Wounds

Synthetic snake venom is one of an increasingly wide range of bioactive ingredients that have been undergoing validation and incorporation into Korean cosmeceutical formulations.¹ This column discusses some of the emerging data in this novel area of medical and dermatologic research. For more detailed information, a review on the therapeutic potential of peptides in animal venom was published in 2003 (Nat Rev Drug Discov. 2003 Oct;2[10]:790-802).

The potential of peptides found in snake venom

Snake venom is known to contain carbohydrates, nucleosides, amino acids, and lipids, as well as enzymatic and nonenzymatic proteins and peptides, with proteins and peptides comprising the primary components.²

There are many different types of peptides in snake venom. The peptides and the small proteins found in snake venoms are known to confer a wide range of biologic activities, including antimicrobial, antihypertensive, analgesic, antitumor, and analgesic, in addition to several others. These peptides have been included in antiaging skin care products.³Pennington et al. have observed that venom-derived peptides appear to have potential as effective therapeutic agents in cosmetic formulations.⁴ In particular, Waglerin peptides appear to act with a Botox-like paralyzing effect and purportedly diminish skin wrinkles.⁵
 

Issues with efficacy of snake venom in skin care products

As with many skin care ingredients, what is seen in cell cultures or a laboratory setting may not translate to real life use. Shelf life, issues during manufacturing, interaction with other ingredients in the product, interactions with other products in the regimen, exposure to air and light, and difficulty of penetration can all affect efficacy. With snake venom in particular, stability and penetration make the efficacy in skin care products questionable.

The problem with many peptides in skin care products is that they are usually larger than 500 Dalton and, therefore, cannot penetrate into the skin. Bos et al. described the “500 Dalton rule” in 2000.⁶ Regardless of these issues, there are several publications looking at snake venom that will be discussed here.
 

Antimicrobial and wound healing activity

In 2011, Samy et al. found that phospholipase A₂ purified from crotalid snake venom expressed antibacterial activity in vitro against various clinical human pathogens. The investigators synthesized peptides based on the sequence homology and ascertained that the synthetic peptides exhibited potent microbicidal properties against Gram-negative and Gram-positive (Staphylococcus aureus) bacteria with diminished toxicity against normal human cells. Subsequently, the investigators used a BALB/c mouse model to show that peptide-treated animals displayed accelerated healing of full-thickness skin wounds, with increased re-epithelialization, collagen production, and angiogenesis. They concluded that the protein/peptide complex developed from snake venoms was effective at fostering wound healing.⁷

In that same year, Samy et al. showed in vivo that the snake venom phospholipase A₂ (svPLA₂) proteins from Viperidae and Elapidae snakes activated innate immunity in the animals tested, providing protection against skin infection caused by S. aureus. In vitro experiments also revealed that svPLA₂ proteins dose dependently exerted bacteriostatic and bactericidal effects on S. aureus.⁸ In 2015, Al-Asmari et al. comparatively assessed the venoms of two cobras,four vipers, a standard antibiotic, and an antimycotic as antimicrobial agents. The methicillin resistant Staphylococcus aureus bacterium was the most susceptible, followed by Gram-positive S. aureus, Escherichia coli, Enterococcus faecalis, and Pseudomonas aeruginosa. While the antibiotic vancomycin was more effective against P. aeruginosa, the venoms more efficiently suppressed the resistant bacteria. The snake venoms had minimal effect on the fungus Candida albicans. The investigators concluded that the snake venoms exhibited antibacterial activity comparable to antibiotics and were more efficient in tackling resistant bacteria.⁹   In a review of animal venoms in 2017, Samy et al. reported that snake venom–derived synthetic peptide/snake cathelicidin exhibits robust antimicrobial and wound healing capacity, despite its instability and risk, and presents as a possible new treatment for S. aureus infections. They indicated that antimicrobial peptides derived from various animal venoms, including snakes, spiders, and scorpions, are in early experimental and preclinical development stages, and these cysteine-rich substances share hydrophobic alpha-helices or beta-sheets that yield lethal pores and membrane-impairing results on bacteria.¹⁰
 

New drugs and emerging indications

An ingredient that is said to mimic waglerin-1, a snake venom–derived peptide, is the main active ingredient in the Hanskin Syn-Ake Peptide Renewal Mask, a Korean product, which reportedly promotes facial muscle relaxation and wrinkle reduction, as the waglerin-1 provokes neuromuscular blockade via reversible antagonism of nicotinic acetylcholine receptors.^2,4,5

Waheed et al. reported in 2017 that recent innovations in molecular research have led to scientific harnessing of the various proteins and peptides found in snake venoms to render them salutary, rather than toxic. Most of the drug development focuses on coagulopathy, hemostasis, and anticancer functions, but research continues in other areas.¹¹ According to An et al., several studies have also been performed on the use of snake venom to treat atopic dermatitis.¹²
 

Conclusion

Snake venom is a substance known primarily for its extreme toxicity, but it seems to offer promise for having beneficial effects in medicine. Due to its size and instability, it is doubtful that snake venom will have utility as a topical application in the dermatologic arsenal. In spite of the lack of convincing evidence, a search on Amazon.com brings up dozens of various skin care products containing snake venom. Much more research is necessary, of course, to see if there are methods to facilitate entry of snake venom into the dermis and if this is even desirable.

Snake venom is, in fact, my favorite example of a skin care ingredient that is a waste of money in skin care products. Do you have any favorite “charlatan skincare ingredients”? If so, feel free to contact me, and I will write a column. As dermatologists, we have a responsibility to debunk skin care marketing claims not supported by scientific evidence. I am here to help.



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. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):1555-69.

2. Munawar A et al. Snake venom peptides: tools of biodiscovery. Toxins (Basel). 2018 Nov 14;10(11):474.

3. Almeida JR et al. Curr Med Chem. 2017;24(30):3254-82.

4. Pennington MW et al. Bioorg Med Chem. 2018 Jun 1;26(10):2738-58.

5. Debono J et al. J Mol Evol. 2017 Jan;84(1):8-11.

6. Bos JD, Meinardi MM. Exp Dermatol. 2000 Jun;9(3):165-9.

7. Samy RP et al. Methods Mol Biol. 2011;716:245-65.

8. Samy RP et al. Curr Med Chem. 2011;18(33):5104-13.

9. Al-Asmari AK et al. Open Microbiol J. 2015 Jul;9:18-25.

10. Perumal Samy R et al. Biochem Pharmacol. 2017 Jun 15;134:127-38.

11. Waheed H et al. Curr Med Chem. 2017;24(17):1874-91.

12. An HJ et al. Br J Pharmacol. 2018 Dec;175(23):4310-24.

Synthetic snake venom is one of an increasingly wide range of bioactive ingredients that have been undergoing validation and incorporation into Korean cosmeceutical formulations.¹ This column discusses some of the emerging data in this novel area of medical and dermatologic research. For more detailed information, a review on the therapeutic potential of peptides in animal venom was published in 2003 (Nat Rev Drug Discov. 2003 Oct;2[10]:790-802).

The potential of peptides found in snake venom

Snake venom is known to contain carbohydrates, nucleosides, amino acids, and lipids, as well as enzymatic and nonenzymatic proteins and peptides, with proteins and peptides comprising the primary components.²

There are many different types of peptides in snake venom. The peptides and the small proteins found in snake venoms are known to confer a wide range of biologic activities, including antimicrobial, antihypertensive, analgesic, antitumor, and analgesic, in addition to several others. These peptides have been included in antiaging skin care products.³Pennington et al. have observed that venom-derived peptides appear to have potential as effective therapeutic agents in cosmetic formulations.⁴ In particular, Waglerin peptides appear to act with a Botox-like paralyzing effect and purportedly diminish skin wrinkles.⁵
 

Issues with efficacy of snake venom in skin care products

As with many skin care ingredients, what is seen in cell cultures or a laboratory setting may not translate to real life use. Shelf life, issues during manufacturing, interaction with other ingredients in the product, interactions with other products in the regimen, exposure to air and light, and difficulty of penetration can all affect efficacy. With snake venom in particular, stability and penetration make the efficacy in skin care products questionable.

The problem with many peptides in skin care products is that they are usually larger than 500 Dalton and, therefore, cannot penetrate into the skin. Bos et al. described the “500 Dalton rule” in 2000.⁶ Regardless of these issues, there are several publications looking at snake venom that will be discussed here.
 

Antimicrobial and wound healing activity

In 2011, Samy et al. found that phospholipase A₂ purified from crotalid snake venom expressed antibacterial activity in vitro against various clinical human pathogens. The investigators synthesized peptides based on the sequence homology and ascertained that the synthetic peptides exhibited potent microbicidal properties against Gram-negative and Gram-positive (Staphylococcus aureus) bacteria with diminished toxicity against normal human cells. Subsequently, the investigators used a BALB/c mouse model to show that peptide-treated animals displayed accelerated healing of full-thickness skin wounds, with increased re-epithelialization, collagen production, and angiogenesis. They concluded that the protein/peptide complex developed from snake venoms was effective at fostering wound healing.⁷

In that same year, Samy et al. showed in vivo that the snake venom phospholipase A₂ (svPLA₂) proteins from Viperidae and Elapidae snakes activated innate immunity in the animals tested, providing protection against skin infection caused by S. aureus. In vitro experiments also revealed that svPLA₂ proteins dose dependently exerted bacteriostatic and bactericidal effects on S. aureus.⁸ In 2015, Al-Asmari et al. comparatively assessed the venoms of two cobras,four vipers, a standard antibiotic, and an antimycotic as antimicrobial agents. The methicillin resistant Staphylococcus aureus bacterium was the most susceptible, followed by Gram-positive S. aureus, Escherichia coli, Enterococcus faecalis, and Pseudomonas aeruginosa. While the antibiotic vancomycin was more effective against P. aeruginosa, the venoms more efficiently suppressed the resistant bacteria. The snake venoms had minimal effect on the fungus Candida albicans. The investigators concluded that the snake venoms exhibited antibacterial activity comparable to antibiotics and were more efficient in tackling resistant bacteria.⁹   In a review of animal venoms in 2017, Samy et al. reported that snake venom–derived synthetic peptide/snake cathelicidin exhibits robust antimicrobial and wound healing capacity, despite its instability and risk, and presents as a possible new treatment for S. aureus infections. They indicated that antimicrobial peptides derived from various animal venoms, including snakes, spiders, and scorpions, are in early experimental and preclinical development stages, and these cysteine-rich substances share hydrophobic alpha-helices or beta-sheets that yield lethal pores and membrane-impairing results on bacteria.¹⁰
 

New drugs and emerging indications

An ingredient that is said to mimic waglerin-1, a snake venom–derived peptide, is the main active ingredient in the Hanskin Syn-Ake Peptide Renewal Mask, a Korean product, which reportedly promotes facial muscle relaxation and wrinkle reduction, as the waglerin-1 provokes neuromuscular blockade via reversible antagonism of nicotinic acetylcholine receptors.^2,4,5

Waheed et al. reported in 2017 that recent innovations in molecular research have led to scientific harnessing of the various proteins and peptides found in snake venoms to render them salutary, rather than toxic. Most of the drug development focuses on coagulopathy, hemostasis, and anticancer functions, but research continues in other areas.¹¹ According to An et al., several studies have also been performed on the use of snake venom to treat atopic dermatitis.¹²
 

Conclusion

Snake venom is a substance known primarily for its extreme toxicity, but it seems to offer promise for having beneficial effects in medicine. Due to its size and instability, it is doubtful that snake venom will have utility as a topical application in the dermatologic arsenal. In spite of the lack of convincing evidence, a search on Amazon.com brings up dozens of various skin care products containing snake venom. Much more research is necessary, of course, to see if there are methods to facilitate entry of snake venom into the dermis and if this is even desirable.

Snake venom is, in fact, my favorite example of a skin care ingredient that is a waste of money in skin care products. Do you have any favorite “charlatan skincare ingredients”? If so, feel free to contact me, and I will write a column. As dermatologists, we have a responsibility to debunk skin care marketing claims not supported by scientific evidence. I am here to help.



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. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):1555-69.

2. Munawar A et al. Snake venom peptides: tools of biodiscovery. Toxins (Basel). 2018 Nov 14;10(11):474.

3. Almeida JR et al. Curr Med Chem. 2017;24(30):3254-82.

4. Pennington MW et al. Bioorg Med Chem. 2018 Jun 1;26(10):2738-58.

5. Debono J et al. J Mol Evol. 2017 Jan;84(1):8-11.

6. Bos JD, Meinardi MM. Exp Dermatol. 2000 Jun;9(3):165-9.

7. Samy RP et al. Methods Mol Biol. 2011;716:245-65.

8. Samy RP et al. Curr Med Chem. 2011;18(33):5104-13.

9. Al-Asmari AK et al. Open Microbiol J. 2015 Jul;9:18-25.

10. Perumal Samy R et al. Biochem Pharmacol. 2017 Jun 15;134:127-38.

11. Waheed H et al. Curr Med Chem. 2017;24(17):1874-91.

12. An HJ et al. Br J Pharmacol. 2018 Dec;175(23):4310-24.

Synthetic snake venom is one of an increasingly wide range of bioactive ingredients that have been undergoing validation and incorporation into Korean cosmeceutical formulations.¹ This column discusses some of the emerging data in this novel area of medical and dermatologic research. For more detailed information, a review on the therapeutic potential of peptides in animal venom was published in 2003 (Nat Rev Drug Discov. 2003 Oct;2[10]:790-802).

The potential of peptides found in snake venom

Snake venom is known to contain carbohydrates, nucleosides, amino acids, and lipids, as well as enzymatic and nonenzymatic proteins and peptides, with proteins and peptides comprising the primary components.²

There are many different types of peptides in snake venom. The peptides and the small proteins found in snake venoms are known to confer a wide range of biologic activities, including antimicrobial, antihypertensive, analgesic, antitumor, and analgesic, in addition to several others. These peptides have been included in antiaging skin care products.³Pennington et al. have observed that venom-derived peptides appear to have potential as effective therapeutic agents in cosmetic formulations.⁴ In particular, Waglerin peptides appear to act with a Botox-like paralyzing effect and purportedly diminish skin wrinkles.⁵
 

Issues with efficacy of snake venom in skin care products

As with many skin care ingredients, what is seen in cell cultures or a laboratory setting may not translate to real life use. Shelf life, issues during manufacturing, interaction with other ingredients in the product, interactions with other products in the regimen, exposure to air and light, and difficulty of penetration can all affect efficacy. With snake venom in particular, stability and penetration make the efficacy in skin care products questionable.

The problem with many peptides in skin care products is that they are usually larger than 500 Dalton and, therefore, cannot penetrate into the skin. Bos et al. described the “500 Dalton rule” in 2000.⁶ Regardless of these issues, there are several publications looking at snake venom that will be discussed here.
 

Antimicrobial and wound healing activity

In 2011, Samy et al. found that phospholipase A₂ purified from crotalid snake venom expressed antibacterial activity in vitro against various clinical human pathogens. The investigators synthesized peptides based on the sequence homology and ascertained that the synthetic peptides exhibited potent microbicidal properties against Gram-negative and Gram-positive (Staphylococcus aureus) bacteria with diminished toxicity against normal human cells. Subsequently, the investigators used a BALB/c mouse model to show that peptide-treated animals displayed accelerated healing of full-thickness skin wounds, with increased re-epithelialization, collagen production, and angiogenesis. They concluded that the protein/peptide complex developed from snake venoms was effective at fostering wound healing.⁷

In that same year, Samy et al. showed in vivo that the snake venom phospholipase A₂ (svPLA₂) proteins from Viperidae and Elapidae snakes activated innate immunity in the animals tested, providing protection against skin infection caused by S. aureus. In vitro experiments also revealed that svPLA₂ proteins dose dependently exerted bacteriostatic and bactericidal effects on S. aureus.⁸ In 2015, Al-Asmari et al. comparatively assessed the venoms of two cobras,four vipers, a standard antibiotic, and an antimycotic as antimicrobial agents. The methicillin resistant Staphylococcus aureus bacterium was the most susceptible, followed by Gram-positive S. aureus, Escherichia coli, Enterococcus faecalis, and Pseudomonas aeruginosa. While the antibiotic vancomycin was more effective against P. aeruginosa, the venoms more efficiently suppressed the resistant bacteria. The snake venoms had minimal effect on the fungus Candida albicans. The investigators concluded that the snake venoms exhibited antibacterial activity comparable to antibiotics and were more efficient in tackling resistant bacteria.⁹   In a review of animal venoms in 2017, Samy et al. reported that snake venom–derived synthetic peptide/snake cathelicidin exhibits robust antimicrobial and wound healing capacity, despite its instability and risk, and presents as a possible new treatment for S. aureus infections. They indicated that antimicrobial peptides derived from various animal venoms, including snakes, spiders, and scorpions, are in early experimental and preclinical development stages, and these cysteine-rich substances share hydrophobic alpha-helices or beta-sheets that yield lethal pores and membrane-impairing results on bacteria.¹⁰
 

New drugs and emerging indications

An ingredient that is said to mimic waglerin-1, a snake venom–derived peptide, is the main active ingredient in the Hanskin Syn-Ake Peptide Renewal Mask, a Korean product, which reportedly promotes facial muscle relaxation and wrinkle reduction, as the waglerin-1 provokes neuromuscular blockade via reversible antagonism of nicotinic acetylcholine receptors.^2,4,5

Waheed et al. reported in 2017 that recent innovations in molecular research have led to scientific harnessing of the various proteins and peptides found in snake venoms to render them salutary, rather than toxic. Most of the drug development focuses on coagulopathy, hemostasis, and anticancer functions, but research continues in other areas.¹¹ According to An et al., several studies have also been performed on the use of snake venom to treat atopic dermatitis.¹²
 

Conclusion

Snake venom is a substance known primarily for its extreme toxicity, but it seems to offer promise for having beneficial effects in medicine. Due to its size and instability, it is doubtful that snake venom will have utility as a topical application in the dermatologic arsenal. In spite of the lack of convincing evidence, a search on Amazon.com brings up dozens of various skin care products containing snake venom. Much more research is necessary, of course, to see if there are methods to facilitate entry of snake venom into the dermis and if this is even desirable.

Snake venom is, in fact, my favorite example of a skin care ingredient that is a waste of money in skin care products. Do you have any favorite “charlatan skincare ingredients”? If so, feel free to contact me, and I will write a column. As dermatologists, we have a responsibility to debunk skin care marketing claims not supported by scientific evidence. I am here to help.



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. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):1555-69.

