Wounds

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.

Sixteen dysregulated genes strongly characterize hidradenitis suppurativa (HS), Andre da Costa, PhD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.

He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.

Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.

“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.

There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.

The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.

Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.

Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.

In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.

The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.

bjancin@mdedge.com

Sixteen dysregulated genes strongly characterize hidradenitis suppurativa (HS), Andre da Costa, PhD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.

He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.

Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.

“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.

There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.

The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.

Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.

Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.

In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.

The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.

bjancin@mdedge.com

Sixteen dysregulated genes strongly characterize hidradenitis suppurativa (HS), Andre da Costa, PhD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.

He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.

Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.

“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.

There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.

The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.

Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.

Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.

In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.

The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.

bjancin@mdedge.com

Delaying surgical reconstruction of fistula structures until after patients with hidradenitis suppurativa (HS) have been on adalimumab for a minimum of 6 months transforms primary wound closure into a highly attractive option, a pilot study suggests.

“Our experience suggests that under the effects of treatment with adalimumab, wound healing disorders with primary wound closure occur less often. And primary wound closure offers advantages over secondary wound healing: shorter length of inpatient stay, lower morbidity, fewer functional problems, and better quality of life,” Gefion Girbig, MD, said at the annual congress of the European Academy of Dermatology and Venereology.

She noted that primary wound closure following surgery for HS is controversial. For example, current German guidelines recommend complete surgical excision of HS lesions, followed by secondary wound healing; the guidelines advise against primary wound closure. But those guidelines were issued back in 2012, years before adalimumab (Humira) achieved regulatory approval as the first and to date only medication indicated for treatment of HS.

Experts agree that while adalimumab has been a difference maker for many patients with HS, surgery is still often necessary. And many surgeons prefer secondary wound healing in HS. That’s because healing by first intention has historically often resulted in complications involving wound healing disorders and infection. These complications necessitate loosening of the primary closure to permit further wound healing by second intention, with a resultant prolonged healing time, explained Dr. Girbig, of the Institute for Health Sciences Research in Dermatology and Nursing at University Medical Center Hamburg-Eppendorf (Germany).

She and her coinvestigators hypothesized that the disordered wound healing is a consequence of the underlying inflammatory disease that lies at the core of HS, and that quelling the inflammation with adalimumab for at least 6 months before performing surgery with primary closure while the anti-TNF therapy continues would reduce the incidence of wound healing disorders.

This was borne out in the group’s small observational pilot study. It included 10 patients with HS who underwent surgery only after at least 6 months on adalimumab. Six had surgery for axillary HS and four for inguinal disease. Only 2 of the 10 developed a wound healing disorder. Both had surgical reconstruction in the inguinal area. Neither case involved infection. Surgical management entailed opening part of the suture to allow simultaneous secondary wound closure.

This 20% incidence of disordered wound healing when primary closure was carried out while systemic inflammation was controlled via adalimumab is markedly lower than rates reported using primary closure without adalimumab. Dr. Girbig and her coinvestigators are now conducting a larger controlled study to confirm their findings.

She reported having no financial conflicts regarding her study.

bjancin@mdedge.com

Delaying surgical reconstruction of fistula structures until after patients with hidradenitis suppurativa (HS) have been on adalimumab for a minimum of 6 months transforms primary wound closure into a highly attractive option, a pilot study suggests.

“Our experience suggests that under the effects of treatment with adalimumab, wound healing disorders with primary wound closure occur less often. And primary wound closure offers advantages over secondary wound healing: shorter length of inpatient stay, lower morbidity, fewer functional problems, and better quality of life,” Gefion Girbig, MD, said at the annual congress of the European Academy of Dermatology and Venereology.

She noted that primary wound closure following surgery for HS is controversial. For example, current German guidelines recommend complete surgical excision of HS lesions, followed by secondary wound healing; the guidelines advise against primary wound closure. But those guidelines were issued back in 2012, years before adalimumab (Humira) achieved regulatory approval as the first and to date only medication indicated for treatment of HS.

Experts agree that while adalimumab has been a difference maker for many patients with HS, surgery is still often necessary. And many surgeons prefer secondary wound healing in HS. That’s because healing by first intention has historically often resulted in complications involving wound healing disorders and infection. These complications necessitate loosening of the primary closure to permit further wound healing by second intention, with a resultant prolonged healing time, explained Dr. Girbig, of the Institute for Health Sciences Research in Dermatology and Nursing at University Medical Center Hamburg-Eppendorf (Germany).

She and her coinvestigators hypothesized that the disordered wound healing is a consequence of the underlying inflammatory disease that lies at the core of HS, and that quelling the inflammation with adalimumab for at least 6 months before performing surgery with primary closure while the anti-TNF therapy continues would reduce the incidence of wound healing disorders.

This was borne out in the group’s small observational pilot study. It included 10 patients with HS who underwent surgery only after at least 6 months on adalimumab. Six had surgery for axillary HS and four for inguinal disease. Only 2 of the 10 developed a wound healing disorder. Both had surgical reconstruction in the inguinal area. Neither case involved infection. Surgical management entailed opening part of the suture to allow simultaneous secondary wound closure.

This 20% incidence of disordered wound healing when primary closure was carried out while systemic inflammation was controlled via adalimumab is markedly lower than rates reported using primary closure without adalimumab. Dr. Girbig and her coinvestigators are now conducting a larger controlled study to confirm their findings.

She reported having no financial conflicts regarding her study.

bjancin@mdedge.com

Delaying surgical reconstruction of fistula structures until after patients with hidradenitis suppurativa (HS) have been on adalimumab for a minimum of 6 months transforms primary wound closure into a highly attractive option, a pilot study suggests.

“Our experience suggests that under the effects of treatment with adalimumab, wound healing disorders with primary wound closure occur less often. And primary wound closure offers advantages over secondary wound healing: shorter length of inpatient stay, lower morbidity, fewer functional problems, and better quality of life,” Gefion Girbig, MD, said at the annual congress of the European Academy of Dermatology and Venereology.

She noted that primary wound closure following surgery for HS is controversial. For example, current German guidelines recommend complete surgical excision of HS lesions, followed by secondary wound healing; the guidelines advise against primary wound closure. But those guidelines were issued back in 2012, years before adalimumab (Humira) achieved regulatory approval as the first and to date only medication indicated for treatment of HS.

Experts agree that while adalimumab has been a difference maker for many patients with HS, surgery is still often necessary. And many surgeons prefer secondary wound healing in HS. That’s because healing by first intention has historically often resulted in complications involving wound healing disorders and infection. These complications necessitate loosening of the primary closure to permit further wound healing by second intention, with a resultant prolonged healing time, explained Dr. Girbig, of the Institute for Health Sciences Research in Dermatology and Nursing at University Medical Center Hamburg-Eppendorf (Germany).

She and her coinvestigators hypothesized that the disordered wound healing is a consequence of the underlying inflammatory disease that lies at the core of HS, and that quelling the inflammation with adalimumab for at least 6 months before performing surgery with primary closure while the anti-TNF therapy continues would reduce the incidence of wound healing disorders.

This was borne out in the group’s small observational pilot study. It included 10 patients with HS who underwent surgery only after at least 6 months on adalimumab. Six had surgery for axillary HS and four for inguinal disease. Only 2 of the 10 developed a wound healing disorder. Both had surgical reconstruction in the inguinal area. Neither case involved infection. Surgical management entailed opening part of the suture to allow simultaneous secondary wound closure.

This 20% incidence of disordered wound healing when primary closure was carried out while systemic inflammation was controlled via adalimumab is markedly lower than rates reported using primary closure without adalimumab. Dr. Girbig and her coinvestigators are now conducting a larger controlled study to confirm their findings.

She reported having no financial conflicts regarding her study.

bjancin@mdedge.com

Mounting evidence suggests it’s a mistake to reject the diagnosis of drug reaction with eosinophilia and systemic symptoms, or DRESS, simply because the interval between initiating a drug and symptom onset is less than 15 days, Sarah Walsh, MD, said at the virtual annual congress of the European Academy of Dermatology and Venereology.

The standard dictum has been that diagnosis of this severe T-cell-mediated drug reaction requires more than a 2-week delay in symptom onset following initial drug intake. But this can steer physicians in the wrong direction and lead to stopping an innocent drug while the true culprit medication remains on board. This adversely affects patient prognosis, since a longer duration of drug exposure after symptom onset is associated with increased hospital length of stay and greater mortality risk, explained Dr. Walsh, clinical lead for dermatology at King’s College Hospital, London.

In addition to sharing recent data demonstrating that DRESS symptoms often occur within just a week or 2 of drug exposure, she highlighted several recent advances in the ability to predict DRESS severity. These include clues provided by rash morphology and histopathology, HLA testing, and a novel scoring system to assess DRESS severity and the risk of potentially fatal cytomegalovirus reactivation.

Short-delay DRESS onset

In a retrospective study of 41 patients with a first episode of DRESS in three French dermatology departments, 14 (34%) had onset within 15 days or less of initial exposure to the causative drug. In 6 of 14 patients in the rapid-onset group the offending drug was an antibiotic, while in another 5 the culprit was iodinated contrast media. In the delayed-onset DRESS group, the chief sensitizers were allopurinol in 8 patients, lamotrigine in 6, carbamazepine in 4, and sulfasalazine in 2; of note, none of these 4 delayed-onset DRESS drugs were implicated in any cases of rapid-onset DRESS. There were no differences in the clinical manifestations of DRESS between the rapid- and delayed-onset groups.

Similarly, dermatologists at Government Medical College in Kerala, India, reported in a retrospective study of 100 consecutive patients with DRESS, the drug reaction emerged within 2 weeks after starting the culprit medication in 36% of cases. Indeed, 11 patients became symptomatic within 3-7 days after beginning the medication; in 10 of the 11 cases, the offending agent was an antibiotic, and in 1 patient it was terbinafine. In the 25 cases of DRESS that arose on day 8-14 of drug therapy, the culprit was phenytoin in 14, antibiotics in 6, and 1 each for clopidogrel, hydroxychloroquine, sodium valproate, lamotrigine, and vitamin D₃.

Both groups of investigators concluded that a short time lag between starting a drug and development of symptoms of a drug reaction shouldn’t rule out DRESS as a possibility provided other criteria consistent with the diagnosis are present. Hallmarks of DRESS include an acute extensive rash, fever greater than 38 degrees C, enlarged lymph nodes at two or more sites, internal organ involvement, a low platelet count, elevated eosinophils, and abnormal lymphocyte levels.
 

Rash morphology and histology as prognostic indicators

Dr. Walsh was the lead investigator in a study that identified four distinct patterns of skin involvement in patients with DRESS. The most common type of rash in this single-center retrospective study of 27 consecutive patients was an urticated papular exanthem, present in 13 of the 27 patients. An erythema multiforme-like reaction was present in 8, exfoliative erythroderma in 3, and a morbilliform erythema in 3 others. The worst prognosis was in the subgroup with an erythema multiforme-like rash.

All 27 patients had hepatic involvement, which was severe in 9 cases. Six of the 9 with severe liver impairment had an erythema multiforme-like rash, compared with just 2 of the 18 with mild or moderate liver involvement; thus, an erythema multiforme-like skin eruption was associated with a fivefold increased likelihood of severe hepatic involvement.

“It is a clinical sign that we take seriously at presentation if atypical target lesions are present,” the dermatologist said.

Separately, Taiwanese investigators compared clinical and histopathologic features in a study of 32 patients with DRESS and 17 with maculopapular exanthem. Interface vacuolization, which was present in 29 of the 32 patients with DRESS, was far more prominent than in the comparator group. Moreover, severe dyskeratosis was significantly associated with more severe liver impairment in the DRESS group.
 

HLA testing

Testing for HLA haplotypes associated with severe drug reactions has a useful role as a screening tool prior to prescribing selected high-risk drugs, Dr. Walsh said. For example, it’s known that 6.8% of individuals of European ancestry carry HLA-A*32:01, an allele that was strongly associated with an increased rate of vancomycin-associated DRESS in a case-control study at Vanderbilt University, Nashville, Tenn. Indeed, 19 of 23 individuals with vancomycin-associated DRESS were HLA-A*32:01 positive, compared with none of 46 vancomycin-tolerant controls. Nineteen percent of HLA-A*32:01-positive patients developed DRESS during treatment with vancomycin, and the drug reaction occurred within 4 weeks.

