their oligomers are considered the main active constituents. Analgesic, anti-inflammatory, antibacterial, hypolipidemic, hypoglycemic, and cytotoxic activities have been associated with these botanicals.⁶

D. cochinchinensis is one source of the ethnomedicine “dragon’s blood” that has long been used in TCM. Contemporary studies have shown that the resin of D. cochinchinensis – key constituents of which include loureirin A, loureirin B, loureirin C, cochinchinenin, socotrin-4’-ol, 4’,7-dihydroxyflavan, 4-methylcholest-7-ene-3-ol, ethylparaben, resveratrol, and hydroxyphenol – exhibits antibacterial, anti-inflammatory, analgesic, antidiabetic, and antitumor activities. It has also been shown to support skin repair.4

In 2017, Wang et al. reported that flavonoids from artificially induced dragon’s blood of D. cambodiana showed antibacterial properties.⁷ The next year, Al Fatimi reported that the dragon’s blood derived from D. cinnabari is a key plant on Yemen’s Socotra Island, where it is used for its antifungal and antioxidant properties to treat various dermal, dental, eye, and gastrointestinal diseases in humans.⁸Croton lechleri (also one of the plants known as dragon’s blood), a medicinal plant found in the Amazon rainforest and characterized by its red sap, has been shown in preclinical studies to display anti-inflammatory, antioxidant, antimicrobial, antifungal, and antineoplastic activity. Pona et al. note that, while clinical studies of C. lechleri suggest wound healing and antiviral effects, the current use of this plant has limited cutaneous applications.⁹

Wound healing activity

In 1995, Pieters et al. performed an in vivo study on rats to assess the wound healing activity of dragon’s blood (Croton spp.) from South America. In comparing the effects with those of synthetic proanthocyanidins, the researchers verified the beneficial impact of dragon’s blood in stimulating wound contraction, crust formation, new collagen development, and epithelial layer regeneration. The dragon’s blood component 3’,4-O-dimethylcedrusin was also found to enhance healing by promoting fibroblast and collagen formation, though it was not as effective as crude dragon’s blood. The authors ascribed this effect to the proanthocyanidins in the plant.¹⁰

Late in 2003, Jones published a literature review on the evidence related to Croton lechleri (known in South America as “sangre de drago” or dragon’s blood) in support of various biological effects, particularly anti-inflammatory and wound healing capability. The results from multiple in vitro and in vivo investigations buttressed previous ethnomedical justifications for the use of dragon’s blood to treat herpes, insect bites, stomach ulcers, tumors, wounds, and diarrhea, as well as other conditions. Jones added that the sap of the plant has exhibited low toxicity and has been well tolerated in clinical studies.¹¹

In 2012, Hu et al. investigated the impact of dragon’s blood powder with varying grain size on the transdermal absorption and adhesion of ZJHX paste, finding that, with decreasing grain size, penetration of dracorhodin increased, thus promoting transdermal permeability and adhesion.¹²

Lieu et al. assessed the wound healing potential of Resina Draconis, derived from D. cochinchinensis, which has long been used in traditional medicines by various cultures. In this 2013 evaluation, the investigators substantiated the traditional uses of this herb for wound healing, using excision and incision models in rats. Animals treated with D. cochinchinensis resin displayed significantly superior wound contraction and tensile strength as compared with controls, with histopathological results revealing better microvessel density and growth factor expression levels.¹³

In 2017, Jiang et al. showed that dracorhodin percolate, derived from dragon’s blood and used extensively to treat wound healing in TCM, accelerated wound healing in Wistar rats.¹⁴ A year later, they found that the use of dracorhodin perchlorate was effective in regulating fibroblast proliferation in vitro and in vivo to promote wound healing in rats. In addition, they noted that phosphorylated–extracellular signal-regulated kinase (ERK) in the wound tissue significantly increased with treatment of dracorhodin perchlorate ointment. The researchers called for clinical trials testing this compound in humans as the next step.¹⁵

In 2015, Namjoyan et al. conducted a randomized, double-blind, placebo-controlled clinical trial in 60 patients (between 14 and 65 years old) to assess the wound healing effect of a dragon’s blood cream on skin tag removal. Patients were visited every third day during this 3-week study, after which a significant difference in mean wound healing duration was identified. The investigators attributed the accelerated wound healing action to the phenolic constituents and alkaloid taspine in the resin. They also concluded that dragon’s blood warrants inclusion in the wound healing arsenal, while calling for studies in larger populations.¹⁶

Conclusion

The red resin extracts of multiple species of plants have and continue to be identified as “dragon’s blood.” This exudate has been used for various medical indications in traditional medicine for several centuries. Despite this lengthy history, modern research is hardly robust. Nevertheless, there are many credible reports of significant salutary activities associated with these resins and some evidence of cutaneous benefits. Much more research is necessary to determine how useful these ingredients are, despite their present use in a number of marketed cosmeceutical agents.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

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