2. Munawar A et al. Snake venom peptides: tools of biodiscovery. Toxins (Basel). 2018 Nov 14;10(11):474.

3. Almeida JR et al. Curr Med Chem. 2017;24(30):3254-82.

4. Pennington MW et al. Bioorg Med Chem. 2018 Jun 1;26(10):2738-58.

5. Debono J et al. J Mol Evol. 2017 Jan;84(1):8-11.

6. Bos JD, Meinardi MM. Exp Dermatol. 2000 Jun;9(3):165-9.

7. Samy RP et al. Methods Mol Biol. 2011;716:245-65.

8. Samy RP et al. Curr Med Chem. 2011;18(33):5104-13.

9. Al-Asmari AK et al. Open Microbiol J. 2015 Jul;9:18-25.

10. Perumal Samy R et al. Biochem Pharmacol. 2017 Jun 15;134:127-38.

11. Waheed H et al. Curr Med Chem. 2017;24(17):1874-91.

12. An HJ et al. Br J Pharmacol. 2018 Dec;175(23):4310-24.

Intraosseous (IO) access can afford a lifesaving means of vascular access in emergency settings, as it allows for the administration of large volumes of fluids, blood products, and medications at high flow rates directly into the highly vascularized osseous medullary cavity.¹ Fortunately, the complication rate with this resuscitative effort is low, with many reports demonstrating complication rates of less than 1%.² The most commonly reported complications include fluid extravasation, osteomyelitis, traumatic bone fracture, and epiphyseal plate damage.^1-3 Although compartment syndrome and skin necrosis have been reported,^4,5 there is no comprehensive list of sequelae resulting from fluid extravasation in the literature, and there are no known studies examining the incidence and types of cutaneous complications. In this study, we sought to evaluate the dermatologic impacts of this procedure.

Methods

We performed a retrospective chart review approved by the institutional review board at a large metropolitan level I trauma center in the Midwestern United States spanning 18 consecutive months to identify all patients who underwent IO line placement, either en route to or upon arrival at the trauma center. The electronic medical records of 113 patients (age range, 10 days–94 years) were identified using either an automated natural language look-up program with keywords including intraosseous access and IO or a Current Procedural Terminology code 36680. Data including patient age, reason for IO insertion, anatomic location of the IO, and complications secondary to IO line placement were recorded.

Results

We identified an overall complication rate of 2.7% (3/113), with only 1 patient showing isolated cutaneous complications from IO line placement. The complications in the first 2 patients included compartment syndrome following IO line placement in the right tibia and needle breakage during IO line placement. The third patient, a 30-year-old heart transplant recipient, developed tense bullae on the left leg 5 days after a resuscitative effort required IO access through the bilateral tibiae. The patient had received vasopressors as well as 750 mL of normal saline through these access points. Two days after resuscitation, she developed an enlarging ecchymosis around the left IO access point. On day 5, cutaneous findings included 2 large firm bullae on a purpuric base overlying the left proximal tibia and patella (Figure 1). After an ultrasound revealed no connection to the underlying joint space, the bullae were incised and drained for patient comfort, as she reported pain and undue pressure at the knee joint on initial dermatologic consultation. These symptoms abated after the procedure. Cultures of bullous fluid were negative for infection. Histopathologic examination revealed a subepidermal split with underlying minimal mixed inflammation, favoring the diagnosis of traumatic bullae.

At a scheduled 7-month dermatology follow-up, the wound bed appeared to be healing well with surrounding scarring with no residual bleeding or drainage (Figure 2) despite the patient reporting a protracted course of wound healing requiring debridement due to eschar formation and multiple follow-up appointments with the wound care service.

Comment

The most commonly reported complications with IO line placement result from fluid infiltration of the subcutaneous tissue secondary to catheter misplacement.^1,3 Extravasated fluid may lead to tissue damage, compartment syndrome, and even tissue necrosis in some cases.^1,4,5 Localized cellulitis and the formation of subcutaneous abscesses also have been reported, albeit rarely.^3,5

In our retrospective cohort review, we identified an additional potential complication of IO line placement that has not been widely reported—development of large traumatic bullae. It is most likely that this patient’s IO catheter became dislodged, resulting in extravasation of fluids into the dermal and subcutaneous tissues.

Our findings support the previously noted complication rate of less than 1% following IO line placement, with an overall complication rate of 2.7% that included only 1 patient with a cutaneous complication.² Given this low incidence, providers may not be used to recognizing such complications, leading to delayed or incorrect diagnosis of these entities. While there are certain conditions in which IO insertion is contraindicated, including severe bone diseases (eg, osteogenesis imperfecta, osteomyelitis), overlying cellulitis, and bone fracture, these conditions are rare and can be avoided in most cases by use of an alternative site for needle insertion.² Due to the widespread utility of this tool and its few contraindications, its use in hospitalized patients is rapidly increasing, necessitating a need for quick recognition of potential complications.

From previous data on the incidence of traumatic blisters with underlying bone fractures, there are several identifiable risk factors that could be extended to patients at high risk for developing cutaneous IO complications secondary to the trauma associated with needle insertion,⁶ including wound-healing impairments in patients with fragile lymphatics, peripheral vascular disease, diabetes, or collagen vascular diseases (eg, lupus, rheumatoid arthritis, Sjögren syndrome). Patients with these conditions should be closely monitored for the development of bullae.⁶ While the patient we highlighted in our study did not have a history of such conditions, her history of cardiac disease, recent resuscitation attempts, and immunosuppression certainly could have contributed to suboptimal tissue agility and repair after IO line placement.

Conclusion

Intraosseous access is a safe, effective, and reliable option for vascular access in both pediatric and adult populations that is widely used in both prehospital (ie, paramedic administered) and hospital settings, including intensive care units, emergency departments, and any acute situation where rapid vascular access is necessary. This retrospective chart review examining the incidence and types of cutaneous complications associated with IO line placement at a level I trauma center revealed a total complication rate similar to those reported in previous studies and also highlighted a unique postprocedural cutaneous finding of traumatic bullae. Although no unified management recommendations currently exist, providers should consider this complication in the differential for hospitalized patients with large, atypical, asymmetric bullae in the absence of an alternative explanation for such skin findings.

Intraosseous (IO) access can afford a lifesaving means of vascular access in emergency settings, as it allows for the administration of large volumes of fluids, blood products, and medications at high flow rates directly into the highly vascularized osseous medullary cavity.¹ Fortunately, the complication rate with this resuscitative effort is low, with many reports demonstrating complication rates of less than 1%.² The most commonly reported complications include fluid extravasation, osteomyelitis, traumatic bone fracture, and epiphyseal plate damage.^1-3 Although compartment syndrome and skin necrosis have been reported,^4,5 there is no comprehensive list of sequelae resulting from fluid extravasation in the literature, and there are no known studies examining the incidence and types of cutaneous complications. In this study, we sought to evaluate the dermatologic impacts of this procedure.

Methods

We performed a retrospective chart review approved by the institutional review board at a large metropolitan level I trauma center in the Midwestern United States spanning 18 consecutive months to identify all patients who underwent IO line placement, either en route to or upon arrival at the trauma center. The electronic medical records of 113 patients (age range, 10 days–94 years) were identified using either an automated natural language look-up program with keywords including intraosseous access and IO or a Current Procedural Terminology code 36680. Data including patient age, reason for IO insertion, anatomic location of the IO, and complications secondary to IO line placement were recorded.

Results

We identified an overall complication rate of 2.7% (3/113), with only 1 patient showing isolated cutaneous complications from IO line placement. The complications in the first 2 patients included compartment syndrome following IO line placement in the right tibia and needle breakage during IO line placement. The third patient, a 30-year-old heart transplant recipient, developed tense bullae on the left leg 5 days after a resuscitative effort required IO access through the bilateral tibiae. The patient had received vasopressors as well as 750 mL of normal saline through these access points. Two days after resuscitation, she developed an enlarging ecchymosis around the left IO access point. On day 5, cutaneous findings included 2 large firm bullae on a purpuric base overlying the left proximal tibia and patella (Figure 1). After an ultrasound revealed no connection to the underlying joint space, the bullae were incised and drained for patient comfort, as she reported pain and undue pressure at the knee joint on initial dermatologic consultation. These symptoms abated after the procedure. Cultures of bullous fluid were negative for infection. Histopathologic examination revealed a subepidermal split with underlying minimal mixed inflammation, favoring the diagnosis of traumatic bullae.

At a scheduled 7-month dermatology follow-up, the wound bed appeared to be healing well with surrounding scarring with no residual bleeding or drainage (Figure 2) despite the patient reporting a protracted course of wound healing requiring debridement due to eschar formation and multiple follow-up appointments with the wound care service.

Comment

The most commonly reported complications with IO line placement result from fluid infiltration of the subcutaneous tissue secondary to catheter misplacement.^1,3 Extravasated fluid may lead to tissue damage, compartment syndrome, and even tissue necrosis in some cases.^1,4,5 Localized cellulitis and the formation of subcutaneous abscesses also have been reported, albeit rarely.^3,5

In our retrospective cohort review, we identified an additional potential complication of IO line placement that has not been widely reported—development of large traumatic bullae. It is most likely that this patient’s IO catheter became dislodged, resulting in extravasation of fluids into the dermal and subcutaneous tissues.

Our findings support the previously noted complication rate of less than 1% following IO line placement, with an overall complication rate of 2.7% that included only 1 patient with a cutaneous complication.² Given this low incidence, providers may not be used to recognizing such complications, leading to delayed or incorrect diagnosis of these entities. While there are certain conditions in which IO insertion is contraindicated, including severe bone diseases (eg, osteogenesis imperfecta, osteomyelitis), overlying cellulitis, and bone fracture, these conditions are rare and can be avoided in most cases by use of an alternative site for needle insertion.² Due to the widespread utility of this tool and its few contraindications, its use in hospitalized patients is rapidly increasing, necessitating a need for quick recognition of potential complications.

From previous data on the incidence of traumatic blisters with underlying bone fractures, there are several identifiable risk factors that could be extended to patients at high risk for developing cutaneous IO complications secondary to the trauma associated with needle insertion,⁶ including wound-healing impairments in patients with fragile lymphatics, peripheral vascular disease, diabetes, or collagen vascular diseases (eg, lupus, rheumatoid arthritis, Sjögren syndrome). Patients with these conditions should be closely monitored for the development of bullae.⁶ While the patient we highlighted in our study did not have a history of such conditions, her history of cardiac disease, recent resuscitation attempts, and immunosuppression certainly could have contributed to suboptimal tissue agility and repair after IO line placement.

Conclusion

Intraosseous access is a safe, effective, and reliable option for vascular access in both pediatric and adult populations that is widely used in both prehospital (ie, paramedic administered) and hospital settings, including intensive care units, emergency departments, and any acute situation where rapid vascular access is necessary. This retrospective chart review examining the incidence and types of cutaneous complications associated with IO line placement at a level I trauma center revealed a total complication rate similar to those reported in previous studies and also highlighted a unique postprocedural cutaneous finding of traumatic bullae. Although no unified management recommendations currently exist, providers should consider this complication in the differential for hospitalized patients with large, atypical, asymmetric bullae in the absence of an alternative explanation for such skin findings.

Intraosseous (IO) access can afford a lifesaving means of vascular access in emergency settings, as it allows for the administration of large volumes of fluids, blood products, and medications at high flow rates directly into the highly vascularized osseous medullary cavity.¹ Fortunately, the complication rate with this resuscitative effort is low, with many reports demonstrating complication rates of less than 1%.² The most commonly reported complications include fluid extravasation, osteomyelitis, traumatic bone fracture, and epiphyseal plate damage.^1-3 Although compartment syndrome and skin necrosis have been reported,^4,5 there is no comprehensive list of sequelae resulting from fluid extravasation in the literature, and there are no known studies examining the incidence and types of cutaneous complications. In this study, we sought to evaluate the dermatologic impacts of this procedure.

Methods

We performed a retrospective chart review approved by the institutional review board at a large metropolitan level I trauma center in the Midwestern United States spanning 18 consecutive months to identify all patients who underwent IO line placement, either en route to or upon arrival at the trauma center. The electronic medical records of 113 patients (age range, 10 days–94 years) were identified using either an automated natural language look-up program with keywords including intraosseous access and IO or a Current Procedural Terminology code 36680. Data including patient age, reason for IO insertion, anatomic location of the IO, and complications secondary to IO line placement were recorded.

Results

We identified an overall complication rate of 2.7% (3/113), with only 1 patient showing isolated cutaneous complications from IO line placement. The complications in the first 2 patients included compartment syndrome following IO line placement in the right tibia and needle breakage during IO line placement. The third patient, a 30-year-old heart transplant recipient, developed tense bullae on the left leg 5 days after a resuscitative effort required IO access through the bilateral tibiae. The patient had received vasopressors as well as 750 mL of normal saline through these access points. Two days after resuscitation, she developed an enlarging ecchymosis around the left IO access point. On day 5, cutaneous findings included 2 large firm bullae on a purpuric base overlying the left proximal tibia and patella (Figure 1). After an ultrasound revealed no connection to the underlying joint space, the bullae were incised and drained for patient comfort, as she reported pain and undue pressure at the knee joint on initial dermatologic consultation. These symptoms abated after the procedure. Cultures of bullous fluid were negative for infection. Histopathologic examination revealed a subepidermal split with underlying minimal mixed inflammation, favoring the diagnosis of traumatic bullae.

At a scheduled 7-month dermatology follow-up, the wound bed appeared to be healing well with surrounding scarring with no residual bleeding or drainage (Figure 2) despite the patient reporting a protracted course of wound healing requiring debridement due to eschar formation and multiple follow-up appointments with the wound care service.

Comment

The most commonly reported complications with IO line placement result from fluid infiltration of the subcutaneous tissue secondary to catheter misplacement.^1,3 Extravasated fluid may lead to tissue damage, compartment syndrome, and even tissue necrosis in some cases.^1,4,5 Localized cellulitis and the formation of subcutaneous abscesses also have been reported, albeit rarely.^3,5

In our retrospective cohort review, we identified an additional potential complication of IO line placement that has not been widely reported—development of large traumatic bullae. It is most likely that this patient’s IO catheter became dislodged, resulting in extravasation of fluids into the dermal and subcutaneous tissues.

Our findings support the previously noted complication rate of less than 1% following IO line placement, with an overall complication rate of 2.7% that included only 1 patient with a cutaneous complication.² Given this low incidence, providers may not be used to recognizing such complications, leading to delayed or incorrect diagnosis of these entities. While there are certain conditions in which IO insertion is contraindicated, including severe bone diseases (eg, osteogenesis imperfecta, osteomyelitis), overlying cellulitis, and bone fracture, these conditions are rare and can be avoided in most cases by use of an alternative site for needle insertion.² Due to the widespread utility of this tool and its few contraindications, its use in hospitalized patients is rapidly increasing, necessitating a need for quick recognition of potential complications.

From previous data on the incidence of traumatic blisters with underlying bone fractures, there are several identifiable risk factors that could be extended to patients at high risk for developing cutaneous IO complications secondary to the trauma associated with needle insertion,⁶ including wound-healing impairments in patients with fragile lymphatics, peripheral vascular disease, diabetes, or collagen vascular diseases (eg, lupus, rheumatoid arthritis, Sjögren syndrome). Patients with these conditions should be closely monitored for the development of bullae.⁶ While the patient we highlighted in our study did not have a history of such conditions, her history of cardiac disease, recent resuscitation attempts, and immunosuppression certainly could have contributed to suboptimal tissue agility and repair after IO line placement.

Conclusion

Intraosseous access is a safe, effective, and reliable option for vascular access in both pediatric and adult populations that is widely used in both prehospital (ie, paramedic administered) and hospital settings, including intensive care units, emergency departments, and any acute situation where rapid vascular access is necessary. This retrospective chart review examining the incidence and types of cutaneous complications associated with IO line placement at a level I trauma center revealed a total complication rate similar to those reported in previous studies and also highlighted a unique postprocedural cutaneous finding of traumatic bullae. Although no unified management recommendations currently exist, providers should consider this complication in the differential for hospitalized patients with large, atypical, asymmetric bullae in the absence of an alternative explanation for such skin findings.

Regarded as dermatologic emergencies, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a spectrum of blistering skin diseases that have a high mortality rate. Because of a misguided immune response to medications or infections, CD8⁺ T lymphocytes release proinflammatory cytokines, giving rise to the extensive epidermal destruction seen in SJS and TEN. The exact pathogenesis of SJS and TEN is still poorly defined, but studies have proposed that T cells mediate keratinocyte (KC) apoptosis through perforin and granzyme release and activation of the Fas/Fas ligand (FasL). Functioning as a transmembrane death receptor in the tumor necrosis factor (TNF) superfamily, Fas (CD95) activates Fas-associated death domain protein, caspases, and nucleases, resulting in organized cell destruction. Likewise, perforin and granzymes also have been shown to play a similar role in apoptosis via activation of caspases.¹

Evidence for the role of TNF-α in SJS and TEN has been supported by findings of elevated levels of TNF-α within the blister fluid, serum, and KC cell surface. Additionally, TNF-α has been shown to upregulate inducible nitric oxide synthase in KCs, causing an accumulation of nitric oxide and subsequent FasL-mediated cell death.^1-3 Notably, studies have demonstrated a relative lack of lymphocytes in the tissue of TEN patients despite the extensive destruction that is observed, thus emphasizing the importance of amplification and cell signaling via inflammatory mediators such as TNF-α.¹ In this proposed model, T cells release IFN-γ, causing KCs to release TNF-α that subsequently promotes the upregulation of the aforementioned FasL.¹ Tumor necrosis factor α also may promote increased MHC class I complex deposition on KC surfaces that may play a role in perforin and granzyme-mediated apoptosis of KCs.¹

There is still debate on the standard of care for the treatment of SJS and TEN, attributed to the absence of randomized controlled trials and the rarity of the disease as well as the numerous conflicting studies evaluating potential treatments.^1,4 Despite conflicting data to support their use, supportive care and intravenous immunoglobulin (IVIG) continue to be common treatments for SJS and TEN in hospitals worldwide. Elucidation of the role of TNF-α has prompted the use of infliximab and etanercept. In a case series of Italian patients with TEN (average SCORTEN, 3.6) treated with the TNF-α antagonist etanercept, no mortality was observed, which was well below the calculated expected mortality of 46.9%.² Our retrospective study compared the use of a TNF antagonist to other therapies in the treatment of SJS/TEN. Our data suggest that etanercept is a lifesaving and disease-modifying therapy.