The investigators noted that testing for HLA-A*32:01 is also useful in DRESS occurring in patients on vancomycin and multiple other drugs because the test’s high negative predictive value may safely allow continued therapy with this potent antibiotic for Gram-positive infections.
 

A DRESS prognostic scoring system

Japanese researchers have developed a scoring system for DRESS for use in monitoring severity of the drug reaction, predicting prognosis, and estimating the risk of developing cytomegalovirus disease and its potentially fatal complications. The scoring system incorporates patient factors, including age, duration of drug exposure after symptom onset; rash characteristics, such as percentage of body surface area involved and presence or absence of erythroderma; appetite loss; and laboratory values.

“It yields a prognostic score that can be used to determine treatment choices, such as immediate intervention with anti-CMV agents. It’s a very useful tool,” Dr. Walsh said.

She reported having no financial conflicts regarding her presentation.

bjancin@mdedge.com

Mounting evidence suggests it’s a mistake to reject the diagnosis of drug reaction with eosinophilia and systemic symptoms, or DRESS, simply because the interval between initiating a drug and symptom onset is less than 15 days, Sarah Walsh, MD, said at the virtual annual congress of the European Academy of Dermatology and Venereology.

The standard dictum has been that diagnosis of this severe T-cell-mediated drug reaction requires more than a 2-week delay in symptom onset following initial drug intake. But this can steer physicians in the wrong direction and lead to stopping an innocent drug while the true culprit medication remains on board. This adversely affects patient prognosis, since a longer duration of drug exposure after symptom onset is associated with increased hospital length of stay and greater mortality risk, explained Dr. Walsh, clinical lead for dermatology at King’s College Hospital, London.

In addition to sharing recent data demonstrating that DRESS symptoms often occur within just a week or 2 of drug exposure, she highlighted several recent advances in the ability to predict DRESS severity. These include clues provided by rash morphology and histopathology, HLA testing, and a novel scoring system to assess DRESS severity and the risk of potentially fatal cytomegalovirus reactivation.

Short-delay DRESS onset

In a retrospective study of 41 patients with a first episode of DRESS in three French dermatology departments, 14 (34%) had onset within 15 days or less of initial exposure to the causative drug. In 6 of 14 patients in the rapid-onset group the offending drug was an antibiotic, while in another 5 the culprit was iodinated contrast media. In the delayed-onset DRESS group, the chief sensitizers were allopurinol in 8 patients, lamotrigine in 6, carbamazepine in 4, and sulfasalazine in 2; of note, none of these 4 delayed-onset DRESS drugs were implicated in any cases of rapid-onset DRESS. There were no differences in the clinical manifestations of DRESS between the rapid- and delayed-onset groups.

Similarly, dermatologists at Government Medical College in Kerala, India, reported in a retrospective study of 100 consecutive patients with DRESS, the drug reaction emerged within 2 weeks after starting the culprit medication in 36% of cases. Indeed, 11 patients became symptomatic within 3-7 days after beginning the medication; in 10 of the 11 cases, the offending agent was an antibiotic, and in 1 patient it was terbinafine. In the 25 cases of DRESS that arose on day 8-14 of drug therapy, the culprit was phenytoin in 14, antibiotics in 6, and 1 each for clopidogrel, hydroxychloroquine, sodium valproate, lamotrigine, and vitamin D₃.

Both groups of investigators concluded that a short time lag between starting a drug and development of symptoms of a drug reaction shouldn’t rule out DRESS as a possibility provided other criteria consistent with the diagnosis are present. Hallmarks of DRESS include an acute extensive rash, fever greater than 38 degrees C, enlarged lymph nodes at two or more sites, internal organ involvement, a low platelet count, elevated eosinophils, and abnormal lymphocyte levels.
 

Rash morphology and histology as prognostic indicators

Dr. Walsh was the lead investigator in a study that identified four distinct patterns of skin involvement in patients with DRESS. The most common type of rash in this single-center retrospective study of 27 consecutive patients was an urticated papular exanthem, present in 13 of the 27 patients. An erythema multiforme-like reaction was present in 8, exfoliative erythroderma in 3, and a morbilliform erythema in 3 others. The worst prognosis was in the subgroup with an erythema multiforme-like rash.

All 27 patients had hepatic involvement, which was severe in 9 cases. Six of the 9 with severe liver impairment had an erythema multiforme-like rash, compared with just 2 of the 18 with mild or moderate liver involvement; thus, an erythema multiforme-like skin eruption was associated with a fivefold increased likelihood of severe hepatic involvement.

“It is a clinical sign that we take seriously at presentation if atypical target lesions are present,” the dermatologist said.

Separately, Taiwanese investigators compared clinical and histopathologic features in a study of 32 patients with DRESS and 17 with maculopapular exanthem. Interface vacuolization, which was present in 29 of the 32 patients with DRESS, was far more prominent than in the comparator group. Moreover, severe dyskeratosis was significantly associated with more severe liver impairment in the DRESS group.
 

HLA testing

Testing for HLA haplotypes associated with severe drug reactions has a useful role as a screening tool prior to prescribing selected high-risk drugs, Dr. Walsh said. For example, it’s known that 6.8% of individuals of European ancestry carry HLA-A*32:01, an allele that was strongly associated with an increased rate of vancomycin-associated DRESS in a case-control study at Vanderbilt University, Nashville, Tenn. Indeed, 19 of 23 individuals with vancomycin-associated DRESS were HLA-A*32:01 positive, compared with none of 46 vancomycin-tolerant controls. Nineteen percent of HLA-A*32:01-positive patients developed DRESS during treatment with vancomycin, and the drug reaction occurred within 4 weeks.

The investigators noted that testing for HLA-A*32:01 is also useful in DRESS occurring in patients on vancomycin and multiple other drugs because the test’s high negative predictive value may safely allow continued therapy with this potent antibiotic for Gram-positive infections.
 

A DRESS prognostic scoring system

Japanese researchers have developed a scoring system for DRESS for use in monitoring severity of the drug reaction, predicting prognosis, and estimating the risk of developing cytomegalovirus disease and its potentially fatal complications. The scoring system incorporates patient factors, including age, duration of drug exposure after symptom onset; rash characteristics, such as percentage of body surface area involved and presence or absence of erythroderma; appetite loss; and laboratory values.

“It yields a prognostic score that can be used to determine treatment choices, such as immediate intervention with anti-CMV agents. It’s a very useful tool,” Dr. Walsh said.

She reported having no financial conflicts regarding her presentation.

bjancin@mdedge.com

Mounting evidence suggests it’s a mistake to reject the diagnosis of drug reaction with eosinophilia and systemic symptoms, or DRESS, simply because the interval between initiating a drug and symptom onset is less than 15 days, Sarah Walsh, MD, said at the virtual annual congress of the European Academy of Dermatology and Venereology.

The standard dictum has been that diagnosis of this severe T-cell-mediated drug reaction requires more than a 2-week delay in symptom onset following initial drug intake. But this can steer physicians in the wrong direction and lead to stopping an innocent drug while the true culprit medication remains on board. This adversely affects patient prognosis, since a longer duration of drug exposure after symptom onset is associated with increased hospital length of stay and greater mortality risk, explained Dr. Walsh, clinical lead for dermatology at King’s College Hospital, London.

In addition to sharing recent data demonstrating that DRESS symptoms often occur within just a week or 2 of drug exposure, she highlighted several recent advances in the ability to predict DRESS severity. These include clues provided by rash morphology and histopathology, HLA testing, and a novel scoring system to assess DRESS severity and the risk of potentially fatal cytomegalovirus reactivation.

Short-delay DRESS onset

In a retrospective study of 41 patients with a first episode of DRESS in three French dermatology departments, 14 (34%) had onset within 15 days or less of initial exposure to the causative drug. In 6 of 14 patients in the rapid-onset group the offending drug was an antibiotic, while in another 5 the culprit was iodinated contrast media. In the delayed-onset DRESS group, the chief sensitizers were allopurinol in 8 patients, lamotrigine in 6, carbamazepine in 4, and sulfasalazine in 2; of note, none of these 4 delayed-onset DRESS drugs were implicated in any cases of rapid-onset DRESS. There were no differences in the clinical manifestations of DRESS between the rapid- and delayed-onset groups.

Similarly, dermatologists at Government Medical College in Kerala, India, reported in a retrospective study of 100 consecutive patients with DRESS, the drug reaction emerged within 2 weeks after starting the culprit medication in 36% of cases. Indeed, 11 patients became symptomatic within 3-7 days after beginning the medication; in 10 of the 11 cases, the offending agent was an antibiotic, and in 1 patient it was terbinafine. In the 25 cases of DRESS that arose on day 8-14 of drug therapy, the culprit was phenytoin in 14, antibiotics in 6, and 1 each for clopidogrel, hydroxychloroquine, sodium valproate, lamotrigine, and vitamin D₃.

Both groups of investigators concluded that a short time lag between starting a drug and development of symptoms of a drug reaction shouldn’t rule out DRESS as a possibility provided other criteria consistent with the diagnosis are present. Hallmarks of DRESS include an acute extensive rash, fever greater than 38 degrees C, enlarged lymph nodes at two or more sites, internal organ involvement, a low platelet count, elevated eosinophils, and abnormal lymphocyte levels.
 

Rash morphology and histology as prognostic indicators

Dr. Walsh was the lead investigator in a study that identified four distinct patterns of skin involvement in patients with DRESS. The most common type of rash in this single-center retrospective study of 27 consecutive patients was an urticated papular exanthem, present in 13 of the 27 patients. An erythema multiforme-like reaction was present in 8, exfoliative erythroderma in 3, and a morbilliform erythema in 3 others. The worst prognosis was in the subgroup with an erythema multiforme-like rash.

All 27 patients had hepatic involvement, which was severe in 9 cases. Six of the 9 with severe liver impairment had an erythema multiforme-like rash, compared with just 2 of the 18 with mild or moderate liver involvement; thus, an erythema multiforme-like skin eruption was associated with a fivefold increased likelihood of severe hepatic involvement.

“It is a clinical sign that we take seriously at presentation if atypical target lesions are present,” the dermatologist said.

Separately, Taiwanese investigators compared clinical and histopathologic features in a study of 32 patients with DRESS and 17 with maculopapular exanthem. Interface vacuolization, which was present in 29 of the 32 patients with DRESS, was far more prominent than in the comparator group. Moreover, severe dyskeratosis was significantly associated with more severe liver impairment in the DRESS group.
 

HLA testing

Testing for HLA haplotypes associated with severe drug reactions has a useful role as a screening tool prior to prescribing selected high-risk drugs, Dr. Walsh said. For example, it’s known that 6.8% of individuals of European ancestry carry HLA-A*32:01, an allele that was strongly associated with an increased rate of vancomycin-associated DRESS in a case-control study at Vanderbilt University, Nashville, Tenn. Indeed, 19 of 23 individuals with vancomycin-associated DRESS were HLA-A*32:01 positive, compared with none of 46 vancomycin-tolerant controls. Nineteen percent of HLA-A*32:01-positive patients developed DRESS during treatment with vancomycin, and the drug reaction occurred within 4 weeks.

The investigators noted that testing for HLA-A*32:01 is also useful in DRESS occurring in patients on vancomycin and multiple other drugs because the test’s high negative predictive value may safely allow continued therapy with this potent antibiotic for Gram-positive infections.
 

A DRESS prognostic scoring system

Japanese researchers have developed a scoring system for DRESS for use in monitoring severity of the drug reaction, predicting prognosis, and estimating the risk of developing cytomegalovirus disease and its potentially fatal complications. The scoring system incorporates patient factors, including age, duration of drug exposure after symptom onset; rash characteristics, such as percentage of body surface area involved and presence or absence of erythroderma; appetite loss; and laboratory values.

“It yields a prognostic score that can be used to determine treatment choices, such as immediate intervention with anti-CMV agents. It’s a very useful tool,” Dr. Walsh said.

