Ecthyma Gangrenosum


Article Author:
Muneeb Shah


Article Editor:
Jonathan Crane


Editors In Chief:
Allison Castro


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
3/3/2019 9:14:59 AM

Introduction

Ecthyma gangrenosum (EG) is a cutaneous infection that most commonly occurs in immunocompromised individuals with fulminant bacteremia. EG was first described in 1897 by Canadian pathologist Dr. Lewellys Barker as a manifestation of Pseudomonas aeruginosa.[1] Although P. aeruginosa remains the most frequent organism identified in EG, other causative pathogens have since been described. Lesions appear as gangrenous ulcers with erythematous borders. EG predominantly affects the axillary and anogenital areas, but the arms, legs, trunk, and face are also sometimes involved. Perivascular invasion and resultant ischemic necrosis of the associated skin result in the classic macroscopic appearance. Prompt recognition and empiric therapy with broad spectrum antipseudomonal agents are of critical importance. Once microbiology results identify the causative pathogen and sensitivities are available, antimicrobial coverage should be narrowed.[2] EG denotes a poor prognosis, particularly in immunocompromised individuals with neutropenia.

Etiology

P. aeruginosa is the most frequent organism identified in ecthyma gangrenosum with one study identifying P. aeruginosa in 74% of cases.[1] P. aeruginosa is a non-lactose fermenting gram-negative aerobic, rod-shaped bacteria. The organism is found in moist environments, is often identified in samples of tap water, and can contaminate hospital equipment leading to nosocomial infections.[3][4] Other causes of EG include methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pyogenesCitrobacter freundii, Escherichia coli, Aeromonas hydrophila, Klebsiella pneumonia, Serratia marcescens, Xanthomonas maltophilia, Morganella morganii, Corynebacterium diphtheriae, Neisseria gonorrhea, Yersinia pestis, fungi like the Candida species), and viruses like herpes simplex virus.[1][5][6][7]

Epidemiology

Ecthyma gangrenosum affects all age groups and genders. Immunocompromised individuals are particularly susceptible to developing this condition, with up to 62% to 75% of affected individuals having an underlying immunodeficiency.[1][8] EG is also known to occur in otherwise healthy immunocompetent individuals.[9] Common predisposing conditions include neutropenia, leukemia, multiple myeloma, diabetes mellitus, malnutrition, and extensive burn wounds.[1][5][7][10][11]

Pathophysiology

Ecthyma gangrenosum is separated into bacteremic and non-bacteremic forms.[7] The bacteremic form of EG is more common than the non-bacteremic form.[1] With bacteremia, the causative organism is spread hematogenously to the capillaries and invades the media and adventitia of arteries and veins. Perivascular invasion ultimately leads to ischemic necrosis of the surrounding skin.[12] In the non-bacteremic form, the lesions develop at the location of direct inoculation into the epidermis. Virulence toxins and enzymes produced by P. aeruginosa, such as exotoxin A, elastase, and Phospholipase C, cause skin and vascular destruction.[8] Multi-drug resistance of P. aeruginosa has increased substantially in recent years making treatment more challenging. Resistance mechanisms include decreased permeability (biofilm formation), antibiotic efflux pumps, antibiotic inactivating mechanisms, and antibiotic target site mutations.[12][13]

Histopathology

Excisional biopsy or punch biopsy with Gram stain, culture, and histopathologic examination can be performed in equivocal cases. In cases of pseudomonal EG, Gram stain shows many gram-negative, rod-shaped bacteria.[14] Wound cultures are frequently positive for P. aeruginosa but may reveal a different causative organism. Microscopic examination reveals an ulcerated zone of necrotic epidermis and dermis with neutrophilic predominance.[14][15] The epidermis adjacent to the necrotic region reveals reactive hyperkeratosis. The underlying subcutaneous tissue may also be involved.[8]

History and Physical

When acquiring a history on presentation, it is important to note the temporal evolution of the lesions, the location of the lesions, any underlying immunosuppressive condition, and other associated symptoms such as cough, fever, or dysuria. In individuals with the bacteremic form of EG, the source of infection is important to ascertain. For example, productive cough or dysuria may reveal a respiratory or urinary source, respectively. In the non-bacteremic form, it is important to note any trauma that may have introduced the infection via direct inoculation.

The lesions of ecthyma gangrenosum begin as painless, round erythematous macules and patches that develop into central pustules with surrounding erythema. A hemorrhagic vesicle appears at the center of the lesion and evolves into a gangrenous ulcer with a black eschar.[1][8] Early lesions may progress to necrotic ulcers in as little as 12 hours.[8] The lesions can be localized and solitary or widespread.[1] 

EG can appear anywhere in the body but most commonly affects the anogenital and axillary areas. The gluteal/perineal area is most common (57%), followed by the extremities (30%), the trunk (6%), and the face (6%).[8] Rare cases of periorbital involvement have also been reported.[8] The entire body should be examined for lesions, and any fluctuance or large areas of necrosis should be noted.