Methods

Twenty-two patients with SJS/TEN were included in this analysis. This included all patients who carried a clinical diagnosis of SJS/TEN with a confirmatory biopsy at our 2 university centers—University of California, Los Angeles, and Keck-LA County-Norris Hospital at the University of Southern California, Los Angeles—from 2013 to 2016. The diagnosis was rendered when a clinical diagnosis of SJS/TEN was given by a dermatologist and a confirmatory biopsy was performed. Every patient given a diagnosis of SJS/TEN at either university system from 2015 onward received an injection of etanercept given the positive results reported by Paradisi et al.²

The 9 patients who presented from 2013 to 2014 to our 2 hospital systems and were given a diagnosis of SJS/TEN received either IVIG or supportive care alone and had an average body surface area (BSA) affected of 23%. The 13 patients who presented from 2015 to 2016 were treated with etanercept in the form of a 50-mg subcutaneous injection given once to the right upper arm. Of this group, 4 patients received dual therapy with both IVIG and etanercept. In the etanercept-treated group (etanercept alone and etanercept plus IVIG), the average BSA affected was 30%. At the time of preliminary diagnosis, all patient medications were evaluated for a possible temporal relationship to the onset of rash and were discontinued if felt to be causative. The causative agent and treatment course for each patient is summarized in Table 1.

Results

A total of 13 patients received etanercept. The mean SCORTEN was 2.2. The observed mortality was 0%, which was markedly lower than the predicted mortality of 24.3% (as determined by linear interpolation). Of this cohort, 9 patients received etanercept alone (mean SCORTEN of 2.1, predicted mortality of 22.9%), whereas 4 patients received a combination of etanercept and IVIG (mean SCORTEN of 2.3, predicted mortality of 27.2%).

The 4 patients who received both etanercept and IVIG received dual therapy for varying reasons. In patient 2 (Table 1), the perceived severity of this case ultimately led to the decision to start IVIG in addition to etanercept, resulting in rapid recovery and discharge after only 1 week of hospitalization. Intravenous immunoglobulin also was given in patient 3 (SCORTEN of 4) and patient 6 (SCORTEN of 2) for progression of disease despite administration of etanercept, with subsequent cessation of progression after the addition of the second agent (IVIG). Patient 12 might have done well on etanercept monotherapy but was administered IVIG as a precautionary measure because of hospital treatment algorithms.

Nine patients did not receive etanercept. Of this group, 5 received IVIG and 4 were managed with supportive care alone. The average SCORTEN for this group was 2.4, only slightly higher than the group that received etanercept (Table 2). The mortality rate in this group was 33%, which was higher than the predicted mortality of 28.1%.

Comment

There is no definitive gold standard treatment of SJS, SJS/TEN overlap, or TEN. However, generally agreed upon management includes immediate discontinuation of the offending medication and supportive therapy with aggressive electrolyte replacement and wound care. Management in a burn unit or intensive care unit is recommended in severe cases. Contention over the efficacy of various medications in the treatment of SJS and TEN continues and largely is due to the rarity of SJS and TEN; studies are small and almost all lack randomization. Therapies that have been used include high-dose steroids, IVIG, plasmapheresis, cyclophosphamide, cyclosporine A, and TNF inhibitors (eg, etanercept, infliximab).¹

Evidence for the use of anti–TNF-α antibodies has been limited thus far, with most of the literature focusing on infliximab and etanercept. Adalimumab, a fully humanized clonal antibody, has no reported cases in the dermatologic literature for use in patients with SJS/TEN. Two case reports of adalimumab paradoxically causing SJS have been documented. In both cases, adalimumab was stopped and patients responded to intravenous corticosteroids and infliximab.^7,8 Similarly, thalidomide has not proven to be a promising anti–TNF-α agent for the treatment of SJS/TEN. In the only attempted randomized controlled trial for SJS and TEN, thalidomide appeared to increase mortality, eventuating in this trial being terminated prior to the planned end date.⁹Infliximab and etanercept have several case reports and a few case series highlighting potentially efficacious application of TNF-α inhibitors for the treatment of SJS/TEN.^10-13 In 2002, Fischer et al¹⁰ reported the first case of TEN treated successfully with a single dose of infliximab 5 mg/kg. Kreft et al¹⁴ reported on etoricoxib-induced TEN that was treated with infliximab 5 mg/kg, which led to re-epithelialization within 5 weeks (notably a 5-week re-epithelialization time is not necessarily an improvement).

In 2005, Hunger et al³ demonstrated TNF-α’s release by KCs in the epidermis and by inflammatory cells in the dermis of a TEN patient. Twenty-four hours after the administration of infliximab 5 mg/kg in these patients, TNF-α was found to be below normal and epidermal detachment ceased.³ Wojtkietwicz et al¹³ demonstrated benefit following an infusion of infliximab 5 mg/kg in a patient whose disease continued to progress despite treatment with dexamethasone and 1.8 g/kg of IVIG.

Then 2 subsequent case series added further support for the efficacy of infliximab in the treatment of TEN. Patmanidis et al¹⁵ and Gaitanis et al¹⁶ reported similar results in 4 patients, each treated with infliximab 5 mg/kg immediately followed by initiation of high-dose IVIG (2 g/kg over 5 days). Zárate-Correa et al¹⁷ reported a 0% mortality rate and near-complete re-epithelialization after 5 to 14 days in 4 patients treated with a single 300-mg dose of infliximab.

However, the success of infliximab in the treatment of TEN has been countered by the pilot study by Paquet et al,¹⁸ which compared the efficacy of 150 mg/kg of N-acetylcysteine alone vs adding infliximab 5 mg/kg to treat 10 TEN patients. The study demonstrated no benefit at 48 hours in the group given infliximab, the time frame in which prior case reports touting infliximab’s benefit claimed the benefit was observed. Similarly, there was no effect on mortality for either treatment modality as assessed by illness auxiliary score.¹⁸

Evidence in support of the use of etanercept in the treatment of SJS/TEN is mounting, and some centers have begun to use it as the first-choice therapy for SJS/TEN. The first case was reported by Famularo et al,¹⁹ in which a patient with TEN was given 2 doses of etanercept 25 mg after failure to improve with prednisolone 1 mg/kg. The patient showed near-complete and rapid re-epithelization in 6 days before death due to disseminated intravascular coagulation 10 days after admission.¹⁹ Gubinelli et al²⁰ and Sadighha²¹ independently reported cases of TEN and TEN/acute generalized exanthematous pustulosis overlap treated with a total of 50 mg of etanercept, demonstrating rapid cessation of lesion progression. Didona et al²² found similar benefit using etanercept 50 mg to treat TEN secondary to rituximab after failure to improve with prednisone and cyclophosphamide. Treatment of TEN with etanercept in an HIV-positive patient also has been reported. Lee et al²³ described a patient who was administered 50-mg and 25-mg injections on days 3 and 5 of hospitalization, respectively, with re-epithelialization occurring by day 8. Finally, Owczarczyk-Saczonek et al²⁴ reported a case of SJS in a patient with a 4-year history of etanercept and sulfasalazine treatment of rheumatoid arthritis; sulfasalazine was stopped, but this patient was continued on etanercept until resolution of skin and mucosal symptoms. However, it is important to consider the possibility of publication bias among these cases selected for their positive outcomes.

Perhaps the most compelling literature regarding the use of etanercept for TEN was described in a case series by Paradisi et al.² This study included 10 patients with TEN, all of whom demonstrated complete re-epithelialization shortly after receiving etanercept 50 mg. Average SCORTEN was 3.6 with a range of 2 to 6. Eight patients in this study had severe comorbidities and all 10 patients survived, with a time to re-epithelialization ranging from 7 to 20 days.² Additionally, a randomized controlled trial showed that 38 etanercept-treated patients had improved mortality (P=.266) and re-epithelialization time (P=.01) compared to patients treated with intravenous methylprednisolone.²⁵Limitations to our study are similar to other reports of SJS/TEN and included the small number of cases and lack of randomization. Additionally, we do not have data available for all patients for time between onset of disease and treatment initiation. Because of these challenges, data presented in this case series is observational only. Additionally, the patients treated with etanercept alone had a slightly lower SCORTEN compared to the group that received IVIG or supportive care alone (2.1 and 2.4 respectively). However, the etanercept-only group actually had higher involvement of epidermal detachment (33%) compared to the non-etanercept group (23%).

Conclusion

Although treatment with etanercept lacks the support of a randomized controlled trial, similar to all other treatments currently used for SJS and TEN, preliminary reports highlight a benefit in disease progression and improvement in time to re-epithelialization. In particular, if etanercept 50 mg subcutaneously is given as monotherapy or is given early in the disease course (prior to other therapies being attempted and ideally within 6 hours of presentation), our data suggest an even greater trend toward improved mortality and decreased time to re-epithelialization. Additionally, our findings may suggest that in some patients, etanercept monotherapy is not an adequate intervention but the addition of IVIG may be helpful; however, the senior author (S.W.) notes anecdotally that in his experience with the patients treated at the University of California Los Angeles, the order of administration of combination therapies—etanercept followed by IVIG—was important in addition to the choice of therapy. These findings are promising enough to warrant a multicenter randomized controlled trial comparing the efficacy of etanercept to other more commonly used treatments for this spectrum of disease, including IVIG and/or cyclosporine. Based on the data presented in this case series, including the 13 patients who received etanercept and had a 0% mortality rate, etanercept may be viewed as a targeted therapeutic intervention for patients with SJS and TEN.

Regarded as dermatologic emergencies, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a spectrum of blistering skin diseases that have a high mortality rate. Because of a misguided immune response to medications or infections, CD8⁺ T lymphocytes release proinflammatory cytokines, giving rise to the extensive epidermal destruction seen in SJS and TEN. The exact pathogenesis of SJS and TEN is still poorly defined, but studies have proposed that T cells mediate keratinocyte (KC) apoptosis through perforin and granzyme release and activation of the Fas/Fas ligand (FasL). Functioning as a transmembrane death receptor in the tumor necrosis factor (TNF) superfamily, Fas (CD95) activates Fas-associated death domain protein, caspases, and nucleases, resulting in organized cell destruction. Likewise, perforin and granzymes also have been shown to play a similar role in apoptosis via activation of caspases.¹

Evidence for the role of TNF-α in SJS and TEN has been supported by findings of elevated levels of TNF-α within the blister fluid, serum, and KC cell surface. Additionally, TNF-α has been shown to upregulate inducible nitric oxide synthase in KCs, causing an accumulation of nitric oxide and subsequent FasL-mediated cell death.^1-3 Notably, studies have demonstrated a relative lack of lymphocytes in the tissue of TEN patients despite the extensive destruction that is observed, thus emphasizing the importance of amplification and cell signaling via inflammatory mediators such as TNF-α.¹ In this proposed model, T cells release IFN-γ, causing KCs to release TNF-α that subsequently promotes the upregulation of the aforementioned FasL.¹ Tumor necrosis factor α also may promote increased MHC class I complex deposition on KC surfaces that may play a role in perforin and granzyme-mediated apoptosis of KCs.¹

There is still debate on the standard of care for the treatment of SJS and TEN, attributed to the absence of randomized controlled trials and the rarity of the disease as well as the numerous conflicting studies evaluating potential treatments.^1,4 Despite conflicting data to support their use, supportive care and intravenous immunoglobulin (IVIG) continue to be common treatments for SJS and TEN in hospitals worldwide. Elucidation of the role of TNF-α has prompted the use of infliximab and etanercept. In a case series of Italian patients with TEN (average SCORTEN, 3.6) treated with the TNF-α antagonist etanercept, no mortality was observed, which was well below the calculated expected mortality of 46.9%.² Our retrospective study compared the use of a TNF antagonist to other therapies in the treatment of SJS/TEN. Our data suggest that etanercept is a lifesaving and disease-modifying therapy.

Methods

Twenty-two patients with SJS/TEN were included in this analysis. This included all patients who carried a clinical diagnosis of SJS/TEN with a confirmatory biopsy at our 2 university centers—University of California, Los Angeles, and Keck-LA County-Norris Hospital at the University of Southern California, Los Angeles—from 2013 to 2016. The diagnosis was rendered when a clinical diagnosis of SJS/TEN was given by a dermatologist and a confirmatory biopsy was performed. Every patient given a diagnosis of SJS/TEN at either university system from 2015 onward received an injection of etanercept given the positive results reported by Paradisi et al.²

The 9 patients who presented from 2013 to 2014 to our 2 hospital systems and were given a diagnosis of SJS/TEN received either IVIG or supportive care alone and had an average body surface area (BSA) affected of 23%. The 13 patients who presented from 2015 to 2016 were treated with etanercept in the form of a 50-mg subcutaneous injection given once to the right upper arm. Of this group, 4 patients received dual therapy with both IVIG and etanercept. In the etanercept-treated group (etanercept alone and etanercept plus IVIG), the average BSA affected was 30%. At the time of preliminary diagnosis, all patient medications were evaluated for a possible temporal relationship to the onset of rash and were discontinued if felt to be causative. The causative agent and treatment course for each patient is summarized in Table 1.

Results

A total of 13 patients received etanercept. The mean SCORTEN was 2.2. The observed mortality was 0%, which was markedly lower than the predicted mortality of 24.3% (as determined by linear interpolation). Of this cohort, 9 patients received etanercept alone (mean SCORTEN of 2.1, predicted mortality of 22.9%), whereas 4 patients received a combination of etanercept and IVIG (mean SCORTEN of 2.3, predicted mortality of 27.2%).

The 4 patients who received both etanercept and IVIG received dual therapy for varying reasons. In patient 2 (Table 1), the perceived severity of this case ultimately led to the decision to start IVIG in addition to etanercept, resulting in rapid recovery and discharge after only 1 week of hospitalization. Intravenous immunoglobulin also was given in patient 3 (SCORTEN of 4) and patient 6 (SCORTEN of 2) for progression of disease despite administration of etanercept, with subsequent cessation of progression after the addition of the second agent (IVIG). Patient 12 might have done well on etanercept monotherapy but was administered IVIG as a precautionary measure because of hospital treatment algorithms.

Nine patients did not receive etanercept. Of this group, 5 received IVIG and 4 were managed with supportive care alone. The average SCORTEN for this group was 2.4, only slightly higher than the group that received etanercept (Table 2). The mortality rate in this group was 33%, which was higher than the predicted mortality of 28.1%.

Comment

There is no definitive gold standard treatment of SJS, SJS/TEN overlap, or TEN. However, generally agreed upon management includes immediate discontinuation of the offending medication and supportive therapy with aggressive electrolyte replacement and wound care. Management in a burn unit or intensive care unit is recommended in severe cases. Contention over the efficacy of various medications in the treatment of SJS and TEN continues and largely is due to the rarity of SJS and TEN; studies are small and almost all lack randomization. Therapies that have been used include high-dose steroids, IVIG, plasmapheresis, cyclophosphamide, cyclosporine A, and TNF inhibitors (eg, etanercept, infliximab).¹

Evidence for the use of anti–TNF-α antibodies has been limited thus far, with most of the literature focusing on infliximab and etanercept. Adalimumab, a fully humanized clonal antibody, has no reported cases in the dermatologic literature for use in patients with SJS/TEN. Two case reports of adalimumab paradoxically causing SJS have been documented. In both cases, adalimumab was stopped and patients responded to intravenous corticosteroids and infliximab.^7,8 Similarly, thalidomide has not proven to be a promising anti–TNF-α agent for the treatment of SJS/TEN. In the only attempted randomized controlled trial for SJS and TEN, thalidomide appeared to increase mortality, eventuating in this trial being terminated prior to the planned end date.⁹Infliximab and etanercept have several case reports and a few case series highlighting potentially efficacious application of TNF-α inhibitors for the treatment of SJS/TEN.^10-13 In 2002, Fischer et al¹⁰ reported the first case of TEN treated successfully with a single dose of infliximab 5 mg/kg. Kreft et al¹⁴ reported on etoricoxib-induced TEN that was treated with infliximab 5 mg/kg, which led to re-epithelialization within 5 weeks (notably a 5-week re-epithelialization time is not necessarily an improvement).

In 2005, Hunger et al³ demonstrated TNF-α’s release by KCs in the epidermis and by inflammatory cells in the dermis of a TEN patient. Twenty-four hours after the administration of infliximab 5 mg/kg in these patients, TNF-α was found to be below normal and epidermal detachment ceased.³ Wojtkietwicz et al¹³ demonstrated benefit following an infusion of infliximab 5 mg/kg in a patient whose disease continued to progress despite treatment with dexamethasone and 1.8 g/kg of IVIG.

Then 2 subsequent case series added further support for the efficacy of infliximab in the treatment of TEN. Patmanidis et al¹⁵ and Gaitanis et al¹⁶ reported similar results in 4 patients, each treated with infliximab 5 mg/kg immediately followed by initiation of high-dose IVIG (2 g/kg over 5 days). Zárate-Correa et al¹⁷ reported a 0% mortality rate and near-complete re-epithelialization after 5 to 14 days in 4 patients treated with a single 300-mg dose of infliximab.

However, the success of infliximab in the treatment of TEN has been countered by the pilot study by Paquet et al,¹⁸ which compared the efficacy of 150 mg/kg of N-acetylcysteine alone vs adding infliximab 5 mg/kg to treat 10 TEN patients. The study demonstrated no benefit at 48 hours in the group given infliximab, the time frame in which prior case reports touting infliximab’s benefit claimed the benefit was observed. Similarly, there was no effect on mortality for either treatment modality as assessed by illness auxiliary score.¹⁸

Evidence in support of the use of etanercept in the treatment of SJS/TEN is mounting, and some centers have begun to use it as the first-choice therapy for SJS/TEN. The first case was reported by Famularo et al,¹⁹ in which a patient with TEN was given 2 doses of etanercept 25 mg after failure to improve with prednisolone 1 mg/kg. The patient showed near-complete and rapid re-epithelization in 6 days before death due to disseminated intravascular coagulation 10 days after admission.¹⁹ Gubinelli et al²⁰ and Sadighha²¹ independently reported cases of TEN and TEN/acute generalized exanthematous pustulosis overlap treated with a total of 50 mg of etanercept, demonstrating rapid cessation of lesion progression. Didona et al²² found similar benefit using etanercept 50 mg to treat TEN secondary to rituximab after failure to improve with prednisone and cyclophosphamide. Treatment of TEN with etanercept in an HIV-positive patient also has been reported. Lee et al²³ described a patient who was administered 50-mg and 25-mg injections on days 3 and 5 of hospitalization, respectively, with re-epithelialization occurring by day 8. Finally, Owczarczyk-Saczonek et al²⁴ reported a case of SJS in a patient with a 4-year history of etanercept and sulfasalazine treatment of rheumatoid arthritis; sulfasalazine was stopped, but this patient was continued on etanercept until resolution of skin and mucosal symptoms. However, it is important to consider the possibility of publication bias among these cases selected for their positive outcomes.