She reported having no financial conflicts regarding her presentation.

bjancin@mdedge.com

The Diagnosis: Anetoderma of Prematurity 

Anetoderma is a rare benign cutaneous disorder characterized by atrophic patches of skin due to dermal thinning. The term anetoderma is derived from the Greek words anetos (relaxed) and derma (skin).¹ The physical appearance of the skin is associated with a reduction or loss of elastic tissue in the dermal layer, as seen on histolopathology.²  

Two forms of anetoderma have been described. Primary anetoderma is an idiopathic form with no preceding inflammatory lesions. Secondary anetoderma is a reactive process linked to a known preceding inflammatory, infectious, autoimmune, or drug-induced condition.³ On histopathology, both primary and secondary anetoderma are characterized by a loss of elastic tissue or elastin fibers in the superficial to mid dermis.²  

Anetoderma of prematurity was first described in 1996 by Prizant et al⁴ in 9 extremely premature (24-29 weeks' gestation) infants in neonatal intensive care units (NICUs). Although the exact mechanism behind anetoderma of prematurity is still unknown, Prizant et al⁴ and other investigators⁵ postulated that application of adhesive monitoring leads in the NICU played a role in the development of the lesions. 

Iatrogenic anetoderma of prematurity is clinically characterized by circumscribed areas of either wrinkled macular depression or pouchlike herniations, ranging from flesh-colored to violaceous hues. Lesion size varies from a few millimeters to several centimeters in diameter, and they often are oval or round in shape.² Although not common, it is possible for the atrophic patches to be preceded by an area of ecchymosis without necrosis or atrophy and, if present, they usually evolve within a few days to the characteristic appearance of anetoderma.³ They are found at discrete sites where monitoring leads or other medical devices are commonly placed, such as the forehead, abdomen, chest, and proximal limbs. 

Lesions of anetoderma of prematurity are not present at birth, which distinguishes them from congenital anetoderma.⁶ It is unclear if the lesions are associated with the degree of prematurity, extremely low birth weight, or other associated factors of preterm birth. Although often clinically diagnosed, the diagnosis can be confirmed by a loss of elastic fibers on histopathology when stained with Verhoeff-van Gieson stain.¹ Over time, the atrophic patches have the potential to evolve into herniated forms of anetoderma. Self-healing or improvement of the lesions often does not occur. Although the lesion is benign, it often requires surgical correction later in life for cosmesis.  

Infants in the NICU are at risk for iatrogenic cutaneous injuries, which rarely may include anetoderma. Anetoderma of prematurity has been linked to the use of monitoring leads, adhesive tape, and other medical devices placed on the skin. Prizant et al⁴ postulated that the cause of anetoderma in these infants was irritants such as skin cleansers, urine, or sweat that may be trapped under the electrodes. Other hypotheses include local hypoxemia due to prolonged pressure from the electrodes on immature skin or excessive traction used when removing adhesive tape from the skin.^7,8 Premature infants may be more susceptible to these lesions because of the reduced epidermal thickness of premature skin; immaturity of skin structure; or functional immaturity of elastin deposition regulators, such as elastase, lysyl oxidase, the complement system, and decay-accelerating factor.³ The diagnosis should be differentiated from congenital anetoderma, which also has been described in premature neonates but is characterized by lesions that are present at birth. Its origins are still unclear, despite having histopathologic features similar to iatrogenic anetoderma.⁹  

Focal dermal hypoplasia (FDH) is the hallmark cutaneous finding in Goltz syndrome, a rare set of congenital abnormalities of the skin, oral structures, musculoskeletal system, and central nervous system. Similar to congenital anetoderma, FDH also is characterized by atrophic cutaneous lesions; however, the cutaneous lesions in FDH appear as linear, streaky atrophic lesions often with telangiectasias that follow Blaschko lines.¹⁰ The cutaneous lesions in FDH often are associated with other noncutaneous signs such as polydactyly or asymmetric limbs.¹⁰ Cutis laxa is caused by an abnormality in the elastic tissue resulting in a loose sagging appearance of the skin and frequently results in an aged facial appearance. There are both acquired and inherited forms that can be either solely cutaneous or present with extracutaneous features, such as cardiac abnormalities or emphysema.¹¹ 

In contrast to the atrophic appearance of anetodermas, connective tissue nevi and nevus lipomatosus superficialis present as hamartomas that either can be present at birth or arise in infancy. Connective tissue nevi are hamartomas of dermal connective tissue that consist of excessive production of collagen, elastin, or glycosaminoglycans and appear as slightly elevated, flesh-colored to yellow nodules or plaques.¹² Connective tissue nevi often are described in association with other diseases, most commonly tuberous sclerosis (shagreen patches) or familial cutaneous collagenoma. Nevus lipomatosus superficialis is an asymptomatic connective tissue hamartoma composed of mature adipocytes in the dermis. The lesions consist of clusters of flesh-colored to yellow, soft, rubbery papules or nodules with a smooth or verrucoid surface that do not cross the midline and may follow Blaschko lines.¹¹ 

With advances in neonatal infant medical care, survival of extremely premature infants is increasing, and it is possible that this rare cutaneous disorder may become more prevalent. Care should be taken to avoid unnecessary pressure on surfaces where electrodes are placed and tightly applied adhesive tape. When electrodes are placed on the ventral side, the child should be placed supine; similarly, place electrodes on the dorsal side when the child is lying prone.⁵ A diagnosis of anetoderma of prematurity later in childhood may be difficult, so knowledge and awareness can help guide pediatricians and dermatologists to a correct diagnosis and prevent unnecessary evaluations and/or concerns. 

The Diagnosis: Anetoderma of Prematurity 

Anetoderma is a rare benign cutaneous disorder characterized by atrophic patches of skin due to dermal thinning. The term anetoderma is derived from the Greek words anetos (relaxed) and derma (skin).¹ The physical appearance of the skin is associated with a reduction or loss of elastic tissue in the dermal layer, as seen on histolopathology.²  

Two forms of anetoderma have been described. Primary anetoderma is an idiopathic form with no preceding inflammatory lesions. Secondary anetoderma is a reactive process linked to a known preceding inflammatory, infectious, autoimmune, or drug-induced condition.³ On histopathology, both primary and secondary anetoderma are characterized by a loss of elastic tissue or elastin fibers in the superficial to mid dermis.²  

Anetoderma of prematurity was first described in 1996 by Prizant et al⁴ in 9 extremely premature (24-29 weeks' gestation) infants in neonatal intensive care units (NICUs). Although the exact mechanism behind anetoderma of prematurity is still unknown, Prizant et al⁴ and other investigators⁵ postulated that application of adhesive monitoring leads in the NICU played a role in the development of the lesions. 

Iatrogenic anetoderma of prematurity is clinically characterized by circumscribed areas of either wrinkled macular depression or pouchlike herniations, ranging from flesh-colored to violaceous hues. Lesion size varies from a few millimeters to several centimeters in diameter, and they often are oval or round in shape.² Although not common, it is possible for the atrophic patches to be preceded by an area of ecchymosis without necrosis or atrophy and, if present, they usually evolve within a few days to the characteristic appearance of anetoderma.³ They are found at discrete sites where monitoring leads or other medical devices are commonly placed, such as the forehead, abdomen, chest, and proximal limbs. 

Lesions of anetoderma of prematurity are not present at birth, which distinguishes them from congenital anetoderma.⁶ It is unclear if the lesions are associated with the degree of prematurity, extremely low birth weight, or other associated factors of preterm birth. Although often clinically diagnosed, the diagnosis can be confirmed by a loss of elastic fibers on histopathology when stained with Verhoeff-van Gieson stain.¹ Over time, the atrophic patches have the potential to evolve into herniated forms of anetoderma. Self-healing or improvement of the lesions often does not occur. Although the lesion is benign, it often requires surgical correction later in life for cosmesis.  

Infants in the NICU are at risk for iatrogenic cutaneous injuries, which rarely may include anetoderma. Anetoderma of prematurity has been linked to the use of monitoring leads, adhesive tape, and other medical devices placed on the skin. Prizant et al⁴ postulated that the cause of anetoderma in these infants was irritants such as skin cleansers, urine, or sweat that may be trapped under the electrodes. Other hypotheses include local hypoxemia due to prolonged pressure from the electrodes on immature skin or excessive traction used when removing adhesive tape from the skin.^7,8 Premature infants may be more susceptible to these lesions because of the reduced epidermal thickness of premature skin; immaturity of skin structure; or functional immaturity of elastin deposition regulators, such as elastase, lysyl oxidase, the complement system, and decay-accelerating factor.³ The diagnosis should be differentiated from congenital anetoderma, which also has been described in premature neonates but is characterized by lesions that are present at birth. Its origins are still unclear, despite having histopathologic features similar to iatrogenic anetoderma.⁹  

Focal dermal hypoplasia (FDH) is the hallmark cutaneous finding in Goltz syndrome, a rare set of congenital abnormalities of the skin, oral structures, musculoskeletal system, and central nervous system. Similar to congenital anetoderma, FDH also is characterized by atrophic cutaneous lesions; however, the cutaneous lesions in FDH appear as linear, streaky atrophic lesions often with telangiectasias that follow Blaschko lines.¹⁰ The cutaneous lesions in FDH often are associated with other noncutaneous signs such as polydactyly or asymmetric limbs.¹⁰ Cutis laxa is caused by an abnormality in the elastic tissue resulting in a loose sagging appearance of the skin and frequently results in an aged facial appearance. There are both acquired and inherited forms that can be either solely cutaneous or present with extracutaneous features, such as cardiac abnormalities or emphysema.¹¹ 

In contrast to the atrophic appearance of anetodermas, connective tissue nevi and nevus lipomatosus superficialis present as hamartomas that either can be present at birth or arise in infancy. Connective tissue nevi are hamartomas of dermal connective tissue that consist of excessive production of collagen, elastin, or glycosaminoglycans and appear as slightly elevated, flesh-colored to yellow nodules or plaques.¹² Connective tissue nevi often are described in association with other diseases, most commonly tuberous sclerosis (shagreen patches) or familial cutaneous collagenoma. Nevus lipomatosus superficialis is an asymptomatic connective tissue hamartoma composed of mature adipocytes in the dermis. The lesions consist of clusters of flesh-colored to yellow, soft, rubbery papules or nodules with a smooth or verrucoid surface that do not cross the midline and may follow Blaschko lines.¹¹ 

With advances in neonatal infant medical care, survival of extremely premature infants is increasing, and it is possible that this rare cutaneous disorder may become more prevalent. Care should be taken to avoid unnecessary pressure on surfaces where electrodes are placed and tightly applied adhesive tape. When electrodes are placed on the ventral side, the child should be placed supine; similarly, place electrodes on the dorsal side when the child is lying prone.⁵ A diagnosis of anetoderma of prematurity later in childhood may be difficult, so knowledge and awareness can help guide pediatricians and dermatologists to a correct diagnosis and prevent unnecessary evaluations and/or concerns. 

The Diagnosis: Anetoderma of Prematurity 

Anetoderma is a rare benign cutaneous disorder characterized by atrophic patches of skin due to dermal thinning. The term anetoderma is derived from the Greek words anetos (relaxed) and derma (skin).¹ The physical appearance of the skin is associated with a reduction or loss of elastic tissue in the dermal layer, as seen on histolopathology.²  

Two forms of anetoderma have been described. Primary anetoderma is an idiopathic form with no preceding inflammatory lesions. Secondary anetoderma is a reactive process linked to a known preceding inflammatory, infectious, autoimmune, or drug-induced condition.³ On histopathology, both primary and secondary anetoderma are characterized by a loss of elastic tissue or elastin fibers in the superficial to mid dermis.²  

Anetoderma of prematurity was first described in 1996 by Prizant et al⁴ in 9 extremely premature (24-29 weeks' gestation) infants in neonatal intensive care units (NICUs). Although the exact mechanism behind anetoderma of prematurity is still unknown, Prizant et al⁴ and other investigators⁵ postulated that application of adhesive monitoring leads in the NICU played a role in the development of the lesions. 