Evaluation

Initial evaluation includes blood cultures, wound cultures, urinalysis, chest radiograph, complete blood count, comprehensive metabolic panel, C-reactive protein, and HIV testing. Procalcitonin and lactate levels are important in those with EG in the setting of sepsis. Evaluation of the lesions with a Wood's lamp may expedite the diagnosis, as P. aeruginosa will appear with green fluorescence.[8][16] Excisional or punch biopsy can be performed in equivocal cases.

Treatment / Management

In individuals with suspected ecthyma gangrenosum, prompt treatment with broad-spectrum antibiotics should be initiated after obtaining blood and wound cultures. 

Initial empiric therapy includes antipseudomonal beta-lactams (piperacillin/tazobactam), cephalosporins (cefepime), fluoroquinolones (levofloxacin), and carbapenems (imipenem). Combination therapy is recommended in high-risk individuals, such as those with neutropenia and septic shock.[12] Once the causative organism and antimicrobial susceptibilities are identified, antimicrobial coverage should be narrowed.[2] In rare cases with a fungal or viral etiology, anti-fungal and anti-viral agents should be started.

Surgical excision of necrotic lesions or abscesses is often necessary. Incision and drainage of abscesses are important for source control of the infection. For necrotic skin lesions, aggressive debridement and grafting may be necessary for lesions larger than 10 cm.[8]

Treatment in the hospital intensive care setting is appropriate for those with sepsis or neutropenia due to the high case fatality rate. For those with non-bacteremic EG, treatment in the outpatient setting may be appropriate. In this setting, oral antipseudomonal agents, such as ciprofloxacin can be considered.

Differential Diagnosis

A thorough history, physical, and basic laboratory studies help differentiate between EG and other causes of skin necrosis. Neutropenia and malignancy in a patient with typical skin lesions should raise suspicion for EG. Other conditions that have similar macroscopic features include autoimmune vasculitides, vasopressor-induced necrosis, calciphylaxis, warfarin-induced necrosis, disseminated intravascular coagulation (DIC), pyoderma gangrenosum, necrolytic migratory erythema, and livedoid vasculopathy.[1][17][18]

In individuals with underlying malignancy and pancytopenia, fibrinogen levels and fibrin split products (d-dimer) can help differentiate DIC from EG. In individuals in the intensive care unit on vasopressors, the distribution of lesions can help differentiate between vasopressor-induced necrosis and EG. Vasopressor-induced necrosis affects the distal extremities, while EG affects the anogenital and axillary areas.[19] Tissue samples are critical when the diagnosis is not clear based on less invasive methods.[20]

Prognosis

Development of EG lesions in individuals with sepsis is associated with a poor prognosis and is fatal in 20% to 77% of patients.[15][21] In individuals with non-bacteremic EG, the mortality rate is significantly lower at 8%.[15] The underlying immunosuppressive state (e.g., malignancy, renal failure, or other) is often the main determinant of clinical outcome.[22] The presence of neutropenia at the time of diagnosis is the most important prognostic factor of mortality.[21]

Pearls and Other Issues

  • P. aeruginosa is the most common causative organism of ecthyma gangrenosum.
  • Lesions appear as gangrenous ulcers with erythematous borders located predominantly in the axillary and anogenital areas.
  • Nearly all individuals with typical skin lesions are immunocompromised, with malignancy being the most common underlying disease state.
  • Neutropenia at the time of diagnosis is the most important prognostic factor.
  • Prompt treatment with intravenous antipseudomonal agents is indicated.
  • Incision and drainage may be performed for abscesses.

Enhancing Healthcare Team Outcomes

Management of ecthyma gangrenosum requires an interprofessional team approach, including providers from infectious disease, surgery, dermatology, hematology, and critical care. The providers involved in treatment depend on the overall clinical picture and whether the patient is being treated in the intensive care unit.

A dermatologist can help in the initial diagnostic workup to determine the cause (Wood's lamp evaluation, punch biopsy) and extent of the lesions. Infectious disease specialists are helpful to determine the selection and length of antibiotic therapy. Surgeons may be needed for incision and drainage of multiple abscesses, surgical debridement of necrotic lesions, or grafting of large area defects. In patients with neutropenia, granulocyte colony-stimulating factor (G-CSF) may be given at the discretion of a hematologist.