Perhaps the most compelling literature regarding the use of etanercept for TEN was described in a case series by Paradisi et al.² This study included 10 patients with TEN, all of whom demonstrated complete re-epithelialization shortly after receiving etanercept 50 mg. Average SCORTEN was 3.6 with a range of 2 to 6. Eight patients in this study had severe comorbidities and all 10 patients survived, with a time to re-epithelialization ranging from 7 to 20 days.² Additionally, a randomized controlled trial showed that 38 etanercept-treated patients had improved mortality (P=.266) and re-epithelialization time (P=.01) compared to patients treated with intravenous methylprednisolone.²⁵Limitations to our study are similar to other reports of SJS/TEN and included the small number of cases and lack of randomization. Additionally, we do not have data available for all patients for time between onset of disease and treatment initiation. Because of these challenges, data presented in this case series is observational only. Additionally, the patients treated with etanercept alone had a slightly lower SCORTEN compared to the group that received IVIG or supportive care alone (2.1 and 2.4 respectively). However, the etanercept-only group actually had higher involvement of epidermal detachment (33%) compared to the non-etanercept group (23%).

Conclusion

Although treatment with etanercept lacks the support of a randomized controlled trial, similar to all other treatments currently used for SJS and TEN, preliminary reports highlight a benefit in disease progression and improvement in time to re-epithelialization. In particular, if etanercept 50 mg subcutaneously is given as monotherapy or is given early in the disease course (prior to other therapies being attempted and ideally within 6 hours of presentation), our data suggest an even greater trend toward improved mortality and decreased time to re-epithelialization. Additionally, our findings may suggest that in some patients, etanercept monotherapy is not an adequate intervention but the addition of IVIG may be helpful; however, the senior author (S.W.) notes anecdotally that in his experience with the patients treated at the University of California Los Angeles, the order of administration of combination therapies—etanercept followed by IVIG—was important in addition to the choice of therapy. These findings are promising enough to warrant a multicenter randomized controlled trial comparing the efficacy of etanercept to other more commonly used treatments for this spectrum of disease, including IVIG and/or cyclosporine. Based on the data presented in this case series, including the 13 patients who received etanercept and had a 0% mortality rate, etanercept may be viewed as a targeted therapeutic intervention for patients with SJS and TEN.

Regarded as dermatologic emergencies, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a spectrum of blistering skin diseases that have a high mortality rate. Because of a misguided immune response to medications or infections, CD8⁺ T lymphocytes release proinflammatory cytokines, giving rise to the extensive epidermal destruction seen in SJS and TEN. The exact pathogenesis of SJS and TEN is still poorly defined, but studies have proposed that T cells mediate keratinocyte (KC) apoptosis through perforin and granzyme release and activation of the Fas/Fas ligand (FasL). Functioning as a transmembrane death receptor in the tumor necrosis factor (TNF) superfamily, Fas (CD95) activates Fas-associated death domain protein, caspases, and nucleases, resulting in organized cell destruction. Likewise, perforin and granzymes also have been shown to play a similar role in apoptosis via activation of caspases.¹

Evidence for the role of TNF-α in SJS and TEN has been supported by findings of elevated levels of TNF-α within the blister fluid, serum, and KC cell surface. Additionally, TNF-α has been shown to upregulate inducible nitric oxide synthase in KCs, causing an accumulation of nitric oxide and subsequent FasL-mediated cell death.^1-3 Notably, studies have demonstrated a relative lack of lymphocytes in the tissue of TEN patients despite the extensive destruction that is observed, thus emphasizing the importance of amplification and cell signaling via inflammatory mediators such as TNF-α.¹ In this proposed model, T cells release IFN-γ, causing KCs to release TNF-α that subsequently promotes the upregulation of the aforementioned FasL.¹ Tumor necrosis factor α also may promote increased MHC class I complex deposition on KC surfaces that may play a role in perforin and granzyme-mediated apoptosis of KCs.¹

There is still debate on the standard of care for the treatment of SJS and TEN, attributed to the absence of randomized controlled trials and the rarity of the disease as well as the numerous conflicting studies evaluating potential treatments.^1,4 Despite conflicting data to support their use, supportive care and intravenous immunoglobulin (IVIG) continue to be common treatments for SJS and TEN in hospitals worldwide. Elucidation of the role of TNF-α has prompted the use of infliximab and etanercept. In a case series of Italian patients with TEN (average SCORTEN, 3.6) treated with the TNF-α antagonist etanercept, no mortality was observed, which was well below the calculated expected mortality of 46.9%.² Our retrospective study compared the use of a TNF antagonist to other therapies in the treatment of SJS/TEN. Our data suggest that etanercept is a lifesaving and disease-modifying therapy.

Methods

Twenty-two patients with SJS/TEN were included in this analysis. This included all patients who carried a clinical diagnosis of SJS/TEN with a confirmatory biopsy at our 2 university centers—University of California, Los Angeles, and Keck-LA County-Norris Hospital at the University of Southern California, Los Angeles—from 2013 to 2016. The diagnosis was rendered when a clinical diagnosis of SJS/TEN was given by a dermatologist and a confirmatory biopsy was performed. Every patient given a diagnosis of SJS/TEN at either university system from 2015 onward received an injection of etanercept given the positive results reported by Paradisi et al.²

The 9 patients who presented from 2013 to 2014 to our 2 hospital systems and were given a diagnosis of SJS/TEN received either IVIG or supportive care alone and had an average body surface area (BSA) affected of 23%. The 13 patients who presented from 2015 to 2016 were treated with etanercept in the form of a 50-mg subcutaneous injection given once to the right upper arm. Of this group, 4 patients received dual therapy with both IVIG and etanercept. In the etanercept-treated group (etanercept alone and etanercept plus IVIG), the average BSA affected was 30%. At the time of preliminary diagnosis, all patient medications were evaluated for a possible temporal relationship to the onset of rash and were discontinued if felt to be causative. The causative agent and treatment course for each patient is summarized in Table 1.

Results

A total of 13 patients received etanercept. The mean SCORTEN was 2.2. The observed mortality was 0%, which was markedly lower than the predicted mortality of 24.3% (as determined by linear interpolation). Of this cohort, 9 patients received etanercept alone (mean SCORTEN of 2.1, predicted mortality of 22.9%), whereas 4 patients received a combination of etanercept and IVIG (mean SCORTEN of 2.3, predicted mortality of 27.2%).

The 4 patients who received both etanercept and IVIG received dual therapy for varying reasons. In patient 2 (Table 1), the perceived severity of this case ultimately led to the decision to start IVIG in addition to etanercept, resulting in rapid recovery and discharge after only 1 week of hospitalization. Intravenous immunoglobulin also was given in patient 3 (SCORTEN of 4) and patient 6 (SCORTEN of 2) for progression of disease despite administration of etanercept, with subsequent cessation of progression after the addition of the second agent (IVIG). Patient 12 might have done well on etanercept monotherapy but was administered IVIG as a precautionary measure because of hospital treatment algorithms.

Nine patients did not receive etanercept. Of this group, 5 received IVIG and 4 were managed with supportive care alone. The average SCORTEN for this group was 2.4, only slightly higher than the group that received etanercept (Table 2). The mortality rate in this group was 33%, which was higher than the predicted mortality of 28.1%.

Comment

There is no definitive gold standard treatment of SJS, SJS/TEN overlap, or TEN. However, generally agreed upon management includes immediate discontinuation of the offending medication and supportive therapy with aggressive electrolyte replacement and wound care. Management in a burn unit or intensive care unit is recommended in severe cases. Contention over the efficacy of various medications in the treatment of SJS and TEN continues and largely is due to the rarity of SJS and TEN; studies are small and almost all lack randomization. Therapies that have been used include high-dose steroids, IVIG, plasmapheresis, cyclophosphamide, cyclosporine A, and TNF inhibitors (eg, etanercept, infliximab).¹

Evidence for the use of anti–TNF-α antibodies has been limited thus far, with most of the literature focusing on infliximab and etanercept. Adalimumab, a fully humanized clonal antibody, has no reported cases in the dermatologic literature for use in patients with SJS/TEN. Two case reports of adalimumab paradoxically causing SJS have been documented. In both cases, adalimumab was stopped and patients responded to intravenous corticosteroids and infliximab.^7,8 Similarly, thalidomide has not proven to be a promising anti–TNF-α agent for the treatment of SJS/TEN. In the only attempted randomized controlled trial for SJS and TEN, thalidomide appeared to increase mortality, eventuating in this trial being terminated prior to the planned end date.⁹Infliximab and etanercept have several case reports and a few case series highlighting potentially efficacious application of TNF-α inhibitors for the treatment of SJS/TEN.^10-13 In 2002, Fischer et al¹⁰ reported the first case of TEN treated successfully with a single dose of infliximab 5 mg/kg. Kreft et al¹⁴ reported on etoricoxib-induced TEN that was treated with infliximab 5 mg/kg, which led to re-epithelialization within 5 weeks (notably a 5-week re-epithelialization time is not necessarily an improvement).

In 2005, Hunger et al³ demonstrated TNF-α’s release by KCs in the epidermis and by inflammatory cells in the dermis of a TEN patient. Twenty-four hours after the administration of infliximab 5 mg/kg in these patients, TNF-α was found to be below normal and epidermal detachment ceased.³ Wojtkietwicz et al¹³ demonstrated benefit following an infusion of infliximab 5 mg/kg in a patient whose disease continued to progress despite treatment with dexamethasone and 1.8 g/kg of IVIG.

Then 2 subsequent case series added further support for the efficacy of infliximab in the treatment of TEN. Patmanidis et al¹⁵ and Gaitanis et al¹⁶ reported similar results in 4 patients, each treated with infliximab 5 mg/kg immediately followed by initiation of high-dose IVIG (2 g/kg over 5 days). Zárate-Correa et al¹⁷ reported a 0% mortality rate and near-complete re-epithelialization after 5 to 14 days in 4 patients treated with a single 300-mg dose of infliximab.

However, the success of infliximab in the treatment of TEN has been countered by the pilot study by Paquet et al,¹⁸ which compared the efficacy of 150 mg/kg of N-acetylcysteine alone vs adding infliximab 5 mg/kg to treat 10 TEN patients. The study demonstrated no benefit at 48 hours in the group given infliximab, the time frame in which prior case reports touting infliximab’s benefit claimed the benefit was observed. Similarly, there was no effect on mortality for either treatment modality as assessed by illness auxiliary score.¹⁸

Evidence in support of the use of etanercept in the treatment of SJS/TEN is mounting, and some centers have begun to use it as the first-choice therapy for SJS/TEN. The first case was reported by Famularo et al,¹⁹ in which a patient with TEN was given 2 doses of etanercept 25 mg after failure to improve with prednisolone 1 mg/kg. The patient showed near-complete and rapid re-epithelization in 6 days before death due to disseminated intravascular coagulation 10 days after admission.¹⁹ Gubinelli et al²⁰ and Sadighha²¹ independently reported cases of TEN and TEN/acute generalized exanthematous pustulosis overlap treated with a total of 50 mg of etanercept, demonstrating rapid cessation of lesion progression. Didona et al²² found similar benefit using etanercept 50 mg to treat TEN secondary to rituximab after failure to improve with prednisone and cyclophosphamide. Treatment of TEN with etanercept in an HIV-positive patient also has been reported. Lee et al²³ described a patient who was administered 50-mg and 25-mg injections on days 3 and 5 of hospitalization, respectively, with re-epithelialization occurring by day 8. Finally, Owczarczyk-Saczonek et al²⁴ reported a case of SJS in a patient with a 4-year history of etanercept and sulfasalazine treatment of rheumatoid arthritis; sulfasalazine was stopped, but this patient was continued on etanercept until resolution of skin and mucosal symptoms. However, it is important to consider the possibility of publication bias among these cases selected for their positive outcomes.

Perhaps the most compelling literature regarding the use of etanercept for TEN was described in a case series by Paradisi et al.² This study included 10 patients with TEN, all of whom demonstrated complete re-epithelialization shortly after receiving etanercept 50 mg. Average SCORTEN was 3.6 with a range of 2 to 6. Eight patients in this study had severe comorbidities and all 10 patients survived, with a time to re-epithelialization ranging from 7 to 20 days.² Additionally, a randomized controlled trial showed that 38 etanercept-treated patients had improved mortality (P=.266) and re-epithelialization time (P=.01) compared to patients treated with intravenous methylprednisolone.²⁵Limitations to our study are similar to other reports of SJS/TEN and included the small number of cases and lack of randomization. Additionally, we do not have data available for all patients for time between onset of disease and treatment initiation. Because of these challenges, data presented in this case series is observational only. Additionally, the patients treated with etanercept alone had a slightly lower SCORTEN compared to the group that received IVIG or supportive care alone (2.1 and 2.4 respectively). However, the etanercept-only group actually had higher involvement of epidermal detachment (33%) compared to the non-etanercept group (23%).

Conclusion

Although treatment with etanercept lacks the support of a randomized controlled trial, similar to all other treatments currently used for SJS and TEN, preliminary reports highlight a benefit in disease progression and improvement in time to re-epithelialization. In particular, if etanercept 50 mg subcutaneously is given as monotherapy or is given early in the disease course (prior to other therapies being attempted and ideally within 6 hours of presentation), our data suggest an even greater trend toward improved mortality and decreased time to re-epithelialization. Additionally, our findings may suggest that in some patients, etanercept monotherapy is not an adequate intervention but the addition of IVIG may be helpful; however, the senior author (S.W.) notes anecdotally that in his experience with the patients treated at the University of California Los Angeles, the order of administration of combination therapies—etanercept followed by IVIG—was important in addition to the choice of therapy. These findings are promising enough to warrant a multicenter randomized controlled trial comparing the efficacy of etanercept to other more commonly used treatments for this spectrum of disease, including IVIG and/or cyclosporine. Based on the data presented in this case series, including the 13 patients who received etanercept and had a 0% mortality rate, etanercept may be viewed as a targeted therapeutic intervention for patients with SJS and TEN.

The risk of amputations in persons with type 1 diabetes in Sweden has decreased over time, suggesting an improvement in the course of disease for these individuals, according to a national registry analysis.

Balkonsky/Thinkstock

The incidence of any amputation trended downward from 2011 to 2019, Sara Hallström, MD, reported at the annual scientific sessions of the American Diabetes Association.

Levels of hemoglobin A1c have also trended downward over time in Sweden among those with type 1 diabetes, while renal function has remained stable among patients who did not undergo amputations, Dr. Hallström said in a virtual presentation.

“Observing stable renal function and decreasing levels of [hemoglobin] A1c, along with decreasing incidence of amputation, indicates a shift in the prognosis of persons with type 1 diabetes,” she said.
 

Drilling down on amputation risk in type 1 diabetes

Lower-extremity amputation is a major source of disability and distress in people with diabetes, and also poses a significant financial burden for the health care system, according to Dr. Hallström of Sahlgrenska University Hospital and the University of Gothenburg (Sweden).

“Limb loss due to amputation is not seldom a final outcome of diabetic foot ulcers,” she said in the presentation.

Most studies of amputation incidence and risk factors have grouped patients with different types of diabetes, though a few recent studies have singled out type 1 diabetes.

Among these is a 2019 study indicating a 40-fold higher risk of amputation among individuals with type 1 diabetes, compared with the general population, based on analysis of Swedish National Diabetes Register data from 1998 to 2013.
 

Trends over time

In the present study, Dr. Hallström and coinvestigators queried that same Swedish registry and identified 46,008 individuals with type 1 diabetes from 1998 to 2019. The mean age was 32.5 years and 55% were male. Overall, 1,519 of these individuals (3.3%) underwent amputation.

The incidence of any amputation fluctuated from 1998 to 2011, followed by a “decreasing trend over time” from 2011 to 2019, Dr. Hallström said.

The incidence of amputation per 1,000 patient-years was 2.84 in the earliest time period of 1998-2001, decreasing to 1.64 in 2017-2019.

Levels of A1c decreased over time, starting at 2012, both in participants with and without amputations, Dr. Hallström said. Renal function over that period remained stable in persons without amputation, and showed a decreasing trend in persons with amputation.

Compared with individuals with no amputations, those undergoing amputation were older (50 years vs. 32 years), had a longer duration of diabetes (34.9 years vs. 16.5 years), and had higher mean A1c, Dr. Hellström said. The amputee group also included a higher proportion of smokers, at 19.4% versus 14.0%, data show.

Risk factors for amputation included renal dysfunction, hyperglycemia, older age, smoking, hypertension, and cardiovascular comorbidities, according to the researcher.
 

U.S. amputations on the rise overall

While authors say results of this study point to a potentially improved prognosis for individuals with type 1 diabetes in Sweden, Robert A. Gabbay, MD, PhD, chief scientific and medical officer of the ADA, said amputation rates remains “concerning” based on U.S. data focused largely on type 2 diabetes.

“The amputation rate is unfortunately rising,” he said. “Sadly, this continues to be an issue.”

Significant health disparities persist, he added, with Black Americans having two- to threefold higher rates of amputations.

To help reduce amputation rates, clinicians should be asking patient about claudication and using simple screening techniques such as inspecting patient’s feet. “The big deal here is preventing ulcer formation, because once the ulcer forms, it often doesn’t heal, and it’s a downward spiral,” he said.

In addition, recent research suggests seeking a second opinion may help: “Many of those amputations could be avoided, in part because people aren’t aware of some of the treatments that can open up the arteries and reestablish blood flow,” he added.

Dr. Hallström reported no conflicts of interest. One coauthor on the study provided disclosures related to Abbott, AstraZeneca, Boehringer Ingelheim, Lilly Diabetes, and Novo Nordisk.

The risk of amputations in persons with type 1 diabetes in Sweden has decreased over time, suggesting an improvement in the course of disease for these individuals, according to a national registry analysis.

Balkonsky/Thinkstock

The incidence of any amputation trended downward from 2011 to 2019, Sara Hallström, MD, reported at the annual scientific sessions of the American Diabetes Association.

Levels of hemoglobin A1c have also trended downward over time in Sweden among those with type 1 diabetes, while renal function has remained stable among patients who did not undergo amputations, Dr. Hallström said in a virtual presentation.