Iatrogenic anetoderma of prematurity is clinically characterized by circumscribed areas of either wrinkled macular depression or pouchlike herniations, ranging from flesh-colored to violaceous hues. Lesion size varies from a few millimeters to several centimeters in diameter, and they often are oval or round in shape.² Although not common, it is possible for the atrophic patches to be preceded by an area of ecchymosis without necrosis or atrophy and, if present, they usually evolve within a few days to the characteristic appearance of anetoderma.³ They are found at discrete sites where monitoring leads or other medical devices are commonly placed, such as the forehead, abdomen, chest, and proximal limbs. 

Lesions of anetoderma of prematurity are not present at birth, which distinguishes them from congenital anetoderma.⁶ It is unclear if the lesions are associated with the degree of prematurity, extremely low birth weight, or other associated factors of preterm birth. Although often clinically diagnosed, the diagnosis can be confirmed by a loss of elastic fibers on histopathology when stained with Verhoeff-van Gieson stain.¹ Over time, the atrophic patches have the potential to evolve into herniated forms of anetoderma. Self-healing or improvement of the lesions often does not occur. Although the lesion is benign, it often requires surgical correction later in life for cosmesis.  

Infants in the NICU are at risk for iatrogenic cutaneous injuries, which rarely may include anetoderma. Anetoderma of prematurity has been linked to the use of monitoring leads, adhesive tape, and other medical devices placed on the skin. Prizant et al⁴ postulated that the cause of anetoderma in these infants was irritants such as skin cleansers, urine, or sweat that may be trapped under the electrodes. Other hypotheses include local hypoxemia due to prolonged pressure from the electrodes on immature skin or excessive traction used when removing adhesive tape from the skin.^7,8 Premature infants may be more susceptible to these lesions because of the reduced epidermal thickness of premature skin; immaturity of skin structure; or functional immaturity of elastin deposition regulators, such as elastase, lysyl oxidase, the complement system, and decay-accelerating factor.³ The diagnosis should be differentiated from congenital anetoderma, which also has been described in premature neonates but is characterized by lesions that are present at birth. Its origins are still unclear, despite having histopathologic features similar to iatrogenic anetoderma.⁹  

Focal dermal hypoplasia (FDH) is the hallmark cutaneous finding in Goltz syndrome, a rare set of congenital abnormalities of the skin, oral structures, musculoskeletal system, and central nervous system. Similar to congenital anetoderma, FDH also is characterized by atrophic cutaneous lesions; however, the cutaneous lesions in FDH appear as linear, streaky atrophic lesions often with telangiectasias that follow Blaschko lines.¹⁰ The cutaneous lesions in FDH often are associated with other noncutaneous signs such as polydactyly or asymmetric limbs.¹⁰ Cutis laxa is caused by an abnormality in the elastic tissue resulting in a loose sagging appearance of the skin and frequently results in an aged facial appearance. There are both acquired and inherited forms that can be either solely cutaneous or present with extracutaneous features, such as cardiac abnormalities or emphysema.¹¹ 

In contrast to the atrophic appearance of anetodermas, connective tissue nevi and nevus lipomatosus superficialis present as hamartomas that either can be present at birth or arise in infancy. Connective tissue nevi are hamartomas of dermal connective tissue that consist of excessive production of collagen, elastin, or glycosaminoglycans and appear as slightly elevated, flesh-colored to yellow nodules or plaques.¹² Connective tissue nevi often are described in association with other diseases, most commonly tuberous sclerosis (shagreen patches) or familial cutaneous collagenoma. Nevus lipomatosus superficialis is an asymptomatic connective tissue hamartoma composed of mature adipocytes in the dermis. The lesions consist of clusters of flesh-colored to yellow, soft, rubbery papules or nodules with a smooth or verrucoid surface that do not cross the midline and may follow Blaschko lines.¹¹ 

With advances in neonatal infant medical care, survival of extremely premature infants is increasing, and it is possible that this rare cutaneous disorder may become more prevalent. Care should be taken to avoid unnecessary pressure on surfaces where electrodes are placed and tightly applied adhesive tape. When electrodes are placed on the ventral side, the child should be placed supine; similarly, place electrodes on the dorsal side when the child is lying prone.⁵ A diagnosis of anetoderma of prematurity later in childhood may be difficult, so knowledge and awareness can help guide pediatricians and dermatologists to a correct diagnosis and prevent unnecessary evaluations and/or concerns. 

Chronic leg ulcers of all types feature a significant inflammatory component for which medical compression therapy is absolutely the best form of anti-inflammatory therapy, Elena Conde Montero, MD, PhD, asserted at the virtual annual congress of the European Academy of Dermatology and Venereology.

In addition to delving into the finer points of compression therapy, she offered other clinical pearls for the treatment of chronic leg ulcers. These included the use of autologous punch grafting to reduce pain as well as promote healing, when to employ adjunctive negative pressure therapy, and the benefits of liquid sevoflurane for highly effective topical analgesia during wound cleansing and debridement.
 

Compression therapy

“If no contraindications exist, compression therapy is the best antihypertensive and anti-inflammatory treatment for all leg ulcers, not only venous leg ulcers,” according to Dr. Conde, a dermatologist at Infanta Leonor University Hospital in Madrid.

The list of absolute contraindications to compression treatment is brief, as highlighted in a recent international consensus statement. The expert writing panel named only four: severe peripheral artery disease, the presence of an epifascial arterial bypass, severe cardiac insufficiency, and true allergy to compression material.

Compression therapy provides multiple salutary effects. These include reduced capillary filtration of fluids to tissue, decreased swelling, enhanced tissue remodeling, better lymphatic drainage, reduced inflammatory cell counts, and increased arterial flow.

“This means that people with mild arterial disease will benefit from active compression because perfusion will improve,” Dr. Conde said.

Similarly, leg ulcers secondary to pyoderma gangrenosum will benefit from the anti-inflammatory effects of compression therapy in conjunction with standard immunotherapy, added the dermatologist, who coauthored a recent publication by the European Wound Management Association entitled “Atypical Wounds: Best Clinical Practices and Challenges.”

Four broad types of compression therapy are available: compression stockings, short-stretch bandages, multicomponent bandage systems, and self-adjusting compression wrap devices. The best clinical outcomes are achieved by individualized selection of a compression method based upon patient characteristics.

Short-stretch, low-elasticity bandages – such as the classic Unna boot loaded with zinc paste and topical corticosteroids – are well suited for patients with large leg ulcers. These bandages feature high working pressures during muscle contraction. They also provide low resting pressures, which is advantageous in patients with peripheral artery disease. The major disadvantage of short-stretch bandages is the need for frequent dressing changes by a nurse or other trained professional, since the compression is quickly lost as an unwanted consequence of the welcome reduction in swelling.

Multicomponent bandage systems feature two to four layers of bandages of differing stiffness, as well as padding material and in many cases pressure indicators. These bandages can often be worn for up to a week without needing to be changed, since they maintain adequate pressure long term. “These are very easy to use by nonexperts,” Dr. Conde noted.

A caveat regarding both short-stretch bandages and the multicomponent bandage systems: before applying them, it’s important to pad at-risk areas against injury caused by high pressures. These high-risk areas include the Achilles tendon, the pretibial region, and the lateral foot.

Self-adjusting compression systems are comprised of strips of short-stretch, low-elasticity fabric, which wrap around the leg and are fixed with Velcro closures. Dr. Conde hailed these devices as “a great innovation in compression therapy, without doubt.” Their major advantage is ease of application and removal by the patient. They are best-suited for treatment of small ulcers in patients who find it difficult to use compression stockings because of obesity or osteoarthritis, in patients who can’t tolerate such stockings because they have peripheral artery disease and the stockings’ high resting pressure is uncomfortable, or in individuals ill-suited for compression bandages because they lack adequate access to nursing care for the required frequent dressing changes.

Compression stockings are a good option for small ulcers. It’s easier for patients to wear shoes with compression stockings and thereby engage in normal everyday activities than with short-stretch bandages. A tip: Many patients find it arduous to don and remove a high-compression stocking that achieves the recommended pressure of 30-40 mm Hg at the point of transition between the Achilles tendon and the calf muscle, but the same effect can be achieved by overlapping two easier-to-use lower-compression stockings.

Punch grafting

This simple, cost-effective outpatient procedure was first described as a means of enhancing wound healing 150 years ago. The method involves utilizing a scalpel, curette, or punch to obtain a series of thin split-thickness skin grafts that contain epidermis and dermis down to the superficial papillary dermis. The grafts, usually harvested from the anterior thigh, are placed on the wound. This is followed by at least 5 days of local pressure and rest to promote graft uptake.

Sequential punch grafting is an excellent option for particularly challenging chronic ulcers, including Martorell hypertensive ischemic leg ulcers and other arteriolopathic ulcers in the elderly.

“Sequential punch grafting of wounds is very common in our clinics, especially for wounds that lack perfect grafting conditions,” Dr. Conde said.

She considers Martorell hypertensive ischemic leg ulcers to be underdiagnosed and undertreated. The Martorell leg ulcer is an exceedingly painful, rapidly progressive ischemic lesion, or bilateral lesions, with inflamed irregular margins. The disorder is caused by obstruction of subcutaneous arterioles in the absence of signs of vasculitis, and generally occurs in older individuals who have had well-controlled hypertension for many years. Diabetes, obesity, dyslipidemia, and peripheral artery disease are common comorbid conditions. The most common form of treatment – bioactive dressings in a moist environment – produces unsatisfactory results because it doesn’t address the inflammatory process.

Dr. Conde and coworkers have published the full details of how they achieved complete healing of Martorell hypertensive ischemic leg ulcers 3-8 weeks after punch grafting in three affected patients, all of whom presented with pain scores of 10/10 refractory even to opioid analgesics. The punch grafting was preceded by 15 days of topical corticosteroids and low-elasticity compression bandages in order to create adequate granulation tissue in the wound bed, which had the added benefit of achieving a 2- to 3-point reduction in pain scores even before the surgical procedure.

The pain-reducing effect of punch grafting isn’t as well appreciated as the wound-healing effect. Dr. Conde was first author of a recent study in which investigators systematically measured pain reduction in 136 patients with hard-to-heal leg ulcers of various etiologies treated with punch grafting. Nearly three-quarters of those who presented with painful ulcers were pain free after punch grafting, and the rest experienced greater than 70% pain reduction.

Pain suppression wasn’t dependent upon the percentage of graft uptake in this study. That’s because, as long as the wound isn’t overcleaned during dressing changes, even grafts that haven’t attached to the wound will release growth factors that promote wound healing, Dr. Conde explained.
 

Adjunctive negative pressure therapy

Portable vacuum-based negative pressure therapy devices are easy to use as a means to promote punch graft uptake. Negative pressure is best employed as an adjunct to punch grafting in suboptimal wound beds, longstanding ulcers, in patients with previous graft failure, or in challenging anatomic locations, such as the Achilles tendon or ankle. Dr. Conde has found the combination of punch grafting and negative pressure therapy especially helpful in patients with clinically inactive pyoderma gangrenosum.

Topical sevoflurane for analgesia

Most of the literature on topical sevoflurane for ulcer care has been published by Spanish researchers, but this form of analgesia deserves much more widespread use, according to Dr. Conde.

Sevoflurane is most often used as a gas in general anesthesia. In liquid form, however, it not only has a rapid, long-lasting analgesic effect when applied to painful leg ulcers, it also promotes healing because it is both antibacterial and a vasodilator. So before performing a potentially painful ulcer or wound cleaning, Dr. Conde recommended protecting perilesional skin with petroleum jelly, then irrigating the ulcer site with liquid sevoflurane. After that, it’s advisable to wait just 5-10 minutes before proceeding.

“It takes effect in much less time than EMLA cream,” she noted.

In one study of 30 adults aged over age 65 years with painful chronic venous ulcers refractory to conventional analgesics who underwent ulcer cleaning supported by topical sevoflurane at a dose of roughly 1 mL/cm² of ulcer area every 2 days for a month, Spanish investigators documented onset of analgesic effect in 2-7 minutes, with a duration of 8-18 hours. The researchers found that the use of backup conventional analgesics ranging from acetaminophen to opioids was diminished. Side effects were limited to mild, transient itching and redness.