For individuals with fulminant sepsis, management in the critical care setting by an intensivist is appropriate due to the high fatality rate of bacteremic EG. Individuals with sepsis are extremely tenuous and careful monitoring with frequent vital sign measurements is of critical importance. Prompt administration of effective antimicrobial therapy is known to improve survival in sepsis.[23] (Level I) In addition to targeting the causative organism, early goal-directed therapy focusing on blood pressure and oxygen saturation has also been shown to improve outcomes and reduce mortality in sepsis.[24] (Level I)


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Ecthyma Gangrenosum - Questions

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A 7-year-old female is brought in by her parents after developing a fever overnight. She has a history of acute lymphocytic leukemia and recently finished a cycle of induction chemotherapy. Vital signs are significant for a temperature of 39C. The physical examination reveals necrotic lesions with erythematous borders in the anogenital area. Laboratory studies reveal pancytopenia and an absolute neutrophil count of 220/microliter. What is the most likely causative organism?



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A 57-year-old patient with a history of testicular cancer presents to the hospital complaining of fever, fatigue and a skin lesion that stated of as a red macule that rapidly developed into a gangrenous ulcer with a central black eschar. He is currently being treated with chemotherapy for his testicular cancer. A CBC is significant for severe neutropenia. He is started on the appropriate treatment for his skin lesion and the clinician explains that hemolytic anemia is a possible side effect of this medication. Which of the following medications was given to the patient?



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A 17-year-old female with acute myelogenous leukemia presents to the emergency department with high fevers and chills. She also has noticed a rash developing on her right foot. Initially, the lesions were red and flat but have since progressed to necrotic areas with red borders, as seen in the image. Laboratory studies are significant for neutropenia and blood cultures grow gram-negative organisms. Which of the following is the most likely causative organism?

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A 65-year-old man is admitted to the intensive care unit with sepsis. He has a history of hypertension, diabetes mellitus, and chronic myelogenous leukemia. His blood pressure is 86/52 mmHg, heart rate 112 beats/min, and respiratory rate 18/min. The physical examination reveals scattered necrotic lesions affecting the anogenital area and the left thigh. Laboratory studies reveal pancytopenia. Blood glucose and creatinine levels are normal. Blood cultures grow Pseudomonas aeruginosa. What is the most likely diagnosis?



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A 24-year-old female presents with fevers, chills, and a new rash. She has a history of acute lymphocytic leukemia. Vital signs are significant for a heart rate of 110 beats/min and a temperature of 39C. The physical examination reveals necrotic lesions with erythematous borders involving the buttocks and the right axilla. The absolute neutrophil count is 120/microliter. Which of the following is the most appropriate empiric therapy?



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A 65-year-old woman presents to the emergency department after developing a fever overnight. She has a history of multiple myeloma and breast cancer. Vital signs are significant for a temperature of 39C, heart rate of 120 beats/min, and respiratory rate of 22/min. The physical examination reveals conjunctival pallor and necrotic lesions with erythematous borders in the anogenital area. Laboratory studies reveal pancytopenia and an absolute neutrophil count of 110/microliter. Cultures from the necrotic lesions reveal gram-negative organisms with many neutrophils. Which of the following is the most important prognostic factor?



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Ecthyma Gangrenosum - References

References

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Korte AKM,Vos JM, Ecthyma Gangrenosum. The New England journal of medicine. 2017 Dec 7     [PubMed]
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Hafner J, Calciphylaxis and Martorell Hypertensive Ischemic Leg Ulcer: Same Pattern - One Pathophysiology. Dermatology (Basel, Switzerland). 2016     [PubMed]
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Martínez-Longoria CA,Rosales-Solis GM,Ocampo-Garza J,Guerrero-González GA,Ocampo-Candiani J, Ecthyma gangrenosum: a report of eight cases. Anais brasileiros de dermatologia. 2017 Sep-Oct     [PubMed]
Grisaru-Soen G,Lerner-Geva L,Keller N,Berger H,Passwell JH,Barzilai A, Pseudomonas aeruginosa bacteremia in children: analysis of trends in prevalence, antibiotic resistance and prognostic factors. The Pediatric infectious disease journal. 2000 Oct     [PubMed]
Kumar A,Roberts D,Wood KE,Light B,Parrillo JE,Sharma S,Suppes R,Feinstein D,Zanotti S,Taiberg L,Gurka D,Kumar A,Cheang M, Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Critical care medicine. 2006 Jun     [PubMed]
Rivers E,Nguyen B,Havstad S,Ressler J,Muzzin A,Knoblich B,Peterson E,Tomlanovich M, Early goal-directed therapy in the treatment of severe sepsis and septic shock. The New England journal of medicine. 2001 Nov 8     [PubMed]

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