“Observing stable renal function and decreasing levels of [hemoglobin] A1c, along with decreasing incidence of amputation, indicates a shift in the prognosis of persons with type 1 diabetes,” she said.
 

Drilling down on amputation risk in type 1 diabetes

Lower-extremity amputation is a major source of disability and distress in people with diabetes, and also poses a significant financial burden for the health care system, according to Dr. Hallström of Sahlgrenska University Hospital and the University of Gothenburg (Sweden).

“Limb loss due to amputation is not seldom a final outcome of diabetic foot ulcers,” she said in the presentation.

Most studies of amputation incidence and risk factors have grouped patients with different types of diabetes, though a few recent studies have singled out type 1 diabetes.

Among these is a 2019 study indicating a 40-fold higher risk of amputation among individuals with type 1 diabetes, compared with the general population, based on analysis of Swedish National Diabetes Register data from 1998 to 2013.
 

Trends over time

In the present study, Dr. Hallström and coinvestigators queried that same Swedish registry and identified 46,008 individuals with type 1 diabetes from 1998 to 2019. The mean age was 32.5 years and 55% were male. Overall, 1,519 of these individuals (3.3%) underwent amputation.

The incidence of any amputation fluctuated from 1998 to 2011, followed by a “decreasing trend over time” from 2011 to 2019, Dr. Hallström said.

The incidence of amputation per 1,000 patient-years was 2.84 in the earliest time period of 1998-2001, decreasing to 1.64 in 2017-2019.

Levels of A1c decreased over time, starting at 2012, both in participants with and without amputations, Dr. Hallström said. Renal function over that period remained stable in persons without amputation, and showed a decreasing trend in persons with amputation.

Compared with individuals with no amputations, those undergoing amputation were older (50 years vs. 32 years), had a longer duration of diabetes (34.9 years vs. 16.5 years), and had higher mean A1c, Dr. Hellström said. The amputee group also included a higher proportion of smokers, at 19.4% versus 14.0%, data show.

Risk factors for amputation included renal dysfunction, hyperglycemia, older age, smoking, hypertension, and cardiovascular comorbidities, according to the researcher.
 

U.S. amputations on the rise overall

While authors say results of this study point to a potentially improved prognosis for individuals with type 1 diabetes in Sweden, Robert A. Gabbay, MD, PhD, chief scientific and medical officer of the ADA, said amputation rates remains “concerning” based on U.S. data focused largely on type 2 diabetes.

“The amputation rate is unfortunately rising,” he said. “Sadly, this continues to be an issue.”

Significant health disparities persist, he added, with Black Americans having two- to threefold higher rates of amputations.

To help reduce amputation rates, clinicians should be asking patient about claudication and using simple screening techniques such as inspecting patient’s feet. “The big deal here is preventing ulcer formation, because once the ulcer forms, it often doesn’t heal, and it’s a downward spiral,” he said.

In addition, recent research suggests seeking a second opinion may help: “Many of those amputations could be avoided, in part because people aren’t aware of some of the treatments that can open up the arteries and reestablish blood flow,” he added.

Dr. Hallström reported no conflicts of interest. One coauthor on the study provided disclosures related to Abbott, AstraZeneca, Boehringer Ingelheim, Lilly Diabetes, and Novo Nordisk.

The risk of amputations in persons with type 1 diabetes in Sweden has decreased over time, suggesting an improvement in the course of disease for these individuals, according to a national registry analysis.

Balkonsky/Thinkstock

The incidence of any amputation trended downward from 2011 to 2019, Sara Hallström, MD, reported at the annual scientific sessions of the American Diabetes Association.

Levels of hemoglobin A1c have also trended downward over time in Sweden among those with type 1 diabetes, while renal function has remained stable among patients who did not undergo amputations, Dr. Hallström said in a virtual presentation.

“Observing stable renal function and decreasing levels of [hemoglobin] A1c, along with decreasing incidence of amputation, indicates a shift in the prognosis of persons with type 1 diabetes,” she said.
 

Drilling down on amputation risk in type 1 diabetes

Lower-extremity amputation is a major source of disability and distress in people with diabetes, and also poses a significant financial burden for the health care system, according to Dr. Hallström of Sahlgrenska University Hospital and the University of Gothenburg (Sweden).

“Limb loss due to amputation is not seldom a final outcome of diabetic foot ulcers,” she said in the presentation.

Most studies of amputation incidence and risk factors have grouped patients with different types of diabetes, though a few recent studies have singled out type 1 diabetes.

Among these is a 2019 study indicating a 40-fold higher risk of amputation among individuals with type 1 diabetes, compared with the general population, based on analysis of Swedish National Diabetes Register data from 1998 to 2013.
 

Trends over time

In the present study, Dr. Hallström and coinvestigators queried that same Swedish registry and identified 46,008 individuals with type 1 diabetes from 1998 to 2019. The mean age was 32.5 years and 55% were male. Overall, 1,519 of these individuals (3.3%) underwent amputation.

The incidence of any amputation fluctuated from 1998 to 2011, followed by a “decreasing trend over time” from 2011 to 2019, Dr. Hallström said.

The incidence of amputation per 1,000 patient-years was 2.84 in the earliest time period of 1998-2001, decreasing to 1.64 in 2017-2019.

Levels of A1c decreased over time, starting at 2012, both in participants with and without amputations, Dr. Hallström said. Renal function over that period remained stable in persons without amputation, and showed a decreasing trend in persons with amputation.

Compared with individuals with no amputations, those undergoing amputation were older (50 years vs. 32 years), had a longer duration of diabetes (34.9 years vs. 16.5 years), and had higher mean A1c, Dr. Hellström said. The amputee group also included a higher proportion of smokers, at 19.4% versus 14.0%, data show.

Risk factors for amputation included renal dysfunction, hyperglycemia, older age, smoking, hypertension, and cardiovascular comorbidities, according to the researcher.
 

U.S. amputations on the rise overall

While authors say results of this study point to a potentially improved prognosis for individuals with type 1 diabetes in Sweden, Robert A. Gabbay, MD, PhD, chief scientific and medical officer of the ADA, said amputation rates remains “concerning” based on U.S. data focused largely on type 2 diabetes.

“The amputation rate is unfortunately rising,” he said. “Sadly, this continues to be an issue.”

Significant health disparities persist, he added, with Black Americans having two- to threefold higher rates of amputations.

To help reduce amputation rates, clinicians should be asking patient about claudication and using simple screening techniques such as inspecting patient’s feet. “The big deal here is preventing ulcer formation, because once the ulcer forms, it often doesn’t heal, and it’s a downward spiral,” he said.

In addition, recent research suggests seeking a second opinion may help: “Many of those amputations could be avoided, in part because people aren’t aware of some of the treatments that can open up the arteries and reestablish blood flow,” he added.

Dr. Hallström reported no conflicts of interest. One coauthor on the study provided disclosures related to Abbott, AstraZeneca, Boehringer Ingelheim, Lilly Diabetes, and Novo Nordisk.

Practice Gap

Many cutaneous surgery wounds can be closed primarily; however, in certain cases, other repair options might be appropriate and should be evaluated on a case-by-case basis with input from the patient. Defects on the dorsal aspect of the hands—where nonmelanoma skin cancer is common and reserve tissue is limited—often heal by secondary intention with good cosmetic and functional results. Patients often express a desire to reduce the time spent in the surgical suite and restrictions on postoperative activity, making secondary intention healing more appealing. An additional advantage is obviation of the need to remove additional tissue in the form of Burow triangles, which would lead to a longer wound. The major disadvantage of secondary intention healing is longer time to wound maturity; we often minimize this disadvantage with purse-string closure to decrease the size of the wound defect, which can be done quickly and without removing additional tissue.

The Technique

An elderly man had 3 nonmelanoma skin cancers—all on the dorsal aspect of the left hand—that were treated on the same day, leaving 3 similar wound defects after Mohs micrographic surgery. The wound defects (distal to proximal) measured 12 mm, 12 mm, and 10 mm in diameter (Figure 1) and were repaired by primary closure, secondary intention, and purse-string circumferential closure, respectively. Purse-string closure¹ was performed with a 4-0 polyglactin 901 suture and left to heal without external sutures (Figure 2). Figure 3 shows the 3 types of repairs immediately following closure. All wounds healed with excellent and essentially equivalent cosmetic results, with excellent patient satisfaction at 6-month follow-up (Figure 4).

Practical Implications

Our case illustrates different modalities of wound repair during precisely the same time frame and essentially on the same location. Skin of the dorsal hand often is tight; depending on the size of the defect, large primary closure can be tedious to perform, can lead to increased wound tension and risk of dehiscence, and can be uncomfortable for the patient during healing. However, primary closure typically will lead to faster healing.

Secondary intention healing and purse-string closure require less surgery and therefore cost less; these modalities yield similar cosmesis and satisfaction. In the appropriate context, secondary intention has been highlighted as a suitable alternative to primary closure^2-4; in our experience (and that of others⁵), patient satisfaction is not diminished with healing by secondary intention. Purse-string closure also can minimize wound size and healing time.

For small shallow wounds on the dorsal hand, dermatologic surgeons should have confidence that secondary intention healing, with or without wound reduction using purse-string repair, likely will lead to acceptable cosmetic and functional results. Of course, repair should be tailored to the circumstances and wishes of the individual patient.

Practice Gap

Many cutaneous surgery wounds can be closed primarily; however, in certain cases, other repair options might be appropriate and should be evaluated on a case-by-case basis with input from the patient. Defects on the dorsal aspect of the hands—where nonmelanoma skin cancer is common and reserve tissue is limited—often heal by secondary intention with good cosmetic and functional results. Patients often express a desire to reduce the time spent in the surgical suite and restrictions on postoperative activity, making secondary intention healing more appealing. An additional advantage is obviation of the need to remove additional tissue in the form of Burow triangles, which would lead to a longer wound. The major disadvantage of secondary intention healing is longer time to wound maturity; we often minimize this disadvantage with purse-string closure to decrease the size of the wound defect, which can be done quickly and without removing additional tissue.

The Technique

An elderly man had 3 nonmelanoma skin cancers—all on the dorsal aspect of the left hand—that were treated on the same day, leaving 3 similar wound defects after Mohs micrographic surgery. The wound defects (distal to proximal) measured 12 mm, 12 mm, and 10 mm in diameter (Figure 1) and were repaired by primary closure, secondary intention, and purse-string circumferential closure, respectively. Purse-string closure¹ was performed with a 4-0 polyglactin 901 suture and left to heal without external sutures (Figure 2). Figure 3 shows the 3 types of repairs immediately following closure. All wounds healed with excellent and essentially equivalent cosmetic results, with excellent patient satisfaction at 6-month follow-up (Figure 4).

Practical Implications

Our case illustrates different modalities of wound repair during precisely the same time frame and essentially on the same location. Skin of the dorsal hand often is tight; depending on the size of the defect, large primary closure can be tedious to perform, can lead to increased wound tension and risk of dehiscence, and can be uncomfortable for the patient during healing. However, primary closure typically will lead to faster healing.

Secondary intention healing and purse-string closure require less surgery and therefore cost less; these modalities yield similar cosmesis and satisfaction. In the appropriate context, secondary intention has been highlighted as a suitable alternative to primary closure^2-4; in our experience (and that of others⁵), patient satisfaction is not diminished with healing by secondary intention. Purse-string closure also can minimize wound size and healing time.

For small shallow wounds on the dorsal hand, dermatologic surgeons should have confidence that secondary intention healing, with or without wound reduction using purse-string repair, likely will lead to acceptable cosmetic and functional results. Of course, repair should be tailored to the circumstances and wishes of the individual patient.

Practice Gap

Many cutaneous surgery wounds can be closed primarily; however, in certain cases, other repair options might be appropriate and should be evaluated on a case-by-case basis with input from the patient. Defects on the dorsal aspect of the hands—where nonmelanoma skin cancer is common and reserve tissue is limited—often heal by secondary intention with good cosmetic and functional results. Patients often express a desire to reduce the time spent in the surgical suite and restrictions on postoperative activity, making secondary intention healing more appealing. An additional advantage is obviation of the need to remove additional tissue in the form of Burow triangles, which would lead to a longer wound. The major disadvantage of secondary intention healing is longer time to wound maturity; we often minimize this disadvantage with purse-string closure to decrease the size of the wound defect, which can be done quickly and without removing additional tissue.

The Technique

An elderly man had 3 nonmelanoma skin cancers—all on the dorsal aspect of the left hand—that were treated on the same day, leaving 3 similar wound defects after Mohs micrographic surgery. The wound defects (distal to proximal) measured 12 mm, 12 mm, and 10 mm in diameter (Figure 1) and were repaired by primary closure, secondary intention, and purse-string circumferential closure, respectively. Purse-string closure¹ was performed with a 4-0 polyglactin 901 suture and left to heal without external sutures (Figure 2). Figure 3 shows the 3 types of repairs immediately following closure. All wounds healed with excellent and essentially equivalent cosmetic results, with excellent patient satisfaction at 6-month follow-up (Figure 4).

Practical Implications

Our case illustrates different modalities of wound repair during precisely the same time frame and essentially on the same location. Skin of the dorsal hand often is tight; depending on the size of the defect, large primary closure can be tedious to perform, can lead to increased wound tension and risk of dehiscence, and can be uncomfortable for the patient during healing. However, primary closure typically will lead to faster healing.

Secondary intention healing and purse-string closure require less surgery and therefore cost less; these modalities yield similar cosmesis and satisfaction. In the appropriate context, secondary intention has been highlighted as a suitable alternative to primary closure^2-4; in our experience (and that of others⁵), patient satisfaction is not diminished with healing by secondary intention. Purse-string closure also can minimize wound size and healing time.

For small shallow wounds on the dorsal hand, dermatologic surgeons should have confidence that secondary intention healing, with or without wound reduction using purse-string repair, likely will lead to acceptable cosmetic and functional results. Of course, repair should be tailored to the circumstances and wishes of the individual patient.

A wide range of products derived from bees, including honey, propolis, bee pollen, bee bread, royal jelly, beeswax, and bee venom, have been used since ancient times for medical purposes.¹ Specifically, bee venom has been used in traditional medicine to treat multiple disorders, including arthritis, cancer, pain, rheumatism, and skin diseases.^2,3 The primary active constituent of bee venom is melittin, an amphiphilic peptide containing 26 amino acid residues and known to impart anti-inflammatory, antibacterial, analgesic, and anticancer effects.^4-7 Additional anti-inflammatory compounds found in bee venom include adolapin, apamin, and phospholipase A2; melittin and phospholipase A2 are also capable of delivering pro-inflammatory activity.^8,9

nedomacki/iStock/Getty Images

The anti-aging, anti-inflammatory, and antibacterial properties of bee venom have been cited as justification for its use as a cosmetic ingredient.¹⁰ In experimental studies, antinociceptive and anti-inflammatory effects have been reported.¹¹ Bee venom phospholipase A2 has also demonstrated notable success in vitro and in vivo in conferring immunomodulatory effects and is a key component in past and continuing use of bee venom therapy for immune-related disorders, such as arthritis.¹²

A recent review of the biomedical literature by Nguyen et al. reveals that bee venom is one of the key ingredients in the booming Korean cosmeceuticals industry.¹³ Kim et al. reviewed the therapeutic applications of bee venom in 2019, noting that anti-inflammatory, antiapoptotic, antifibrotic, antimicrobial, and anticancer properties have been cited in experimental and clinical reports, with cutaneous treatments ranging from acne, alopecia, and atopic dermatitis to melanoma, morphea, photoaging, psoriasis, vitiligo, wounds, and wrinkles.1⁴ This column focuses on the use of bee venom in acupuncture and wound healing, as well as some other potential applications of this bee product used for millennia.

Acupuncture

Bee venom acupuncture entails the application of bee venom to the tips of acupuncture needles, which are then applied to acupoints on the skin. Cherniack and Govorushko state that several small studies in humans show that bee venom acupuncture has been used effectively to treat various musculoskeletal and neurological conditions.⁸ 

In 2016, Sur et al. explored the effects of bee venom acupuncture on atopic dermatitis in a mouse model with lesions induced by trimellitic anhydride. Bee venom treatment was found to significantly ease inflammation, lesion thickness, and lymph node weight. Suppression of T-cell proliferation and infiltration, Th1 and Th2 cytokine synthesis, and interleukin (IL)-4 and immunoglobulin E (IgE) production was also noted.¹⁵

A case report by Hwang and Kim in 2018 described the successful use of bee venom acupuncture in the treatment of a 64-year-old Korean woman with circumscribed morphea resulting from systemic sclerosis. Subcutaneous bee venom acupuncture along the margins resolved pruritus through 2 months of follow-up.¹¹

Wound healing

A study by Hozzein et al. in 2018 on protecting functional macrophages from apoptosis and improving Nrf2, Ang-1, and Tie-2 signaling in diabetic wound healing in mice revealed that bee venom supports immune function, thus promoting healing from diabetic wounds.(16) Previously, this team had shown that bee venom facilitates wound healing in diabetic mice by inhibiting the activation of transcription factor-3 and inducible nitric oxide synthase-mediated stress.¹⁷

In early 2020, Nakashima et al. reported their results showing that bee venom-derived phospholipase A2 augmented poly(I:C)-induced activation in human keratinocytes, suggesting that it could play a role in wound healing promotion through enhanced TLR3 responses.¹⁸

Alopecia

A 2016 study on the effect of bee venom on alopecia in C57BL/6 mice by Park et al. showed that the bee toxin dose-dependently stimulated proliferation of several growth factors, including fibroblast growth factors 2 and 7, as compared with the control group. Bee venom also suppressed transition from the anagen to catagen phases, nurtured hair growth, and presented the potential as a strong 5α-reductase inhibitor.¹⁹

Anticancer and anti-arthritic activity

In 2007, Son et al. reported that the various peptides (melittin, apamin, adolapin, the mast-cell-degranulating peptide), enzymes (i.e., phospholipase A2), as well as biologically active amines (i.e., histamine and epinephrine) and nonpeptide components in bee venom are thought to account for multiple pharmaceutical properties that yield anti-arthritis, antinociceptive, and anticancer effects.²

In 2019, Lim et al. determined that bee venom and melittin inhibited the growth and migration of melanoma cells (B16F10, A375SM, and SK-MEL-28) by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways. They concluded that melittin has the potential for use in preventing and treating malignant melanoma.⁴

Phototoxicity

Heo et al. conducted phototoxicity and skin sensitization studies of bee venom, as well as a bee venom from which they removed phospholipase A2, and determined that both were nonphototoxic substances and did not act as sensitizers.²⁰

Han et al. assessed the skin safety of bee venom on tests in healthy male Hartley guinea pigs in 2017 and found that bee venom application engendered no toxic reactions, including any signs of cutaneous phototoxicity or skin photosensitization, and is likely safe for inclusion as a topical skin care ingredient.¹⁰

Antiwrinkle activity

Han et al. also evaluated the beneficial effects of bee venom serum on facial wrinkles in a small study on humans (22 South Korean women between 30 and 49 years old), finding clinical improvements as seen through reductions in wrinkle count, average wrinkle depth, and total wrinkle area. The authors, noting that this was the first clinical study to assess the results of using bee venom cosmetics on facial skin, also cited the relative safety of the product, which presents nominal irritation potential, and acknowledged its present use in the cosmetics industry.²¹

Conclusion

Bees play a critical role in the web of life as they pollinate approximately one-third of our food. Bee products such as honey, propolis, royal jelly, beeswax, pollen, and venom have also been found to exhibit significant biological activities, including several that benefit the skin. Perhaps counterintuitively, given our awareness of the painful and potentially serious reactions to bee stings, bee venom has also been found to deliver multiple salutary effects. More research is necessary to ascertain the viability of using bee venom as a reliable treatment for the various cutaneous conditions for which it demonstrates potential benefits. Current evidence presents justification for further investigation.