Dr. Conde reported having no financial conflicts of interest regarding her presentation.

bjancin@mdedge.com

Chronic leg ulcers of all types feature a significant inflammatory component for which medical compression therapy is absolutely the best form of anti-inflammatory therapy, Elena Conde Montero, MD, PhD, asserted at the virtual annual congress of the European Academy of Dermatology and Venereology.

In addition to delving into the finer points of compression therapy, she offered other clinical pearls for the treatment of chronic leg ulcers. These included the use of autologous punch grafting to reduce pain as well as promote healing, when to employ adjunctive negative pressure therapy, and the benefits of liquid sevoflurane for highly effective topical analgesia during wound cleansing and debridement.
 

Compression therapy

“If no contraindications exist, compression therapy is the best antihypertensive and anti-inflammatory treatment for all leg ulcers, not only venous leg ulcers,” according to Dr. Conde, a dermatologist at Infanta Leonor University Hospital in Madrid.

The list of absolute contraindications to compression treatment is brief, as highlighted in a recent international consensus statement. The expert writing panel named only four: severe peripheral artery disease, the presence of an epifascial arterial bypass, severe cardiac insufficiency, and true allergy to compression material.

Compression therapy provides multiple salutary effects. These include reduced capillary filtration of fluids to tissue, decreased swelling, enhanced tissue remodeling, better lymphatic drainage, reduced inflammatory cell counts, and increased arterial flow.

“This means that people with mild arterial disease will benefit from active compression because perfusion will improve,” Dr. Conde said.

Similarly, leg ulcers secondary to pyoderma gangrenosum will benefit from the anti-inflammatory effects of compression therapy in conjunction with standard immunotherapy, added the dermatologist, who coauthored a recent publication by the European Wound Management Association entitled “Atypical Wounds: Best Clinical Practices and Challenges.”

Four broad types of compression therapy are available: compression stockings, short-stretch bandages, multicomponent bandage systems, and self-adjusting compression wrap devices. The best clinical outcomes are achieved by individualized selection of a compression method based upon patient characteristics.

Short-stretch, low-elasticity bandages – such as the classic Unna boot loaded with zinc paste and topical corticosteroids – are well suited for patients with large leg ulcers. These bandages feature high working pressures during muscle contraction. They also provide low resting pressures, which is advantageous in patients with peripheral artery disease. The major disadvantage of short-stretch bandages is the need for frequent dressing changes by a nurse or other trained professional, since the compression is quickly lost as an unwanted consequence of the welcome reduction in swelling.

Multicomponent bandage systems feature two to four layers of bandages of differing stiffness, as well as padding material and in many cases pressure indicators. These bandages can often be worn for up to a week without needing to be changed, since they maintain adequate pressure long term. “These are very easy to use by nonexperts,” Dr. Conde noted.

A caveat regarding both short-stretch bandages and the multicomponent bandage systems: before applying them, it’s important to pad at-risk areas against injury caused by high pressures. These high-risk areas include the Achilles tendon, the pretibial region, and the lateral foot.

Self-adjusting compression systems are comprised of strips of short-stretch, low-elasticity fabric, which wrap around the leg and are fixed with Velcro closures. Dr. Conde hailed these devices as “a great innovation in compression therapy, without doubt.” Their major advantage is ease of application and removal by the patient. They are best-suited for treatment of small ulcers in patients who find it difficult to use compression stockings because of obesity or osteoarthritis, in patients who can’t tolerate such stockings because they have peripheral artery disease and the stockings’ high resting pressure is uncomfortable, or in individuals ill-suited for compression bandages because they lack adequate access to nursing care for the required frequent dressing changes.

Compression stockings are a good option for small ulcers. It’s easier for patients to wear shoes with compression stockings and thereby engage in normal everyday activities than with short-stretch bandages. A tip: Many patients find it arduous to don and remove a high-compression stocking that achieves the recommended pressure of 30-40 mm Hg at the point of transition between the Achilles tendon and the calf muscle, but the same effect can be achieved by overlapping two easier-to-use lower-compression stockings.

Punch grafting

This simple, cost-effective outpatient procedure was first described as a means of enhancing wound healing 150 years ago. The method involves utilizing a scalpel, curette, or punch to obtain a series of thin split-thickness skin grafts that contain epidermis and dermis down to the superficial papillary dermis. The grafts, usually harvested from the anterior thigh, are placed on the wound. This is followed by at least 5 days of local pressure and rest to promote graft uptake.

Sequential punch grafting is an excellent option for particularly challenging chronic ulcers, including Martorell hypertensive ischemic leg ulcers and other arteriolopathic ulcers in the elderly.

“Sequential punch grafting of wounds is very common in our clinics, especially for wounds that lack perfect grafting conditions,” Dr. Conde said.

She considers Martorell hypertensive ischemic leg ulcers to be underdiagnosed and undertreated. The Martorell leg ulcer is an exceedingly painful, rapidly progressive ischemic lesion, or bilateral lesions, with inflamed irregular margins. The disorder is caused by obstruction of subcutaneous arterioles in the absence of signs of vasculitis, and generally occurs in older individuals who have had well-controlled hypertension for many years. Diabetes, obesity, dyslipidemia, and peripheral artery disease are common comorbid conditions. The most common form of treatment – bioactive dressings in a moist environment – produces unsatisfactory results because it doesn’t address the inflammatory process.

Dr. Conde and coworkers have published the full details of how they achieved complete healing of Martorell hypertensive ischemic leg ulcers 3-8 weeks after punch grafting in three affected patients, all of whom presented with pain scores of 10/10 refractory even to opioid analgesics. The punch grafting was preceded by 15 days of topical corticosteroids and low-elasticity compression bandages in order to create adequate granulation tissue in the wound bed, which had the added benefit of achieving a 2- to 3-point reduction in pain scores even before the surgical procedure.

The pain-reducing effect of punch grafting isn’t as well appreciated as the wound-healing effect. Dr. Conde was first author of a recent study in which investigators systematically measured pain reduction in 136 patients with hard-to-heal leg ulcers of various etiologies treated with punch grafting. Nearly three-quarters of those who presented with painful ulcers were pain free after punch grafting, and the rest experienced greater than 70% pain reduction.

Pain suppression wasn’t dependent upon the percentage of graft uptake in this study. That’s because, as long as the wound isn’t overcleaned during dressing changes, even grafts that haven’t attached to the wound will release growth factors that promote wound healing, Dr. Conde explained.
 

Adjunctive negative pressure therapy

Portable vacuum-based negative pressure therapy devices are easy to use as a means to promote punch graft uptake. Negative pressure is best employed as an adjunct to punch grafting in suboptimal wound beds, longstanding ulcers, in patients with previous graft failure, or in challenging anatomic locations, such as the Achilles tendon or ankle. Dr. Conde has found the combination of punch grafting and negative pressure therapy especially helpful in patients with clinically inactive pyoderma gangrenosum.

Topical sevoflurane for analgesia

Most of the literature on topical sevoflurane for ulcer care has been published by Spanish researchers, but this form of analgesia deserves much more widespread use, according to Dr. Conde.

Sevoflurane is most often used as a gas in general anesthesia. In liquid form, however, it not only has a rapid, long-lasting analgesic effect when applied to painful leg ulcers, it also promotes healing because it is both antibacterial and a vasodilator. So before performing a potentially painful ulcer or wound cleaning, Dr. Conde recommended protecting perilesional skin with petroleum jelly, then irrigating the ulcer site with liquid sevoflurane. After that, it’s advisable to wait just 5-10 minutes before proceeding.

“It takes effect in much less time than EMLA cream,” she noted.

In one study of 30 adults aged over age 65 years with painful chronic venous ulcers refractory to conventional analgesics who underwent ulcer cleaning supported by topical sevoflurane at a dose of roughly 1 mL/cm² of ulcer area every 2 days for a month, Spanish investigators documented onset of analgesic effect in 2-7 minutes, with a duration of 8-18 hours. The researchers found that the use of backup conventional analgesics ranging from acetaminophen to opioids was diminished. Side effects were limited to mild, transient itching and redness.

Dr. Conde reported having no financial conflicts of interest regarding her presentation.

bjancin@mdedge.com

Chronic leg ulcers of all types feature a significant inflammatory component for which medical compression therapy is absolutely the best form of anti-inflammatory therapy, Elena Conde Montero, MD, PhD, asserted at the virtual annual congress of the European Academy of Dermatology and Venereology.

In addition to delving into the finer points of compression therapy, she offered other clinical pearls for the treatment of chronic leg ulcers. These included the use of autologous punch grafting to reduce pain as well as promote healing, when to employ adjunctive negative pressure therapy, and the benefits of liquid sevoflurane for highly effective topical analgesia during wound cleansing and debridement.
 

Compression therapy

“If no contraindications exist, compression therapy is the best antihypertensive and anti-inflammatory treatment for all leg ulcers, not only venous leg ulcers,” according to Dr. Conde, a dermatologist at Infanta Leonor University Hospital in Madrid.

The list of absolute contraindications to compression treatment is brief, as highlighted in a recent international consensus statement. The expert writing panel named only four: severe peripheral artery disease, the presence of an epifascial arterial bypass, severe cardiac insufficiency, and true allergy to compression material.

Compression therapy provides multiple salutary effects. These include reduced capillary filtration of fluids to tissue, decreased swelling, enhanced tissue remodeling, better lymphatic drainage, reduced inflammatory cell counts, and increased arterial flow.

“This means that people with mild arterial disease will benefit from active compression because perfusion will improve,” Dr. Conde said.

Similarly, leg ulcers secondary to pyoderma gangrenosum will benefit from the anti-inflammatory effects of compression therapy in conjunction with standard immunotherapy, added the dermatologist, who coauthored a recent publication by the European Wound Management Association entitled “Atypical Wounds: Best Clinical Practices and Challenges.”

Four broad types of compression therapy are available: compression stockings, short-stretch bandages, multicomponent bandage systems, and self-adjusting compression wrap devices. The best clinical outcomes are achieved by individualized selection of a compression method based upon patient characteristics.

Short-stretch, low-elasticity bandages – such as the classic Unna boot loaded with zinc paste and topical corticosteroids – are well suited for patients with large leg ulcers. These bandages feature high working pressures during muscle contraction. They also provide low resting pressures, which is advantageous in patients with peripheral artery disease. The major disadvantage of short-stretch bandages is the need for frequent dressing changes by a nurse or other trained professional, since the compression is quickly lost as an unwanted consequence of the welcome reduction in swelling.

Multicomponent bandage systems feature two to four layers of bandages of differing stiffness, as well as padding material and in many cases pressure indicators. These bandages can often be worn for up to a week without needing to be changed, since they maintain adequate pressure long term. “These are very easy to use by nonexperts,” Dr. Conde noted.

A caveat regarding both short-stretch bandages and the multicomponent bandage systems: before applying them, it’s important to pad at-risk areas against injury caused by high pressures. These high-risk areas include the Achilles tendon, the pretibial region, and the lateral foot.

Self-adjusting compression systems are comprised of strips of short-stretch, low-elasticity fabric, which wrap around the leg and are fixed with Velcro closures. Dr. Conde hailed these devices as “a great innovation in compression therapy, without doubt.” Their major advantage is ease of application and removal by the patient. They are best-suited for treatment of small ulcers in patients who find it difficult to use compression stockings because of obesity or osteoarthritis, in patients who can’t tolerate such stockings because they have peripheral artery disease and the stockings’ high resting pressure is uncomfortable, or in individuals ill-suited for compression bandages because they lack adequate access to nursing care for the required frequent dressing changes.

Compression stockings are a good option for small ulcers. It’s easier for patients to wear shoes with compression stockings and thereby engage in normal everyday activities than with short-stretch bandages. A tip: Many patients find it arduous to don and remove a high-compression stocking that achieves the recommended pressure of 30-40 mm Hg at the point of transition between the Achilles tendon and the calf muscle, but the same effect can be achieved by overlapping two easier-to-use lower-compression stockings.

