Ecthyma Gangrenosum

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 tap water samples, and can contaminate hospital equipment leading to nosocomial infections.[3][4] Other causes of EG include methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pyogenes, Citrobacter freundii, Escherichia coli, Aeromonas hydrophila, Klebsiella pneumoniae, 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 patients 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 with similar macroscopic features include autoimmune vasculitides, vasopressor-induced necrosis, calciphylaxis, warfarin-induced necrosis, and 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

The 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]

Complications

EG is a life-threatening infection often complicated by septic shock. Prompt clinician recognition and appropriate antimicrobial therapy are necessary to achieve optimal outcomes.