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. Kurek-Górecka A et al. Molecules. 2020 Jan 28;25(3):556.

2. Son DJ et al. Pharmacol Ther. 2007 Aug;115(2):246-70.

3. Lee G, Bae H. Molecules. 2016 May 11;21(5):616.

4. Lim HN et al. Molecules. 2019 Mar 7;24(5):929.

5. Gu H et al. Mol Med Rep. 2018 Oct;18(4):3711-8. 6. You CE et al. Ann Dermatol. 2016 Oct;28(5):593-9. 7. An HJ et al. Int J Mol Med. 2014 Nov;34(5):1341-8. 8. Cherniack EP, Govorushko S. Toxicon. 2018 Nov;154:74-8. 9. Cornara L et al. Front Pharmacol. 2017 Jun 28;8:412.

10. Han SM et al. J Cosmet Dermatol. 2017 Dec;16(4):e68-e75.

11. Hwang JH, Kim KH. Medicine (Baltimore). 2018 Dec;97(49):e13404. 12. Lee G, Bae H. Toxins (Basel). 2016 Feb 22;8(2):48. 13. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):1555-69.

14. Kim H et al. Toxins (Basel). 2019 Jun 27:11(7):374.

15. Sur B et al. BMC Complement Altern Med. 2016 Jan 29;16:38. 16. Hozzein WN et al. Mol Immunol. 2018 Nov;103:322-35. 17. Badr G et al. J Cell Physiol. 2016 Oct;231(10):2159-71. 18. Nakashima A et al. Int Immunol. 2020 May 30;32(6):371-83. 19. Park S et al. Biol Pharm Bull. 2016 Jun 1;39(6):1060-8.

20. Heo Y et al. Evid Based Complement Alternat Med. 2015;2015:157367. 21. Han SM et al. Clin Interv Aging. 2015 Oct 1;10:1587-92.

A wide range of products derived from bees, including honey, propolis, bee pollen, bee bread, royal jelly, beeswax, and bee venom, have been used since ancient times for medical purposes.¹ Specifically, bee venom has been used in traditional medicine to treat multiple disorders, including arthritis, cancer, pain, rheumatism, and skin diseases.^2,3 The primary active constituent of bee venom is melittin, an amphiphilic peptide containing 26 amino acid residues and known to impart anti-inflammatory, antibacterial, analgesic, and anticancer effects.^4-7 Additional anti-inflammatory compounds found in bee venom include adolapin, apamin, and phospholipase A2; melittin and phospholipase A2 are also capable of delivering pro-inflammatory activity.^8,9

nedomacki/iStock/Getty Images

The anti-aging, anti-inflammatory, and antibacterial properties of bee venom have been cited as justification for its use as a cosmetic ingredient.¹⁰ In experimental studies, antinociceptive and anti-inflammatory effects have been reported.¹¹ Bee venom phospholipase A2 has also demonstrated notable success in vitro and in vivo in conferring immunomodulatory effects and is a key component in past and continuing use of bee venom therapy for immune-related disorders, such as arthritis.¹²

A recent review of the biomedical literature by Nguyen et al. reveals that bee venom is one of the key ingredients in the booming Korean cosmeceuticals industry.¹³ Kim et al. reviewed the therapeutic applications of bee venom in 2019, noting that anti-inflammatory, antiapoptotic, antifibrotic, antimicrobial, and anticancer properties have been cited in experimental and clinical reports, with cutaneous treatments ranging from acne, alopecia, and atopic dermatitis to melanoma, morphea, photoaging, psoriasis, vitiligo, wounds, and wrinkles.1⁴ This column focuses on the use of bee venom in acupuncture and wound healing, as well as some other potential applications of this bee product used for millennia.

Acupuncture

Bee venom acupuncture entails the application of bee venom to the tips of acupuncture needles, which are then applied to acupoints on the skin. Cherniack and Govorushko state that several small studies in humans show that bee venom acupuncture has been used effectively to treat various musculoskeletal and neurological conditions.⁸ 

In 2016, Sur et al. explored the effects of bee venom acupuncture on atopic dermatitis in a mouse model with lesions induced by trimellitic anhydride. Bee venom treatment was found to significantly ease inflammation, lesion thickness, and lymph node weight. Suppression of T-cell proliferation and infiltration, Th1 and Th2 cytokine synthesis, and interleukin (IL)-4 and immunoglobulin E (IgE) production was also noted.¹⁵

A case report by Hwang and Kim in 2018 described the successful use of bee venom acupuncture in the treatment of a 64-year-old Korean woman with circumscribed morphea resulting from systemic sclerosis. Subcutaneous bee venom acupuncture along the margins resolved pruritus through 2 months of follow-up.¹¹

Wound healing

A study by Hozzein et al. in 2018 on protecting functional macrophages from apoptosis and improving Nrf2, Ang-1, and Tie-2 signaling in diabetic wound healing in mice revealed that bee venom supports immune function, thus promoting healing from diabetic wounds.(16) Previously, this team had shown that bee venom facilitates wound healing in diabetic mice by inhibiting the activation of transcription factor-3 and inducible nitric oxide synthase-mediated stress.¹⁷

In early 2020, Nakashima et al. reported their results showing that bee venom-derived phospholipase A2 augmented poly(I:C)-induced activation in human keratinocytes, suggesting that it could play a role in wound healing promotion through enhanced TLR3 responses.¹⁸

Alopecia

A 2016 study on the effect of bee venom on alopecia in C57BL/6 mice by Park et al. showed that the bee toxin dose-dependently stimulated proliferation of several growth factors, including fibroblast growth factors 2 and 7, as compared with the control group. Bee venom also suppressed transition from the anagen to catagen phases, nurtured hair growth, and presented the potential as a strong 5α-reductase inhibitor.¹⁹

Anticancer and anti-arthritic activity

In 2007, Son et al. reported that the various peptides (melittin, apamin, adolapin, the mast-cell-degranulating peptide), enzymes (i.e., phospholipase A2), as well as biologically active amines (i.e., histamine and epinephrine) and nonpeptide components in bee venom are thought to account for multiple pharmaceutical properties that yield anti-arthritis, antinociceptive, and anticancer effects.²

In 2019, Lim et al. determined that bee venom and melittin inhibited the growth and migration of melanoma cells (B16F10, A375SM, and SK-MEL-28) by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways. They concluded that melittin has the potential for use in preventing and treating malignant melanoma.⁴

Phototoxicity

Heo et al. conducted phototoxicity and skin sensitization studies of bee venom, as well as a bee venom from which they removed phospholipase A2, and determined that both were nonphototoxic substances and did not act as sensitizers.²⁰

Han et al. assessed the skin safety of bee venom on tests in healthy male Hartley guinea pigs in 2017 and found that bee venom application engendered no toxic reactions, including any signs of cutaneous phototoxicity or skin photosensitization, and is likely safe for inclusion as a topical skin care ingredient.¹⁰

Antiwrinkle activity

Han et al. also evaluated the beneficial effects of bee venom serum on facial wrinkles in a small study on humans (22 South Korean women between 30 and 49 years old), finding clinical improvements as seen through reductions in wrinkle count, average wrinkle depth, and total wrinkle area. The authors, noting that this was the first clinical study to assess the results of using bee venom cosmetics on facial skin, also cited the relative safety of the product, which presents nominal irritation potential, and acknowledged its present use in the cosmetics industry.²¹

Conclusion

Bees play a critical role in the web of life as they pollinate approximately one-third of our food. Bee products such as honey, propolis, royal jelly, beeswax, pollen, and venom have also been found to exhibit significant biological activities, including several that benefit the skin. Perhaps counterintuitively, given our awareness of the painful and potentially serious reactions to bee stings, bee venom has also been found to deliver multiple salutary effects. More research is necessary to ascertain the viability of using bee venom as a reliable treatment for the various cutaneous conditions for which it demonstrates potential benefits. Current evidence presents justification for further investigation.

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. Kurek-Górecka A et al. Molecules. 2020 Jan 28;25(3):556.

2. Son DJ et al. Pharmacol Ther. 2007 Aug;115(2):246-70.

3. Lee G, Bae H. Molecules. 2016 May 11;21(5):616.

4. Lim HN et al. Molecules. 2019 Mar 7;24(5):929.

5. Gu H et al. Mol Med Rep. 2018 Oct;18(4):3711-8. 6. You CE et al. Ann Dermatol. 2016 Oct;28(5):593-9. 7. An HJ et al. Int J Mol Med. 2014 Nov;34(5):1341-8. 8. Cherniack EP, Govorushko S. Toxicon. 2018 Nov;154:74-8. 9. Cornara L et al. Front Pharmacol. 2017 Jun 28;8:412.

10. Han SM et al. J Cosmet Dermatol. 2017 Dec;16(4):e68-e75.

11. Hwang JH, Kim KH. Medicine (Baltimore). 2018 Dec;97(49):e13404. 12. Lee G, Bae H. Toxins (Basel). 2016 Feb 22;8(2):48. 13. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):1555-69.

14. Kim H et al. Toxins (Basel). 2019 Jun 27:11(7):374.

15. Sur B et al. BMC Complement Altern Med. 2016 Jan 29;16:38. 16. Hozzein WN et al. Mol Immunol. 2018 Nov;103:322-35. 17. Badr G et al. J Cell Physiol. 2016 Oct;231(10):2159-71. 18. Nakashima A et al. Int Immunol. 2020 May 30;32(6):371-83. 19. Park S et al. Biol Pharm Bull. 2016 Jun 1;39(6):1060-8.

20. Heo Y et al. Evid Based Complement Alternat Med. 2015;2015:157367. 21. Han SM et al. Clin Interv Aging. 2015 Oct 1;10:1587-92.

A wide range of products derived from bees, including honey, propolis, bee pollen, bee bread, royal jelly, beeswax, and bee venom, have been used since ancient times for medical purposes.¹ Specifically, bee venom has been used in traditional medicine to treat multiple disorders, including arthritis, cancer, pain, rheumatism, and skin diseases.^2,3 The primary active constituent of bee venom is melittin, an amphiphilic peptide containing 26 amino acid residues and known to impart anti-inflammatory, antibacterial, analgesic, and anticancer effects.^4-7 Additional anti-inflammatory compounds found in bee venom include adolapin, apamin, and phospholipase A2; melittin and phospholipase A2 are also capable of delivering pro-inflammatory activity.^8,9

nedomacki/iStock/Getty Images

The anti-aging, anti-inflammatory, and antibacterial properties of bee venom have been cited as justification for its use as a cosmetic ingredient.¹⁰ In experimental studies, antinociceptive and anti-inflammatory effects have been reported.¹¹ Bee venom phospholipase A2 has also demonstrated notable success in vitro and in vivo in conferring immunomodulatory effects and is a key component in past and continuing use of bee venom therapy for immune-related disorders, such as arthritis.¹²

A recent review of the biomedical literature by Nguyen et al. reveals that bee venom is one of the key ingredients in the booming Korean cosmeceuticals industry.¹³ Kim et al. reviewed the therapeutic applications of bee venom in 2019, noting that anti-inflammatory, antiapoptotic, antifibrotic, antimicrobial, and anticancer properties have been cited in experimental and clinical reports, with cutaneous treatments ranging from acne, alopecia, and atopic dermatitis to melanoma, morphea, photoaging, psoriasis, vitiligo, wounds, and wrinkles.1⁴ This column focuses on the use of bee venom in acupuncture and wound healing, as well as some other potential applications of this bee product used for millennia.

Acupuncture

Bee venom acupuncture entails the application of bee venom to the tips of acupuncture needles, which are then applied to acupoints on the skin. Cherniack and Govorushko state that several small studies in humans show that bee venom acupuncture has been used effectively to treat various musculoskeletal and neurological conditions.⁸ 

In 2016, Sur et al. explored the effects of bee venom acupuncture on atopic dermatitis in a mouse model with lesions induced by trimellitic anhydride. Bee venom treatment was found to significantly ease inflammation, lesion thickness, and lymph node weight. Suppression of T-cell proliferation and infiltration, Th1 and Th2 cytokine synthesis, and interleukin (IL)-4 and immunoglobulin E (IgE) production was also noted.¹⁵

A case report by Hwang and Kim in 2018 described the successful use of bee venom acupuncture in the treatment of a 64-year-old Korean woman with circumscribed morphea resulting from systemic sclerosis. Subcutaneous bee venom acupuncture along the margins resolved pruritus through 2 months of follow-up.¹¹

Wound healing

A study by Hozzein et al. in 2018 on protecting functional macrophages from apoptosis and improving Nrf2, Ang-1, and Tie-2 signaling in diabetic wound healing in mice revealed that bee venom supports immune function, thus promoting healing from diabetic wounds.(16) Previously, this team had shown that bee venom facilitates wound healing in diabetic mice by inhibiting the activation of transcription factor-3 and inducible nitric oxide synthase-mediated stress.¹⁷

In early 2020, Nakashima et al. reported their results showing that bee venom-derived phospholipase A2 augmented poly(I:C)-induced activation in human keratinocytes, suggesting that it could play a role in wound healing promotion through enhanced TLR3 responses.¹⁸

Alopecia

A 2016 study on the effect of bee venom on alopecia in C57BL/6 mice by Park et al. showed that the bee toxin dose-dependently stimulated proliferation of several growth factors, including fibroblast growth factors 2 and 7, as compared with the control group. Bee venom also suppressed transition from the anagen to catagen phases, nurtured hair growth, and presented the potential as a strong 5α-reductase inhibitor.¹⁹

Anticancer and anti-arthritic activity

In 2007, Son et al. reported that the various peptides (melittin, apamin, adolapin, the mast-cell-degranulating peptide), enzymes (i.e., phospholipase A2), as well as biologically active amines (i.e., histamine and epinephrine) and nonpeptide components in bee venom are thought to account for multiple pharmaceutical properties that yield anti-arthritis, antinociceptive, and anticancer effects.²

In 2019, Lim et al. determined that bee venom and melittin inhibited the growth and migration of melanoma cells (B16F10, A375SM, and SK-MEL-28) by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways. They concluded that melittin has the potential for use in preventing and treating malignant melanoma.⁴

Phototoxicity

Heo et al. conducted phototoxicity and skin sensitization studies of bee venom, as well as a bee venom from which they removed phospholipase A2, and determined that both were nonphototoxic substances and did not act as sensitizers.²⁰

Han et al. assessed the skin safety of bee venom on tests in healthy male Hartley guinea pigs in 2017 and found that bee venom application engendered no toxic reactions, including any signs of cutaneous phototoxicity or skin photosensitization, and is likely safe for inclusion as a topical skin care ingredient.¹⁰

Antiwrinkle activity

Han et al. also evaluated the beneficial effects of bee venom serum on facial wrinkles in a small study on humans (22 South Korean women between 30 and 49 years old), finding clinical improvements as seen through reductions in wrinkle count, average wrinkle depth, and total wrinkle area. The authors, noting that this was the first clinical study to assess the results of using bee venom cosmetics on facial skin, also cited the relative safety of the product, which presents nominal irritation potential, and acknowledged its present use in the cosmetics industry.²¹

Conclusion

Bees play a critical role in the web of life as they pollinate approximately one-third of our food. Bee products such as honey, propolis, royal jelly, beeswax, pollen, and venom have also been found to exhibit significant biological activities, including several that benefit the skin. Perhaps counterintuitively, given our awareness of the painful and potentially serious reactions to bee stings, bee venom has also been found to deliver multiple salutary effects. More research is necessary to ascertain the viability of using bee venom as a reliable treatment for the various cutaneous conditions for which it demonstrates potential benefits. Current evidence presents justification for further investigation.

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. Kurek-Górecka A et al. Molecules. 2020 Jan 28;25(3):556.

2. Son DJ et al. Pharmacol Ther. 2007 Aug;115(2):246-70.

3. Lee G, Bae H. Molecules. 2016 May 11;21(5):616.

4. Lim HN et al. Molecules. 2019 Mar 7;24(5):929.

5. Gu H et al. Mol Med Rep. 2018 Oct;18(4):3711-8. 6. You CE et al. Ann Dermatol. 2016 Oct;28(5):593-9. 7. An HJ et al. Int J Mol Med. 2014 Nov;34(5):1341-8. 8. Cherniack EP, Govorushko S. Toxicon. 2018 Nov;154:74-8. 9. Cornara L et al. Front Pharmacol. 2017 Jun 28;8:412.

10. Han SM et al. J Cosmet Dermatol. 2017 Dec;16(4):e68-e75.

11. Hwang JH, Kim KH. Medicine (Baltimore). 2018 Dec;97(49):e13404. 12. Lee G, Bae H. Toxins (Basel). 2016 Feb 22;8(2):48. 13. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):1555-69.

14. Kim H et al. Toxins (Basel). 2019 Jun 27:11(7):374.

15. Sur B et al. BMC Complement Altern Med. 2016 Jan 29;16:38. 16. Hozzein WN et al. Mol Immunol. 2018 Nov;103:322-35. 17. Badr G et al. J Cell Physiol. 2016 Oct;231(10):2159-71. 18. Nakashima A et al. Int Immunol. 2020 May 30;32(6):371-83. 19. Park S et al. Biol Pharm Bull. 2016 Jun 1;39(6):1060-8.