Punch grafting

This simple, cost-effective outpatient procedure was first described as a means of enhancing wound healing 150 years ago. The method involves utilizing a scalpel, curette, or punch to obtain a series of thin split-thickness skin grafts that contain epidermis and dermis down to the superficial papillary dermis. The grafts, usually harvested from the anterior thigh, are placed on the wound. This is followed by at least 5 days of local pressure and rest to promote graft uptake.

Sequential punch grafting is an excellent option for particularly challenging chronic ulcers, including Martorell hypertensive ischemic leg ulcers and other arteriolopathic ulcers in the elderly.

“Sequential punch grafting of wounds is very common in our clinics, especially for wounds that lack perfect grafting conditions,” Dr. Conde said.

She considers Martorell hypertensive ischemic leg ulcers to be underdiagnosed and undertreated. The Martorell leg ulcer is an exceedingly painful, rapidly progressive ischemic lesion, or bilateral lesions, with inflamed irregular margins. The disorder is caused by obstruction of subcutaneous arterioles in the absence of signs of vasculitis, and generally occurs in older individuals who have had well-controlled hypertension for many years. Diabetes, obesity, dyslipidemia, and peripheral artery disease are common comorbid conditions. The most common form of treatment – bioactive dressings in a moist environment – produces unsatisfactory results because it doesn’t address the inflammatory process.

Dr. Conde and coworkers have published the full details of how they achieved complete healing of Martorell hypertensive ischemic leg ulcers 3-8 weeks after punch grafting in three affected patients, all of whom presented with pain scores of 10/10 refractory even to opioid analgesics. The punch grafting was preceded by 15 days of topical corticosteroids and low-elasticity compression bandages in order to create adequate granulation tissue in the wound bed, which had the added benefit of achieving a 2- to 3-point reduction in pain scores even before the surgical procedure.

The pain-reducing effect of punch grafting isn’t as well appreciated as the wound-healing effect. Dr. Conde was first author of a recent study in which investigators systematically measured pain reduction in 136 patients with hard-to-heal leg ulcers of various etiologies treated with punch grafting. Nearly three-quarters of those who presented with painful ulcers were pain free after punch grafting, and the rest experienced greater than 70% pain reduction.

Pain suppression wasn’t dependent upon the percentage of graft uptake in this study. That’s because, as long as the wound isn’t overcleaned during dressing changes, even grafts that haven’t attached to the wound will release growth factors that promote wound healing, Dr. Conde explained.
 

Adjunctive negative pressure therapy

Portable vacuum-based negative pressure therapy devices are easy to use as a means to promote punch graft uptake. Negative pressure is best employed as an adjunct to punch grafting in suboptimal wound beds, longstanding ulcers, in patients with previous graft failure, or in challenging anatomic locations, such as the Achilles tendon or ankle. Dr. Conde has found the combination of punch grafting and negative pressure therapy especially helpful in patients with clinically inactive pyoderma gangrenosum.

Topical sevoflurane for analgesia

Most of the literature on topical sevoflurane for ulcer care has been published by Spanish researchers, but this form of analgesia deserves much more widespread use, according to Dr. Conde.

Sevoflurane is most often used as a gas in general anesthesia. In liquid form, however, it not only has a rapid, long-lasting analgesic effect when applied to painful leg ulcers, it also promotes healing because it is both antibacterial and a vasodilator. So before performing a potentially painful ulcer or wound cleaning, Dr. Conde recommended protecting perilesional skin with petroleum jelly, then irrigating the ulcer site with liquid sevoflurane. After that, it’s advisable to wait just 5-10 minutes before proceeding.

“It takes effect in much less time than EMLA cream,” she noted.

In one study of 30 adults aged over age 65 years with painful chronic venous ulcers refractory to conventional analgesics who underwent ulcer cleaning supported by topical sevoflurane at a dose of roughly 1 mL/cm² of ulcer area every 2 days for a month, Spanish investigators documented onset of analgesic effect in 2-7 minutes, with a duration of 8-18 hours. The researchers found that the use of backup conventional analgesics ranging from acetaminophen to opioids was diminished. Side effects were limited to mild, transient itching and redness.

Dr. Conde reported having no financial conflicts of interest regarding her presentation.

bjancin@mdedge.com

Practice Gap

Practical patient positioning is a commonly overlooked method of tension control during excision and repair that allows for easier closure.¹ Although positioning is a basic step in dermatologic surgery, it often is difficult and awkward for both the patient and physician. Here, we describe basic principles in patient positioning that increase tension across the surgical site during excision and reduce tension during closure. By reducing the amount of work required for excision and closure, procedures are completed more quickly, which increases efficiency. These techniques should be considered during dermatologic surgery at sites that are subject to both high tension and repetitive motion, such as the upper back and lower extremities.

Technique: Upper Back Procedures

When removing lesions on the upper back, lying completely prone is uncomfortable for the patient and leaves the shoulders hyperextended.² Instead, position the patient with the arms extended anteriorly, hugging a pillow, while lying prone or on one side (Figure 1). In this position, excision of the lesion is facilitated by increased tension across the upper back. In addition, this position is notably more comfortable for the patient. During closure, the patient should lie on the side contralateral to the surgical site, with the elbow resting at the hip and the ipsilateral arm lying parallel to the torso (Figure 2).

Following procedures on the upper back and shoulders, we typically recommend that the patient wear an arm sling on the ipsilateral side for 1 week. Doing so reliably limits mobility postoperatively and does not require the patient to constantly monitor their movement.

Technique: Lower Extremity Procedures

Anterior Lower Extremity
During excision of a lesion on the anterior lower extremity, we recommend that the patient be positioned with their knee bent and heel resting on the examination table. Ideally, the knee is flexed at approximately a 45° angle (Figure 3).³ In this position, excision of the lesion is facilitated by increased tension across the anterior lower extremity. During closure of these lesions, the patient should lie supine with the knee fully extended and the leg resting on the surgical bed or a pillow.

Posterior Lower Extremity
During excision of lesions on the posterior lower extremity, the patient should be positioned lying prone, with the knee fully extended, resting on the surgical bed or a pillow, which facilitates excision of the lesion by increasing tension across the site. During closure of these lesions, the patient should lie on the side contralateral to the surgical site, with the leg fully extended for support. The surgical leg should be flexed at the knee at approximately a 45° angle (Figure 4).

Practice Implications

Despite being an important step, patient positioning is an often-overlooked component of dermatologic surgery. Positioning becomes even more important in areas of high tension and repetitive motion, such as the upper back and lower extremities, where the risk of wound dehiscence and poor scar cosmesis is increased.¹ Experienced dermatologic surgeons should utilize patient positioning, taking advantage of tension instead of working against it.

We have found that these 2 simple principles can aid in simplifying the excision and repair processes. Increasing tension across the surgical site during excision reduces the work required by the surgeon to reach the appropriate depth. Conversely, decreased tension across the surgical site decreases the work required for closure. These principles should be considered prior to the procedure; the patient should then be positioned in a way that maximizes tension across the surgical site during excision and minimizes tension across the surgical site during closure.

Incorporating these techniques, especially at sites that are subject to both high tension and repetitive motion, such as the upper back and lower extremities, not only increases efficiency but may also reduce the risk for wound dehiscence once the patient returns home and maintains their normal level of physical activity.

Practice Gap

Practical patient positioning is a commonly overlooked method of tension control during excision and repair that allows for easier closure.¹ Although positioning is a basic step in dermatologic surgery, it often is difficult and awkward for both the patient and physician. Here, we describe basic principles in patient positioning that increase tension across the surgical site during excision and reduce tension during closure. By reducing the amount of work required for excision and closure, procedures are completed more quickly, which increases efficiency. These techniques should be considered during dermatologic surgery at sites that are subject to both high tension and repetitive motion, such as the upper back and lower extremities.

Technique: Upper Back Procedures

When removing lesions on the upper back, lying completely prone is uncomfortable for the patient and leaves the shoulders hyperextended.² Instead, position the patient with the arms extended anteriorly, hugging a pillow, while lying prone or on one side (Figure 1). In this position, excision of the lesion is facilitated by increased tension across the upper back. In addition, this position is notably more comfortable for the patient. During closure, the patient should lie on the side contralateral to the surgical site, with the elbow resting at the hip and the ipsilateral arm lying parallel to the torso (Figure 2).

Following procedures on the upper back and shoulders, we typically recommend that the patient wear an arm sling on the ipsilateral side for 1 week. Doing so reliably limits mobility postoperatively and does not require the patient to constantly monitor their movement.

Technique: Lower Extremity Procedures

Anterior Lower Extremity
During excision of a lesion on the anterior lower extremity, we recommend that the patient be positioned with their knee bent and heel resting on the examination table. Ideally, the knee is flexed at approximately a 45° angle (Figure 3).³ In this position, excision of the lesion is facilitated by increased tension across the anterior lower extremity. During closure of these lesions, the patient should lie supine with the knee fully extended and the leg resting on the surgical bed or a pillow.

Posterior Lower Extremity
During excision of lesions on the posterior lower extremity, the patient should be positioned lying prone, with the knee fully extended, resting on the surgical bed or a pillow, which facilitates excision of the lesion by increasing tension across the site. During closure of these lesions, the patient should lie on the side contralateral to the surgical site, with the leg fully extended for support. The surgical leg should be flexed at the knee at approximately a 45° angle (Figure 4).

Practice Implications

Despite being an important step, patient positioning is an often-overlooked component of dermatologic surgery. Positioning becomes even more important in areas of high tension and repetitive motion, such as the upper back and lower extremities, where the risk of wound dehiscence and poor scar cosmesis is increased.¹ Experienced dermatologic surgeons should utilize patient positioning, taking advantage of tension instead of working against it.

We have found that these 2 simple principles can aid in simplifying the excision and repair processes. Increasing tension across the surgical site during excision reduces the work required by the surgeon to reach the appropriate depth. Conversely, decreased tension across the surgical site decreases the work required for closure. These principles should be considered prior to the procedure; the patient should then be positioned in a way that maximizes tension across the surgical site during excision and minimizes tension across the surgical site during closure.

Incorporating these techniques, especially at sites that are subject to both high tension and repetitive motion, such as the upper back and lower extremities, not only increases efficiency but may also reduce the risk for wound dehiscence once the patient returns home and maintains their normal level of physical activity.

Practice Gap

Practical patient positioning is a commonly overlooked method of tension control during excision and repair that allows for easier closure.¹ Although positioning is a basic step in dermatologic surgery, it often is difficult and awkward for both the patient and physician. Here, we describe basic principles in patient positioning that increase tension across the surgical site during excision and reduce tension during closure. By reducing the amount of work required for excision and closure, procedures are completed more quickly, which increases efficiency. These techniques should be considered during dermatologic surgery at sites that are subject to both high tension and repetitive motion, such as the upper back and lower extremities.

Technique: Upper Back Procedures

When removing lesions on the upper back, lying completely prone is uncomfortable for the patient and leaves the shoulders hyperextended.² Instead, position the patient with the arms extended anteriorly, hugging a pillow, while lying prone or on one side (Figure 1). In this position, excision of the lesion is facilitated by increased tension across the upper back. In addition, this position is notably more comfortable for the patient. During closure, the patient should lie on the side contralateral to the surgical site, with the elbow resting at the hip and the ipsilateral arm lying parallel to the torso (Figure 2).

Following procedures on the upper back and shoulders, we typically recommend that the patient wear an arm sling on the ipsilateral side for 1 week. Doing so reliably limits mobility postoperatively and does not require the patient to constantly monitor their movement.

Technique: Lower Extremity Procedures

Anterior Lower Extremity
During excision of a lesion on the anterior lower extremity, we recommend that the patient be positioned with their knee bent and heel resting on the examination table. Ideally, the knee is flexed at approximately a 45° angle (Figure 3).³ In this position, excision of the lesion is facilitated by increased tension across the anterior lower extremity. During closure of these lesions, the patient should lie supine with the knee fully extended and the leg resting on the surgical bed or a pillow.

Posterior Lower Extremity
During excision of lesions on the posterior lower extremity, the patient should be positioned lying prone, with the knee fully extended, resting on the surgical bed or a pillow, which facilitates excision of the lesion by increasing tension across the site. During closure of these lesions, the patient should lie on the side contralateral to the surgical site, with the leg fully extended for support. The surgical leg should be flexed at the knee at approximately a 45° angle (Figure 4).

Practice Implications

Despite being an important step, patient positioning is an often-overlooked component of dermatologic surgery. Positioning becomes even more important in areas of high tension and repetitive motion, such as the upper back and lower extremities, where the risk of wound dehiscence and poor scar cosmesis is increased.¹ Experienced dermatologic surgeons should utilize patient positioning, taking advantage of tension instead of working against it.

We have found that these 2 simple principles can aid in simplifying the excision and repair processes. Increasing tension across the surgical site during excision reduces the work required by the surgeon to reach the appropriate depth. Conversely, decreased tension across the surgical site decreases the work required for closure. These principles should be considered prior to the procedure; the patient should then be positioned in a way that maximizes tension across the surgical site during excision and minimizes tension across the surgical site during closure.

Incorporating these techniques, especially at sites that are subject to both high tension and repetitive motion, such as the upper back and lower extremities, not only increases efficiency but may also reduce the risk for wound dehiscence once the patient returns home and maintains their normal level of physical activity.

Sponges are among the oldest animals on earth, appearing more than 640 million years ago before the Cambrian explosion, a period when most major animal phyla appeared in the fossil records.¹ More than 10,000 species of sponges have been identified worldwide and are distributed from polar to tropical regions in both marine (Figure 1) and freshwater (Figure 2) environments. They inhabit both shallow waters as well as depths of more than 2800 m, with shallower sponges tending to be more vibrantly colored than their deeper counterparts. The wide-ranging habitats of sponges have led to size variations from as small as 0.05 mm to more than 3 m in height.² Their taxonomic phylum, Porifera (meaning pore bearers), is derived from the millions of pores lining the surface of the sponge that are used to filter planktonic organisms.³ Flagellated epithelioid cells called choanocytes line the internal chambers of sponges, creating a water current that promotes filter feeding as well as nutrient absorption across their microvilli.⁴ The body walls of many sponges consist of a collagenous skeleton made up of spongin and spicules of silicon dioxide (silica) or calcium carbonate embedded in the spongin connective tissue matrix.⁵ Bath sponges lack silica spicules.

Sponges have been used in medicine for centuries. The first use in Western culture was recorded in 405 bce in The Frogs, a comedy by Aristophanes in which a sponge was placed on a character’s heart following a syncopal episode. Additionally, in many Hippocratic writings, the use of sponges is outlined in the treatment of a variety of ailments. Similarly, the ancient Chinese and Greeks used burnt sponge and seaweed as a source of iodine to treat goiters.^6,7 Modern research focuses on the use of sponge metabolites for their antineoplastic, antimicrobial, and anti-inflammatory effects.⁸ Identification of spongouridine and spongothymidine from the sponge Tectitethya crypta led to the development of cytarabine and gemcitabine⁸ as well as the discovery of the antiviral agent vidarabine.⁹ The monoclonal antibody assay for the detection of shellfish poisoning was prepared using the sponge Halichondria okadai.¹⁰

Mechanisms and Symptoms of Injury

Bathing sponges (silk sponges) derived from Spongia officinalis are harmless. Other sponges can exert their damaging effects through a variety of mechanisms that lead to dermatologic manifestations (eTable). Some species of sponges produce and secrete toxic metabolites (eg, crinotoxins) onto the body surface or into the surrounding water. They also are capable of synthesizing a mucous slime that can be irritating to human skin. Direct trauma also can be caused by fragments of the silica or calcium carbonate sponge skeleton penetrating the skin. Stinging members of the phylum Cnidaria can colonize the sponge, leading to injury when a human handles the sponge.^25-27

Sponge dermatitis can be divided into 2 major categories: an initial pruritic dermatitis (Figure 3) that occurs within 20 minutes to a few hours after contact and a delayed irritant dermatitis caused by penetration of the spicules and chemical agents into skin.²⁸ Importantly, different species can lead to varying manifestations.

Management

Treatment should consist of an initial decontamination; the skin should be dried, and adhesive tape or rubber cement should be utilized to remove any spicules embedded in the skin. Diluted vinegar soaks should be initiated for 10 to 30 minutes on the affected area(s) 3 or 4 times daily.¹⁹ The initial decontamination should occur immediately, as delay may lead to persistent purulent bullae that may take months to heal. Topical steroids may be used following the initial decontamination to help relieve inflammation. Antihistamines and nonsteroidal anti-inflammatory drugs may be used to alleviate pruritus and pain, respectively. Severe cases may require systemic glucocorticoids. Additionally, immunization status against tetanus toxoid should be assessed.³⁵ In the event of an anaphylactic reaction, it is important to maintain a patent airway and normalized blood pressure through the use of intramuscular epinephrine.³⁶ Frequent follow-up is warranted, as serious secondary infections can develop.³⁷ Patients also should be counseled on the potential for delayed dermatologic reactions, including erythema multiforme. Contact between humans and coastal environments has been increasing in the last few decades; therefore, an increase in contact with sponges is to be expected.²²

Sponges are among the oldest animals on earth, appearing more than 640 million years ago before the Cambrian explosion, a period when most major animal phyla appeared in the fossil records.¹ More than 10,000 species of sponges have been identified worldwide and are distributed from polar to tropical regions in both marine (Figure 1) and freshwater (Figure 2) environments. They inhabit both shallow waters as well as depths of more than 2800 m, with shallower sponges tending to be more vibrantly colored than their deeper counterparts. The wide-ranging habitats of sponges have led to size variations from as small as 0.05 mm to more than 3 m in height.² Their taxonomic phylum, Porifera (meaning pore bearers), is derived from the millions of pores lining the surface of the sponge that are used to filter planktonic organisms.³ Flagellated epithelioid cells called choanocytes line the internal chambers of sponges, creating a water current that promotes filter feeding as well as nutrient absorption across their microvilli.⁴ The body walls of many sponges consist of a collagenous skeleton made up of spongin and spicules of silicon dioxide (silica) or calcium carbonate embedded in the spongin connective tissue matrix.⁵ Bath sponges lack silica spicules.

Sponges have been used in medicine for centuries. The first use in Western culture was recorded in 405 bce in The Frogs, a comedy by Aristophanes in which a sponge was placed on a character’s heart following a syncopal episode. Additionally, in many Hippocratic writings, the use of sponges is outlined in the treatment of a variety of ailments. Similarly, the ancient Chinese and Greeks used burnt sponge and seaweed as a source of iodine to treat goiters.^6,7 Modern research focuses on the use of sponge metabolites for their antineoplastic, antimicrobial, and anti-inflammatory effects.⁸ Identification of spongouridine and spongothymidine from the sponge Tectitethya crypta led to the development of cytarabine and gemcitabine⁸ as well as the discovery of the antiviral agent vidarabine.⁹ The monoclonal antibody assay for the detection of shellfish poisoning was prepared using the sponge Halichondria okadai.¹⁰

Mechanisms and Symptoms of Injury

Bathing sponges (silk sponges) derived from Spongia officinalis are harmless. Other sponges can exert their damaging effects through a variety of mechanisms that lead to dermatologic manifestations (eTable). Some species of sponges produce and secrete toxic metabolites (eg, crinotoxins) onto the body surface or into the surrounding water. They also are capable of synthesizing a mucous slime that can be irritating to human skin. Direct trauma also can be caused by fragments of the silica or calcium carbonate sponge skeleton penetrating the skin. Stinging members of the phylum Cnidaria can colonize the sponge, leading to injury when a human handles the sponge.^25-27

Sponge dermatitis can be divided into 2 major categories: an initial pruritic dermatitis (Figure 3) that occurs within 20 minutes to a few hours after contact and a delayed irritant dermatitis caused by penetration of the spicules and chemical agents into skin.²⁸ Importantly, different species can lead to varying manifestations.

Management

Treatment should consist of an initial decontamination; the skin should be dried, and adhesive tape or rubber cement should be utilized to remove any spicules embedded in the skin. Diluted vinegar soaks should be initiated for 10 to 30 minutes on the affected area(s) 3 or 4 times daily.¹⁹ The initial decontamination should occur immediately, as delay may lead to persistent purulent bullae that may take months to heal. Topical steroids may be used following the initial decontamination to help relieve inflammation. Antihistamines and nonsteroidal anti-inflammatory drugs may be used to alleviate pruritus and pain, respectively. Severe cases may require systemic glucocorticoids. Additionally, immunization status against tetanus toxoid should be assessed.³⁵ In the event of an anaphylactic reaction, it is important to maintain a patent airway and normalized blood pressure through the use of intramuscular epinephrine.³⁶ Frequent follow-up is warranted, as serious secondary infections can develop.³⁷ Patients also should be counseled on the potential for delayed dermatologic reactions, including erythema multiforme. Contact between humans and coastal environments has been increasing in the last few decades; therefore, an increase in contact with sponges is to be expected.²²

Sponges are among the oldest animals on earth, appearing more than 640 million years ago before the Cambrian explosion, a period when most major animal phyla appeared in the fossil records.¹ More than 10,000 species of sponges have been identified worldwide and are distributed from polar to tropical regions in both marine (Figure 1) and freshwater (Figure 2) environments. They inhabit both shallow waters as well as depths of more than 2800 m, with shallower sponges tending to be more vibrantly colored than their deeper counterparts. The wide-ranging habitats of sponges have led to size variations from as small as 0.05 mm to more than 3 m in height.² Their taxonomic phylum, Porifera (meaning pore bearers), is derived from the millions of pores lining the surface of the sponge that are used to filter planktonic organisms.³ Flagellated epithelioid cells called choanocytes line the internal chambers of sponges, creating a water current that promotes filter feeding as well as nutrient absorption across their microvilli.⁴ The body walls of many sponges consist of a collagenous skeleton made up of spongin and spicules of silicon dioxide (silica) or calcium carbonate embedded in the spongin connective tissue matrix.⁵ Bath sponges lack silica spicules.

Sponges have been used in medicine for centuries. The first use in Western culture was recorded in 405 bce in The Frogs, a comedy by Aristophanes in which a sponge was placed on a character’s heart following a syncopal episode. Additionally, in many Hippocratic writings, the use of sponges is outlined in the treatment of a variety of ailments. Similarly, the ancient Chinese and Greeks used burnt sponge and seaweed as a source of iodine to treat goiters.^6,7 Modern research focuses on the use of sponge metabolites for their antineoplastic, antimicrobial, and anti-inflammatory effects.⁸ Identification of spongouridine and spongothymidine from the sponge Tectitethya crypta led to the development of cytarabine and gemcitabine⁸ as well as the discovery of the antiviral agent vidarabine.⁹ The monoclonal antibody assay for the detection of shellfish poisoning was prepared using the sponge Halichondria okadai.¹⁰

Mechanisms and Symptoms of Injury

Bathing sponges (silk sponges) derived from Spongia officinalis are harmless. Other sponges can exert their damaging effects through a variety of mechanisms that lead to dermatologic manifestations (eTable). Some species of sponges produce and secrete toxic metabolites (eg, crinotoxins) onto the body surface or into the surrounding water. They also are capable of synthesizing a mucous slime that can be irritating to human skin. Direct trauma also can be caused by fragments of the silica or calcium carbonate sponge skeleton penetrating the skin. Stinging members of the phylum Cnidaria can colonize the sponge, leading to injury when a human handles the sponge.^25-27

Sponge dermatitis can be divided into 2 major categories: an initial pruritic dermatitis (Figure 3) that occurs within 20 minutes to a few hours after contact and a delayed irritant dermatitis caused by penetration of the spicules and chemical agents into skin.²⁸ Importantly, different species can lead to varying manifestations.