20. Heo Y et al. Evid Based Complement Alternat Med. 2015;2015:157367. 21. Han SM et al. Clin Interv Aging. 2015 Oct 1;10:1587-92.

Practice Gap

Management of surgical wounds is a critical component of postsurgical care for patients during recovery at home.¹ However, postoperative wound care can be troublesome, time consuming, and expensive. Common problems with current standard dressings include an increased risk for infection, pain, and wound damage with frequent dressing changes.^2-4

Patients often are unable to take proper care of wounds themselves and may not have the financial means or social support to have others assist them.^4-6 For these patients, the option of a hassle-free dressing that they can leave on until their follow-up appointment is preferred. In our experience, what we call a 24-7 bandage has been remarkably successful in patients who are vulnerable to wound complications.

We report a comfortable, effective, and simple technique for wound dressings after dermatologic surgery.

The Technique

In Figure 1, we demonstrate a simple dressing technique that can be used to optimize wound healing in patients unable to provide adequate wound care for themselves:

1. The surgical site is covered with mupirocin ointment, followed by bismuth tribromophenate gauze (Figure 1A). The bismuth-impregnated gauze helps make the dressing nonadherent and moderately occlusive. It also adds moisture to the wound bed.

2. The gauze is then covered with excess mupirocin. A nonadherent dressing is applied (Figure 1B).

3. The entire area is covered with gauze and cover-roll nonlatex bandaging tape to ensure maximum adhesion (Figures 1C and 1D).

4. When the surgical site is on an extremity, it is wrapped in a self-adherent wrap or bandage roll to prevent clothing from pulling the tape loose.

Once this dressing technique is performed in the office, the bandage requires no wound care at home other than ensuring that the bandage is kept dry. The 24-7 dressing can be left on the surgical site for 7 days until the follow-up appointment. If necessary, it also can be applied for a second week after bolster removal or for multiple weeks following advanced flap repair.

Our patients find this dressing comfortable and unobtrusive. It is easy for the staff to apply and inexpensive.

Practical Implications

We have treated approximately 200 patients with the 24-7 dressing technique. Our experience is that these patients demonstrated an excellent aesthetic outcome without complications (Figure 2). We have successfully utilized the dressing in several anatomic locations, including the arms, legs, neck, face, and scalp. We use mupirocin for its antimicrobial activity, but we have not performed a study at our clinic looking at the difference between rate of infection and wound healing using mupirocin vs petrolatum. We prefer adding bulk gauze under the tape and leaving the dressing on for 7 days. We seldom have issues with bleeding, and if there is an issue, the patient is told to come back to our clinic so we can change the bandage for them.

This dressing technique is cost-effective to the patient and clinical staff, provides protection from potential injury to the sutures, decreases the risk for infection, and removes the stress and burden on the patient and family of frequent dressing changes. Furthermore, by preventing patient manipulation and frequent removal of the dressing, the wound retains adequate moisture during healing. This technique also can be applied to a variety of outpatient procedures other than Mohs micrographic surgery.

We hope that our colleagues find this 24-7 dressing technique for dressing wounds after dermatologic surgery useful in patient populations vulnerable to wound complications.

Practice Gap

Management of surgical wounds is a critical component of postsurgical care for patients during recovery at home.¹ However, postoperative wound care can be troublesome, time consuming, and expensive. Common problems with current standard dressings include an increased risk for infection, pain, and wound damage with frequent dressing changes.^2-4

Patients often are unable to take proper care of wounds themselves and may not have the financial means or social support to have others assist them.^4-6 For these patients, the option of a hassle-free dressing that they can leave on until their follow-up appointment is preferred. In our experience, what we call a 24-7 bandage has been remarkably successful in patients who are vulnerable to wound complications.

We report a comfortable, effective, and simple technique for wound dressings after dermatologic surgery.

The Technique

In Figure 1, we demonstrate a simple dressing technique that can be used to optimize wound healing in patients unable to provide adequate wound care for themselves:

1. The surgical site is covered with mupirocin ointment, followed by bismuth tribromophenate gauze (Figure 1A). The bismuth-impregnated gauze helps make the dressing nonadherent and moderately occlusive. It also adds moisture to the wound bed.

2. The gauze is then covered with excess mupirocin. A nonadherent dressing is applied (Figure 1B).

3. The entire area is covered with gauze and cover-roll nonlatex bandaging tape to ensure maximum adhesion (Figures 1C and 1D).

4. When the surgical site is on an extremity, it is wrapped in a self-adherent wrap or bandage roll to prevent clothing from pulling the tape loose.

Once this dressing technique is performed in the office, the bandage requires no wound care at home other than ensuring that the bandage is kept dry. The 24-7 dressing can be left on the surgical site for 7 days until the follow-up appointment. If necessary, it also can be applied for a second week after bolster removal or for multiple weeks following advanced flap repair.

Our patients find this dressing comfortable and unobtrusive. It is easy for the staff to apply and inexpensive.

Practical Implications

We have treated approximately 200 patients with the 24-7 dressing technique. Our experience is that these patients demonstrated an excellent aesthetic outcome without complications (Figure 2). We have successfully utilized the dressing in several anatomic locations, including the arms, legs, neck, face, and scalp. We use mupirocin for its antimicrobial activity, but we have not performed a study at our clinic looking at the difference between rate of infection and wound healing using mupirocin vs petrolatum. We prefer adding bulk gauze under the tape and leaving the dressing on for 7 days. We seldom have issues with bleeding, and if there is an issue, the patient is told to come back to our clinic so we can change the bandage for them.

This dressing technique is cost-effective to the patient and clinical staff, provides protection from potential injury to the sutures, decreases the risk for infection, and removes the stress and burden on the patient and family of frequent dressing changes. Furthermore, by preventing patient manipulation and frequent removal of the dressing, the wound retains adequate moisture during healing. This technique also can be applied to a variety of outpatient procedures other than Mohs micrographic surgery.

We hope that our colleagues find this 24-7 dressing technique for dressing wounds after dermatologic surgery useful in patient populations vulnerable to wound complications.

Practice Gap

Management of surgical wounds is a critical component of postsurgical care for patients during recovery at home.¹ However, postoperative wound care can be troublesome, time consuming, and expensive. Common problems with current standard dressings include an increased risk for infection, pain, and wound damage with frequent dressing changes.^2-4

Patients often are unable to take proper care of wounds themselves and may not have the financial means or social support to have others assist them.^4-6 For these patients, the option of a hassle-free dressing that they can leave on until their follow-up appointment is preferred. In our experience, what we call a 24-7 bandage has been remarkably successful in patients who are vulnerable to wound complications.

We report a comfortable, effective, and simple technique for wound dressings after dermatologic surgery.

The Technique

In Figure 1, we demonstrate a simple dressing technique that can be used to optimize wound healing in patients unable to provide adequate wound care for themselves:

1. The surgical site is covered with mupirocin ointment, followed by bismuth tribromophenate gauze (Figure 1A). The bismuth-impregnated gauze helps make the dressing nonadherent and moderately occlusive. It also adds moisture to the wound bed.

2. The gauze is then covered with excess mupirocin. A nonadherent dressing is applied (Figure 1B).

3. The entire area is covered with gauze and cover-roll nonlatex bandaging tape to ensure maximum adhesion (Figures 1C and 1D).

4. When the surgical site is on an extremity, it is wrapped in a self-adherent wrap or bandage roll to prevent clothing from pulling the tape loose.

Once this dressing technique is performed in the office, the bandage requires no wound care at home other than ensuring that the bandage is kept dry. The 24-7 dressing can be left on the surgical site for 7 days until the follow-up appointment. If necessary, it also can be applied for a second week after bolster removal or for multiple weeks following advanced flap repair.

Our patients find this dressing comfortable and unobtrusive. It is easy for the staff to apply and inexpensive.

Practical Implications

We have treated approximately 200 patients with the 24-7 dressing technique. Our experience is that these patients demonstrated an excellent aesthetic outcome without complications (Figure 2). We have successfully utilized the dressing in several anatomic locations, including the arms, legs, neck, face, and scalp. We use mupirocin for its antimicrobial activity, but we have not performed a study at our clinic looking at the difference between rate of infection and wound healing using mupirocin vs petrolatum. We prefer adding bulk gauze under the tape and leaving the dressing on for 7 days. We seldom have issues with bleeding, and if there is an issue, the patient is told to come back to our clinic so we can change the bandage for them.

This dressing technique is cost-effective to the patient and clinical staff, provides protection from potential injury to the sutures, decreases the risk for infection, and removes the stress and burden on the patient and family of frequent dressing changes. Furthermore, by preventing patient manipulation and frequent removal of the dressing, the wound retains adequate moisture during healing. This technique also can be applied to a variety of outpatient procedures other than Mohs micrographic surgery.

We hope that our colleagues find this 24-7 dressing technique for dressing wounds after dermatologic surgery useful in patient populations vulnerable to wound complications.

The upper lip poses challenges during reconstruction. Distortion of well-defined anatomic structures, including the vermilion border, oral commissures, Cupid’s bow, and philtrum, leads to noticeable deformities. Furthermore, maintenance of upper and lower lip function is essential for verbal communication, facial expression, and controlled opening of the oral cavity.

Similar to a prior review focused on the lower lip,¹ we conducted a review of the literature using the PubMed database (1976-2017) and the following search terms: upper lip, lower lip, anatomy, comparison, cadaver, histology, local flap, and reconstruction. We reviewed studies that assessed anatomic and histologic characteristics of the upper and the lower lips, function of the upper lip, mechanics of local flaps, and upper lip reconstruction techniques including local flaps and regional flaps. Articles with an emphasis on free flaps were excluded.

The initial search resulted in 1326 articles. Of these, 1201 were excluded after abstracts were screened. Full-text review of the remaining 125 articles resulted in exclusion of 85 papers (9 foreign language, 4 duplicates, and 72 irrelevant). Among the 40 articles eligible for inclusion, 12 articles discussed anatomy and histology of the upper lip, 9 examined function of the upper lip, and 19 reviewed available techniques for reconstruction of the upper lip.

In this article, we review the anatomy and function of the upper lip as well as various repair techniques to provide the reconstructive surgeon with greater familiarity with the local flaps and an algorithmic approach for upper lip reconstruction.

Anatomic Characteristics of the Upper Lip

The muscular component of the upper lip primarily is comprised of the orbicularis oris (OO) muscle divided into 2 distinct concentric components: pars peripheralis and pars marginalis.^2,3 It is discontinuous in some individuals.⁴ Although OO is the primary muscle of the lower lip, the upper lip is remarkably complex. Orbicularis oris and 3 additional muscles contribute to upper lip function: depressor septi nasi, the alar portion of the nasalis, and levator labii superioris alaeque nasi (LLSAN).⁵

The modiolus, a muscular structure located just lateral to the commissures, serves as a convergence point for facial muscle animation and lip function while distributing contraction forces between the lips and face.⁶ It is imperative to preserve its location in reconstruction to allow for good functional and aesthetic outcomes.

The upper lip is divided into 3 distinct aesthetic subunits: the philtrum and 1 lateral subunit on each side.^7,8 Its unique surface features include the Cupid’s bow, vermilion tubercle, and philtral columns. The philtral columns are created by the dermal insertion on each side of the OO, which originates from the modiolus, decussates, and inserts into the skin of the contralateral philtral groove.^2,9-11 The OO has additional insertions into the dermis lateral to the philtrum.⁵ During its course across the midline, it decreases its insertions, leading to the formation and thinness of the philtral dimple.⁹ The philtral shape primarily is due to the intermingling of LLSAN and the pars peripheralis in an axial plane. The LLSAN enters superolateral to the ipsilateral philtral ridge and courses along this ridge to contribute to the philtral shape.² Formation of the philtrum’s contour arises from the opposing force of both muscles pulling the skin in opposite directions.^2,5 The vermilion tubercle arises from the dermal insertion of the pars marginalis originating from the ipsilateral modiolus and follows the vermilion border.² The Cupid’s bow is part of the white roll at the vermilion-cutaneous junction produced by the anterior projection of the pars peripheralis.¹⁰ The complex anatomy of this structure explains the intricacy of lip reconstructions in this area.

Function of the Upper Lip

Although the primary purpose of OO is sphincteric function, the upper lip’s key role is coverage of dentition and facial animation.¹² The latter is achieved through the relationship of multiple muscles, including levator labii superioris, levator septi nasi, risorius, zygomaticus minor, zygomaticus major, levator anguli oris, and buccinator.^7,13-17 Their smooth coordination results in various facial expressions. In comparison, the lower lip is critical for preservation of oral competence, prevention of drooling, eating, and speech due to the actions of OO and vertical support from the mentalis muscle.^1,18-22

Reconstructive Methods for the Upper Lip

Multiple options are available for reconstruction of upper lip defects, with the aim to preserve facial animation and coverage of dentition. When animation muscles are involved, restoring function is the goal, which can be achieved by placing sutures to reapproximate the muscle edges in smaller defects or anchor the remaining muscle edge to preserve deep structures in larger defects, respecting the vector of contraction and attempting simulation of the muscle function. Additionally, restoration of the continuity of OO also is important for good aesthetic and functional outcomes.

Janis²³ proposed the rule of thirds to approach upper and lower lip reconstruction. Using these rules, we briefly analyze the available flaps focusing on animation, OO restoration, preservation of the modiolus position, and sensation for each (eTable).

Nasolabial (ie, melolabial) flaps are suggested for repair of defects up to one-third of the upper lip, especially when the vermilion is unaffected, or in lateral defects with or without commissure involvement.^7,24-28 This flap is based on the facial artery and may be used as a direct transposition, V-Y advancement, or island flap with good aesthetic and functional outcomes (Figure 1).^29,30 There is limited literature regarding the effects on animation. However, it may be beneficial in avoiding microstomia, as regional tissue is transferred from the cheek area, maintaining upper lip length. Additionally, the location of the modiolus often is unaffected, especially when the flap is harvested above the level of the muscle, providing superior facial animation function. Flap design is critical in areas lateral to the commissure and over the modiolus, as distortion of its position can occur.²⁶ Similar to crescentic advancement, it is important to exercise caution in male patients, as non–hair-bearing tissue can be transferred to the upper lip. Reported adverse outcomes of the nasolabial flap include a thin flat upper lip, obliteration of the Cupid’s bow, and hypoesthesia that may improve over time.³⁰

The Yu flap, a sensate single-stage rotational advancement flap, can be used in a variety of ways for repair of upper lip defects, depending on the size and location.²⁶ Lateral defects up to one-half of the upper lip should be repaired with a unilateral reverse Yu flap, central defects up to one-half of the upper lip can be reconstructed with bilateral reverse Yu flaps, and defects up to two-thirds of the upper lip can be repaired with bilateral Yu flaps. This flap restores OO continuity and thus preserves sphincter function, minimizes oral incompetence, and has a low risk of microstomia. The muscles of facial animation are preserved, yet the modiolus is not. Good aesthetic outcomes have been reported depending on the location of the Yu flap because scars can be placed in the nasolabial sulcus, commissures, or medially to recreate the philtrum.²⁶

The Estlander flap is a single-stage flap utilizing donor tissue from the opposing lip for reconstruction of lateral defects up to two-thirds of the upper lip with commissure and philtrum involvement (Figure 3).^8,23,32 It is an insensate flap that alters the position of the modiolus, distorting oral and facial animation.²³ The superomedial position of the modiolus is better tolerated in the upper lip because it increases the relaxation tone of the lower lip and simulates the vector of contraction of major animation muscles, positively impacting the sphincteric function of the reconstructed lip. Sphincteric function action is not as impaired compared with the lower lip because the new position of the modiolus tightens the lower lip and prevents drooling.³³ When designing the flap, one should consider that the inferior labial artery has been reported to remain with 10 mm of the superior border of the lower lip; therefore, pedicles of the Abbe and Estlander flaps should be at least 10 mm from the vermilion border to preserve vascular supply.^34,35

The Karapandzic flap, a modified Gilles fan flap, can be employed for repair of central defects up to two-thirds of the upper lip.^{8,23,32,36-39} The bilateral advancement of full-thickness adjacent tissue edges preserves neurovascular structures allowing sensation and restores OO continuation.⁴⁰ Prior studies have shown the average distance of the superior labial artery emergence from the facial artery and labial commissure is 12.1 mm; thus, at least 12.1 mm of tissue from the commissure should be preserved to prevent vascular compromise in Karapandzic flaps.^34,35 The modiolus position is altered, and facial animation muscles are disrupted, consequently impairing facial animation, especially elevation of the lip.³⁶ The philtrum is obliterated, producing unfavorable aesthetic outcomes. Finally, the upper lip is thinner and smaller in volume than the lower lip, increasing the risk for microstomia compared with the lower lip with a similar reconstructive technique.³⁶

Defects larger than two-thirds of the upper lip require a Bernard Burrow flap, distant free flap, or combination of multiple regional and local flaps dependent on the characteristics of the defect.^36,41 Distant free flaps are beyond the scope of this review. The Bernard Burrow flap consists of bilaterally opposing cheek advancement flaps. It is an insensate flap that does not restore OO continuity, producing minimal muscle function and poor animation. Microstomia is a common adverse outcome.³⁶

Conclusion

Comprehensive understanding of labial anatomy and its intimate relationship to function and aesthetics of the upper lip are critical. Flap anatomy and mechanics are key factors for successful reconstruction. The purpose of this article is to utilize knowledge of histology, anatomy, and function of the upper lip to improve the outcomes of reconstruction. The Abbe flap often is utilized for reconstruction of the philtrum and central upper lip defects, though it is a less desirable option for lower lip reconstruction. The Karapandzic flap, while sensate and restorative of OO continuity, may have less optimal functional and cosmetic results compared with its use in the lower lip. Regarding lateral defects involving the commissure, the Estlander flap provides a reasonable option for the upper lip when compared with its use in lower lip defects, where outcomes are usually inferior.

The upper lip poses challenges during reconstruction. Distortion of well-defined anatomic structures, including the vermilion border, oral commissures, Cupid’s bow, and philtrum, leads to noticeable deformities. Furthermore, maintenance of upper and lower lip function is essential for verbal communication, facial expression, and controlled opening of the oral cavity.