Management

Treatment should consist of an initial decontamination; the skin should be dried, and adhesive tape or rubber cement should be utilized to remove any spicules embedded in the skin. Diluted vinegar soaks should be initiated for 10 to 30 minutes on the affected area(s) 3 or 4 times daily.¹⁹ The initial decontamination should occur immediately, as delay may lead to persistent purulent bullae that may take months to heal. Topical steroids may be used following the initial decontamination to help relieve inflammation. Antihistamines and nonsteroidal anti-inflammatory drugs may be used to alleviate pruritus and pain, respectively. Severe cases may require systemic glucocorticoids. Additionally, immunization status against tetanus toxoid should be assessed.³⁵ In the event of an anaphylactic reaction, it is important to maintain a patent airway and normalized blood pressure through the use of intramuscular epinephrine.³⁶ Frequent follow-up is warranted, as serious secondary infections can develop.³⁷ Patients also should be counseled on the potential for delayed dermatologic reactions, including erythema multiforme. Contact between humans and coastal environments has been increasing in the last few decades; therefore, an increase in contact with sponges is to be expected.²²

Wound cultures from patients with the rare disease epidermolysis bullosa (EB) were most frequently positive for Staphylococcus aureus (SA), Pseudomonas aeruginosa (PA), and Streptococcus pyogenes (GAS) – and antibiotic resistance was common – in a retrospective analysis of over 700 wound cultures from 158 patients across the United States and Canada.

The findings from the EB Clinical Characterization and Outcomes Database speak to the value of surveillance cultures with routine testing for microbial resistance – including mupirocin resistance – and to the importance of antibiotic stewardship not only for oral antibiotics but for topicals as well, according to Laura E. Levin, MD, and Kimberly D. Morel, MD, of the departments of dermatology and pediatrics, Columbia University Irving Medical Center, New York, the lead and senior authors, respectively, of the paper recently published in Pediatric Dermatology.

Almost all of the 158 patients with at least one wound culture recorded in the database from the period of 2001-2018 had one or more positive culture results. Of 152 patients with positive cultures, 131 (86%) were positive for SA and 56 (37%) and 34 (22%) were positive for PA and GAS, respectively. Other bacteria isolated included Corynebacterium spp and Proteus spp. Nearly half (47%) of patients with SA-positive cultures had methicillin-resistant SA, and 68% had methicillin-susceptible SA. (Some patients grew both MSSA and MRSA at different points in time.)

Mupirocin-susceptibility testing was performed at only some of the 13 participating centers. Of 15 patients whose cultures had recorded SA mupirocin-susceptibility testing, 11 had cultures positive for mupirocin-susceptible SA and 6 (40%) had mupirocin-resistant SA isolates (2 patients grew both). Of these six patients, half had isolates that were also methicillin-resistant.

Mupirocin, a topical antibiotic, has been a cornerstone of decolonization regimens for MSSA and MRSA, but resistance has been demonstrated in other research as well and is not specific to EB, wrote Dr. Levin, Dr. Morel, and coauthors.

“Pediatric dermatologists often rely on topical antimicrobials in the treatment of patients’ open wounds to both prevent and treat infection, depending on the clinical scenario,” and surveillance cultures with routine testing for mupirocin resistance can help guide antibiotic choice and management strategies, Dr. Levin said in an interview.

More broadly, she added, “it’s helpful to know what bacteria are routinely colonizing wounds, not causing infection, versus those that are more likely to be associated with infection, chronic wounds, or the risk of developing skin cancer ... [to know] which wounds need to be treated more aggressively.”

A subset of patients with EB have been known to be at risk for squamous cell carcinoma, and research is implicating certain bacteria “as contributing to wound inflammation,” Dr. Morel said in an interview.

SCC was reported in 23 out of 717 patients in the database – but fewer than half of the patients with SCC had recorded wound cultures. The small numbers precluded the identification of microbes that may confer significant risk.

Correlating particular microbes with clinical features also will take more research. About half (57%) of the patients with recorded wound cultures had wounds with purulent exudate or other features of clinical infection. However, the presence or absence of clinical signs of infection was not temporally correlated with culture results in the database.

The 158 patients with recorded wound cultures had a mean age of 12.8 years and represented a range of EB subtypes.

PA was present in the wounds of patients as young as 1 month old, the authors noted. Investigators are “looking to further study PA and characterize clinical features ... to understand more about this microbe and its impact on patients with EB,” Dr. Morel said.

In the meantime, the analysis reaffirms the importance of antibiotic stewardship. Mupirocin is labeled to be used three times a day for a short period of time, but “tends to be prescribed and used less judiciously than intended,” Dr. Morel said. “It’s important [not to overuse it]. We have seen that patients’ culture results become sensitive to mupirocin again in the future when they avoid it for a period of time.”

The work was supported by the EB Research Partnership and EB Medical Research Foundation, as well as an NIH/NCATS grant. No investigator disclosures were listed.

SOURCE: Pediatr Dermatol. 2020 Nov 28. doi: 10.1111/pde.14444.

Wound cultures from patients with the rare disease epidermolysis bullosa (EB) were most frequently positive for Staphylococcus aureus (SA), Pseudomonas aeruginosa (PA), and Streptococcus pyogenes (GAS) – and antibiotic resistance was common – in a retrospective analysis of over 700 wound cultures from 158 patients across the United States and Canada.

The findings from the EB Clinical Characterization and Outcomes Database speak to the value of surveillance cultures with routine testing for microbial resistance – including mupirocin resistance – and to the importance of antibiotic stewardship not only for oral antibiotics but for topicals as well, according to Laura E. Levin, MD, and Kimberly D. Morel, MD, of the departments of dermatology and pediatrics, Columbia University Irving Medical Center, New York, the lead and senior authors, respectively, of the paper recently published in Pediatric Dermatology.

Almost all of the 158 patients with at least one wound culture recorded in the database from the period of 2001-2018 had one or more positive culture results. Of 152 patients with positive cultures, 131 (86%) were positive for SA and 56 (37%) and 34 (22%) were positive for PA and GAS, respectively. Other bacteria isolated included Corynebacterium spp and Proteus spp. Nearly half (47%) of patients with SA-positive cultures had methicillin-resistant SA, and 68% had methicillin-susceptible SA. (Some patients grew both MSSA and MRSA at different points in time.)

Mupirocin-susceptibility testing was performed at only some of the 13 participating centers. Of 15 patients whose cultures had recorded SA mupirocin-susceptibility testing, 11 had cultures positive for mupirocin-susceptible SA and 6 (40%) had mupirocin-resistant SA isolates (2 patients grew both). Of these six patients, half had isolates that were also methicillin-resistant.

Mupirocin, a topical antibiotic, has been a cornerstone of decolonization regimens for MSSA and MRSA, but resistance has been demonstrated in other research as well and is not specific to EB, wrote Dr. Levin, Dr. Morel, and coauthors.

“Pediatric dermatologists often rely on topical antimicrobials in the treatment of patients’ open wounds to both prevent and treat infection, depending on the clinical scenario,” and surveillance cultures with routine testing for mupirocin resistance can help guide antibiotic choice and management strategies, Dr. Levin said in an interview.

More broadly, she added, “it’s helpful to know what bacteria are routinely colonizing wounds, not causing infection, versus those that are more likely to be associated with infection, chronic wounds, or the risk of developing skin cancer ... [to know] which wounds need to be treated more aggressively.”

A subset of patients with EB have been known to be at risk for squamous cell carcinoma, and research is implicating certain bacteria “as contributing to wound inflammation,” Dr. Morel said in an interview.

SCC was reported in 23 out of 717 patients in the database – but fewer than half of the patients with SCC had recorded wound cultures. The small numbers precluded the identification of microbes that may confer significant risk.

Correlating particular microbes with clinical features also will take more research. About half (57%) of the patients with recorded wound cultures had wounds with purulent exudate or other features of clinical infection. However, the presence or absence of clinical signs of infection was not temporally correlated with culture results in the database.

The 158 patients with recorded wound cultures had a mean age of 12.8 years and represented a range of EB subtypes.

PA was present in the wounds of patients as young as 1 month old, the authors noted. Investigators are “looking to further study PA and characterize clinical features ... to understand more about this microbe and its impact on patients with EB,” Dr. Morel said.

In the meantime, the analysis reaffirms the importance of antibiotic stewardship. Mupirocin is labeled to be used three times a day for a short period of time, but “tends to be prescribed and used less judiciously than intended,” Dr. Morel said. “It’s important [not to overuse it]. We have seen that patients’ culture results become sensitive to mupirocin again in the future when they avoid it for a period of time.”

The work was supported by the EB Research Partnership and EB Medical Research Foundation, as well as an NIH/NCATS grant. No investigator disclosures were listed.

SOURCE: Pediatr Dermatol. 2020 Nov 28. doi: 10.1111/pde.14444.

Wound cultures from patients with the rare disease epidermolysis bullosa (EB) were most frequently positive for Staphylococcus aureus (SA), Pseudomonas aeruginosa (PA), and Streptococcus pyogenes (GAS) – and antibiotic resistance was common – in a retrospective analysis of over 700 wound cultures from 158 patients across the United States and Canada.

The findings from the EB Clinical Characterization and Outcomes Database speak to the value of surveillance cultures with routine testing for microbial resistance – including mupirocin resistance – and to the importance of antibiotic stewardship not only for oral antibiotics but for topicals as well, according to Laura E. Levin, MD, and Kimberly D. Morel, MD, of the departments of dermatology and pediatrics, Columbia University Irving Medical Center, New York, the lead and senior authors, respectively, of the paper recently published in Pediatric Dermatology.

Almost all of the 158 patients with at least one wound culture recorded in the database from the period of 2001-2018 had one or more positive culture results. Of 152 patients with positive cultures, 131 (86%) were positive for SA and 56 (37%) and 34 (22%) were positive for PA and GAS, respectively. Other bacteria isolated included Corynebacterium spp and Proteus spp. Nearly half (47%) of patients with SA-positive cultures had methicillin-resistant SA, and 68% had methicillin-susceptible SA. (Some patients grew both MSSA and MRSA at different points in time.)

Mupirocin-susceptibility testing was performed at only some of the 13 participating centers. Of 15 patients whose cultures had recorded SA mupirocin-susceptibility testing, 11 had cultures positive for mupirocin-susceptible SA and 6 (40%) had mupirocin-resistant SA isolates (2 patients grew both). Of these six patients, half had isolates that were also methicillin-resistant.

Mupirocin, a topical antibiotic, has been a cornerstone of decolonization regimens for MSSA and MRSA, but resistance has been demonstrated in other research as well and is not specific to EB, wrote Dr. Levin, Dr. Morel, and coauthors.

“Pediatric dermatologists often rely on topical antimicrobials in the treatment of patients’ open wounds to both prevent and treat infection, depending on the clinical scenario,” and surveillance cultures with routine testing for mupirocin resistance can help guide antibiotic choice and management strategies, Dr. Levin said in an interview.

More broadly, she added, “it’s helpful to know what bacteria are routinely colonizing wounds, not causing infection, versus those that are more likely to be associated with infection, chronic wounds, or the risk of developing skin cancer ... [to know] which wounds need to be treated more aggressively.”

A subset of patients with EB have been known to be at risk for squamous cell carcinoma, and research is implicating certain bacteria “as contributing to wound inflammation,” Dr. Morel said in an interview.

SCC was reported in 23 out of 717 patients in the database – but fewer than half of the patients with SCC had recorded wound cultures. The small numbers precluded the identification of microbes that may confer significant risk.

Correlating particular microbes with clinical features also will take more research. About half (57%) of the patients with recorded wound cultures had wounds with purulent exudate or other features of clinical infection. However, the presence or absence of clinical signs of infection was not temporally correlated with culture results in the database.

The 158 patients with recorded wound cultures had a mean age of 12.8 years and represented a range of EB subtypes.

PA was present in the wounds of patients as young as 1 month old, the authors noted. Investigators are “looking to further study PA and characterize clinical features ... to understand more about this microbe and its impact on patients with EB,” Dr. Morel said.

In the meantime, the analysis reaffirms the importance of antibiotic stewardship. Mupirocin is labeled to be used three times a day for a short period of time, but “tends to be prescribed and used less judiciously than intended,” Dr. Morel said. “It’s important [not to overuse it]. We have seen that patients’ culture results become sensitive to mupirocin again in the future when they avoid it for a period of time.”

The work was supported by the EB Research Partnership and EB Medical Research Foundation, as well as an NIH/NCATS grant. No investigator disclosures were listed.

SOURCE: Pediatr Dermatol. 2020 Nov 28. doi: 10.1111/pde.14444.