Similar to a prior review focused on the lower lip,¹ we conducted a review of the literature using the PubMed database (1976-2017) and the following search terms: upper lip, lower lip, anatomy, comparison, cadaver, histology, local flap, and reconstruction. We reviewed studies that assessed anatomic and histologic characteristics of the upper and the lower lips, function of the upper lip, mechanics of local flaps, and upper lip reconstruction techniques including local flaps and regional flaps. Articles with an emphasis on free flaps were excluded.

The initial search resulted in 1326 articles. Of these, 1201 were excluded after abstracts were screened. Full-text review of the remaining 125 articles resulted in exclusion of 85 papers (9 foreign language, 4 duplicates, and 72 irrelevant). Among the 40 articles eligible for inclusion, 12 articles discussed anatomy and histology of the upper lip, 9 examined function of the upper lip, and 19 reviewed available techniques for reconstruction of the upper lip.

In this article, we review the anatomy and function of the upper lip as well as various repair techniques to provide the reconstructive surgeon with greater familiarity with the local flaps and an algorithmic approach for upper lip reconstruction.

Anatomic Characteristics of the Upper Lip

The muscular component of the upper lip primarily is comprised of the orbicularis oris (OO) muscle divided into 2 distinct concentric components: pars peripheralis and pars marginalis.^2,3 It is discontinuous in some individuals.⁴ Although OO is the primary muscle of the lower lip, the upper lip is remarkably complex. Orbicularis oris and 3 additional muscles contribute to upper lip function: depressor septi nasi, the alar portion of the nasalis, and levator labii superioris alaeque nasi (LLSAN).⁵

The modiolus, a muscular structure located just lateral to the commissures, serves as a convergence point for facial muscle animation and lip function while distributing contraction forces between the lips and face.⁶ It is imperative to preserve its location in reconstruction to allow for good functional and aesthetic outcomes.

The upper lip is divided into 3 distinct aesthetic subunits: the philtrum and 1 lateral subunit on each side.^7,8 Its unique surface features include the Cupid’s bow, vermilion tubercle, and philtral columns. The philtral columns are created by the dermal insertion on each side of the OO, which originates from the modiolus, decussates, and inserts into the skin of the contralateral philtral groove.^2,9-11 The OO has additional insertions into the dermis lateral to the philtrum.⁵ During its course across the midline, it decreases its insertions, leading to the formation and thinness of the philtral dimple.⁹ The philtral shape primarily is due to the intermingling of LLSAN and the pars peripheralis in an axial plane. The LLSAN enters superolateral to the ipsilateral philtral ridge and courses along this ridge to contribute to the philtral shape.² Formation of the philtrum’s contour arises from the opposing force of both muscles pulling the skin in opposite directions.^2,5 The vermilion tubercle arises from the dermal insertion of the pars marginalis originating from the ipsilateral modiolus and follows the vermilion border.² The Cupid’s bow is part of the white roll at the vermilion-cutaneous junction produced by the anterior projection of the pars peripheralis.¹⁰ The complex anatomy of this structure explains the intricacy of lip reconstructions in this area.

Function of the Upper Lip

Although the primary purpose of OO is sphincteric function, the upper lip’s key role is coverage of dentition and facial animation.¹² The latter is achieved through the relationship of multiple muscles, including levator labii superioris, levator septi nasi, risorius, zygomaticus minor, zygomaticus major, levator anguli oris, and buccinator.^7,13-17 Their smooth coordination results in various facial expressions. In comparison, the lower lip is critical for preservation of oral competence, prevention of drooling, eating, and speech due to the actions of OO and vertical support from the mentalis muscle.^1,18-22

Reconstructive Methods for the Upper Lip

Multiple options are available for reconstruction of upper lip defects, with the aim to preserve facial animation and coverage of dentition. When animation muscles are involved, restoring function is the goal, which can be achieved by placing sutures to reapproximate the muscle edges in smaller defects or anchor the remaining muscle edge to preserve deep structures in larger defects, respecting the vector of contraction and attempting simulation of the muscle function. Additionally, restoration of the continuity of OO also is important for good aesthetic and functional outcomes.

Janis²³ proposed the rule of thirds to approach upper and lower lip reconstruction. Using these rules, we briefly analyze the available flaps focusing on animation, OO restoration, preservation of the modiolus position, and sensation for each (eTable).

Nasolabial (ie, melolabial) flaps are suggested for repair of defects up to one-third of the upper lip, especially when the vermilion is unaffected, or in lateral defects with or without commissure involvement.^7,24-28 This flap is based on the facial artery and may be used as a direct transposition, V-Y advancement, or island flap with good aesthetic and functional outcomes (Figure 1).^29,30 There is limited literature regarding the effects on animation. However, it may be beneficial in avoiding microstomia, as regional tissue is transferred from the cheek area, maintaining upper lip length. Additionally, the location of the modiolus often is unaffected, especially when the flap is harvested above the level of the muscle, providing superior facial animation function. Flap design is critical in areas lateral to the commissure and over the modiolus, as distortion of its position can occur.²⁶ Similar to crescentic advancement, it is important to exercise caution in male patients, as non–hair-bearing tissue can be transferred to the upper lip. Reported adverse outcomes of the nasolabial flap include a thin flat upper lip, obliteration of the Cupid’s bow, and hypoesthesia that may improve over time.³⁰

The Yu flap, a sensate single-stage rotational advancement flap, can be used in a variety of ways for repair of upper lip defects, depending on the size and location.²⁶ Lateral defects up to one-half of the upper lip should be repaired with a unilateral reverse Yu flap, central defects up to one-half of the upper lip can be reconstructed with bilateral reverse Yu flaps, and defects up to two-thirds of the upper lip can be repaired with bilateral Yu flaps. This flap restores OO continuity and thus preserves sphincter function, minimizes oral incompetence, and has a low risk of microstomia. The muscles of facial animation are preserved, yet the modiolus is not. Good aesthetic outcomes have been reported depending on the location of the Yu flap because scars can be placed in the nasolabial sulcus, commissures, or medially to recreate the philtrum.²⁶

The Estlander flap is a single-stage flap utilizing donor tissue from the opposing lip for reconstruction of lateral defects up to two-thirds of the upper lip with commissure and philtrum involvement (Figure 3).^8,23,32 It is an insensate flap that alters the position of the modiolus, distorting oral and facial animation.²³ The superomedial position of the modiolus is better tolerated in the upper lip because it increases the relaxation tone of the lower lip and simulates the vector of contraction of major animation muscles, positively impacting the sphincteric function of the reconstructed lip. Sphincteric function action is not as impaired compared with the lower lip because the new position of the modiolus tightens the lower lip and prevents drooling.³³ When designing the flap, one should consider that the inferior labial artery has been reported to remain with 10 mm of the superior border of the lower lip; therefore, pedicles of the Abbe and Estlander flaps should be at least 10 mm from the vermilion border to preserve vascular supply.^34,35

The Karapandzic flap, a modified Gilles fan flap, can be employed for repair of central defects up to two-thirds of the upper lip.^{8,23,32,36-39} The bilateral advancement of full-thickness adjacent tissue edges preserves neurovascular structures allowing sensation and restores OO continuation.⁴⁰ Prior studies have shown the average distance of the superior labial artery emergence from the facial artery and labial commissure is 12.1 mm; thus, at least 12.1 mm of tissue from the commissure should be preserved to prevent vascular compromise in Karapandzic flaps.^34,35 The modiolus position is altered, and facial animation muscles are disrupted, consequently impairing facial animation, especially elevation of the lip.³⁶ The philtrum is obliterated, producing unfavorable aesthetic outcomes. Finally, the upper lip is thinner and smaller in volume than the lower lip, increasing the risk for microstomia compared with the lower lip with a similar reconstructive technique.³⁶

Defects larger than two-thirds of the upper lip require a Bernard Burrow flap, distant free flap, or combination of multiple regional and local flaps dependent on the characteristics of the defect.^36,41 Distant free flaps are beyond the scope of this review. The Bernard Burrow flap consists of bilaterally opposing cheek advancement flaps. It is an insensate flap that does not restore OO continuity, producing minimal muscle function and poor animation. Microstomia is a common adverse outcome.³⁶

Conclusion

Comprehensive understanding of labial anatomy and its intimate relationship to function and aesthetics of the upper lip are critical. Flap anatomy and mechanics are key factors for successful reconstruction. The purpose of this article is to utilize knowledge of histology, anatomy, and function of the upper lip to improve the outcomes of reconstruction. The Abbe flap often is utilized for reconstruction of the philtrum and central upper lip defects, though it is a less desirable option for lower lip reconstruction. The Karapandzic flap, while sensate and restorative of OO continuity, may have less optimal functional and cosmetic results compared with its use in the lower lip. Regarding lateral defects involving the commissure, the Estlander flap provides a reasonable option for the upper lip when compared with its use in lower lip defects, where outcomes are usually inferior.

The upper lip poses challenges during reconstruction. Distortion of well-defined anatomic structures, including the vermilion border, oral commissures, Cupid’s bow, and philtrum, leads to noticeable deformities. Furthermore, maintenance of upper and lower lip function is essential for verbal communication, facial expression, and controlled opening of the oral cavity.

Similar to a prior review focused on the lower lip,¹ we conducted a review of the literature using the PubMed database (1976-2017) and the following search terms: upper lip, lower lip, anatomy, comparison, cadaver, histology, local flap, and reconstruction. We reviewed studies that assessed anatomic and histologic characteristics of the upper and the lower lips, function of the upper lip, mechanics of local flaps, and upper lip reconstruction techniques including local flaps and regional flaps. Articles with an emphasis on free flaps were excluded.

The initial search resulted in 1326 articles. Of these, 1201 were excluded after abstracts were screened. Full-text review of the remaining 125 articles resulted in exclusion of 85 papers (9 foreign language, 4 duplicates, and 72 irrelevant). Among the 40 articles eligible for inclusion, 12 articles discussed anatomy and histology of the upper lip, 9 examined function of the upper lip, and 19 reviewed available techniques for reconstruction of the upper lip.

In this article, we review the anatomy and function of the upper lip as well as various repair techniques to provide the reconstructive surgeon with greater familiarity with the local flaps and an algorithmic approach for upper lip reconstruction.

Anatomic Characteristics of the Upper Lip

The muscular component of the upper lip primarily is comprised of the orbicularis oris (OO) muscle divided into 2 distinct concentric components: pars peripheralis and pars marginalis.^2,3 It is discontinuous in some individuals.⁴ Although OO is the primary muscle of the lower lip, the upper lip is remarkably complex. Orbicularis oris and 3 additional muscles contribute to upper lip function: depressor septi nasi, the alar portion of the nasalis, and levator labii superioris alaeque nasi (LLSAN).⁵

The modiolus, a muscular structure located just lateral to the commissures, serves as a convergence point for facial muscle animation and lip function while distributing contraction forces between the lips and face.⁶ It is imperative to preserve its location in reconstruction to allow for good functional and aesthetic outcomes.

The upper lip is divided into 3 distinct aesthetic subunits: the philtrum and 1 lateral subunit on each side.^7,8 Its unique surface features include the Cupid’s bow, vermilion tubercle, and philtral columns. The philtral columns are created by the dermal insertion on each side of the OO, which originates from the modiolus, decussates, and inserts into the skin of the contralateral philtral groove.^2,9-11 The OO has additional insertions into the dermis lateral to the philtrum.⁵ During its course across the midline, it decreases its insertions, leading to the formation and thinness of the philtral dimple.⁹ The philtral shape primarily is due to the intermingling of LLSAN and the pars peripheralis in an axial plane. The LLSAN enters superolateral to the ipsilateral philtral ridge and courses along this ridge to contribute to the philtral shape.² Formation of the philtrum’s contour arises from the opposing force of both muscles pulling the skin in opposite directions.^2,5 The vermilion tubercle arises from the dermal insertion of the pars marginalis originating from the ipsilateral modiolus and follows the vermilion border.² The Cupid’s bow is part of the white roll at the vermilion-cutaneous junction produced by the anterior projection of the pars peripheralis.¹⁰ The complex anatomy of this structure explains the intricacy of lip reconstructions in this area.

Function of the Upper Lip

Although the primary purpose of OO is sphincteric function, the upper lip’s key role is coverage of dentition and facial animation.¹² The latter is achieved through the relationship of multiple muscles, including levator labii superioris, levator septi nasi, risorius, zygomaticus minor, zygomaticus major, levator anguli oris, and buccinator.^7,13-17 Their smooth coordination results in various facial expressions. In comparison, the lower lip is critical for preservation of oral competence, prevention of drooling, eating, and speech due to the actions of OO and vertical support from the mentalis muscle.^1,18-22

Reconstructive Methods for the Upper Lip

Multiple options are available for reconstruction of upper lip defects, with the aim to preserve facial animation and coverage of dentition. When animation muscles are involved, restoring function is the goal, which can be achieved by placing sutures to reapproximate the muscle edges in smaller defects or anchor the remaining muscle edge to preserve deep structures in larger defects, respecting the vector of contraction and attempting simulation of the muscle function. Additionally, restoration of the continuity of OO also is important for good aesthetic and functional outcomes.

Janis²³ proposed the rule of thirds to approach upper and lower lip reconstruction. Using these rules, we briefly analyze the available flaps focusing on animation, OO restoration, preservation of the modiolus position, and sensation for each (eTable).

Nasolabial (ie, melolabial) flaps are suggested for repair of defects up to one-third of the upper lip, especially when the vermilion is unaffected, or in lateral defects with or without commissure involvement.^7,24-28 This flap is based on the facial artery and may be used as a direct transposition, V-Y advancement, or island flap with good aesthetic and functional outcomes (Figure 1).^29,30 There is limited literature regarding the effects on animation. However, it may be beneficial in avoiding microstomia, as regional tissue is transferred from the cheek area, maintaining upper lip length. Additionally, the location of the modiolus often is unaffected, especially when the flap is harvested above the level of the muscle, providing superior facial animation function. Flap design is critical in areas lateral to the commissure and over the modiolus, as distortion of its position can occur.²⁶ Similar to crescentic advancement, it is important to exercise caution in male patients, as non–hair-bearing tissue can be transferred to the upper lip. Reported adverse outcomes of the nasolabial flap include a thin flat upper lip, obliteration of the Cupid’s bow, and hypoesthesia that may improve over time.³⁰

The Yu flap, a sensate single-stage rotational advancement flap, can be used in a variety of ways for repair of upper lip defects, depending on the size and location.²⁶ Lateral defects up to one-half of the upper lip should be repaired with a unilateral reverse Yu flap, central defects up to one-half of the upper lip can be reconstructed with bilateral reverse Yu flaps, and defects up to two-thirds of the upper lip can be repaired with bilateral Yu flaps. This flap restores OO continuity and thus preserves sphincter function, minimizes oral incompetence, and has a low risk of microstomia. The muscles of facial animation are preserved, yet the modiolus is not. Good aesthetic outcomes have been reported depending on the location of the Yu flap because scars can be placed in the nasolabial sulcus, commissures, or medially to recreate the philtrum.²⁶

The Estlander flap is a single-stage flap utilizing donor tissue from the opposing lip for reconstruction of lateral defects up to two-thirds of the upper lip with commissure and philtrum involvement (Figure 3).^8,23,32 It is an insensate flap that alters the position of the modiolus, distorting oral and facial animation.²³ The superomedial position of the modiolus is better tolerated in the upper lip because it increases the relaxation tone of the lower lip and simulates the vector of contraction of major animation muscles, positively impacting the sphincteric function of the reconstructed lip. Sphincteric function action is not as impaired compared with the lower lip because the new position of the modiolus tightens the lower lip and prevents drooling.³³ When designing the flap, one should consider that the inferior labial artery has been reported to remain with 10 mm of the superior border of the lower lip; therefore, pedicles of the Abbe and Estlander flaps should be at least 10 mm from the vermilion border to preserve vascular supply.^34,35

The Karapandzic flap, a modified Gilles fan flap, can be employed for repair of central defects up to two-thirds of the upper lip.^{8,23,32,36-39} The bilateral advancement of full-thickness adjacent tissue edges preserves neurovascular structures allowing sensation and restores OO continuation.⁴⁰ Prior studies have shown the average distance of the superior labial artery emergence from the facial artery and labial commissure is 12.1 mm; thus, at least 12.1 mm of tissue from the commissure should be preserved to prevent vascular compromise in Karapandzic flaps.^34,35 The modiolus position is altered, and facial animation muscles are disrupted, consequently impairing facial animation, especially elevation of the lip.³⁶ The philtrum is obliterated, producing unfavorable aesthetic outcomes. Finally, the upper lip is thinner and smaller in volume than the lower lip, increasing the risk for microstomia compared with the lower lip with a similar reconstructive technique.³⁶

Defects larger than two-thirds of the upper lip require a Bernard Burrow flap, distant free flap, or combination of multiple regional and local flaps dependent on the characteristics of the defect.^36,41 Distant free flaps are beyond the scope of this review. The Bernard Burrow flap consists of bilaterally opposing cheek advancement flaps. It is an insensate flap that does not restore OO continuity, producing minimal muscle function and poor animation. Microstomia is a common adverse outcome.³⁶

Conclusion

Comprehensive understanding of labial anatomy and its intimate relationship to function and aesthetics of the upper lip are critical. Flap anatomy and mechanics are key factors for successful reconstruction. The purpose of this article is to utilize knowledge of histology, anatomy, and function of the upper lip to improve the outcomes of reconstruction. The Abbe flap often is utilized for reconstruction of the philtrum and central upper lip defects, though it is a less desirable option for lower lip reconstruction. The Karapandzic flap, while sensate and restorative of OO continuity, may have less optimal functional and cosmetic results compared with its use in the lower lip. Regarding lateral defects involving the commissure, the Estlander flap provides a reasonable option for the upper lip when compared with its use in lower lip defects, where outcomes are usually inferior.

To the Editor:

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

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

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

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

To the Editor:

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

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

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

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

To the Editor:

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

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

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

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

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

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

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

Epidemiology

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

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

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

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

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

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

Etiology

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

Clinical Presentation

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

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

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

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

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

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

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

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

Diagnosis

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

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

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

Management

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

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

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

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

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

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

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

Prevention

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

Conclusion

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

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

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

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

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

Epidemiology

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

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

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

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

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

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

Etiology

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

Clinical Presentation

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

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

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

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

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

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

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

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

Diagnosis

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

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

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

Management

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

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

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

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

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

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

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

Prevention

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

Conclusion

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

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

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

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

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

Epidemiology

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

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

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

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

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

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

Etiology

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

Clinical Presentation

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

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

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

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

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

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

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

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

Diagnosis

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

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

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

Management

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

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

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

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

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

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

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

Prevention

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

Conclusion

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

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