INTRODUCTION

Necrotizing soft-tissue infections are rare but highly lethal infections. The spectrum of disease encompasses necrotizing forms of cellulitis, myositis, and fasciitis. Also known as "flesh-eating disease," necrotizing fasciitis (NF) describes a clinical syndrome in which there is necrosis of subcutaneous tissue and fascia with relative sparing of the underlying muscle.1 The incidence of NF increases with age, with NF occurring most often among adults older than 60 years. Men experience 2.5 times greater incidence of NF on average than women across all age groups.2,3

PATHOGENESIS

Necrotizing fasciitis is characterized by widespread necrosis of the subcutaneous tissue and fascia. Often, this is caused by bacterial invasion through the epidermis due to trauma (eg, injection, cut, chronic wound/boil) that compromises skin integrity.4,5 Rarely, NF will develop in a healthy individual after a minor trauma without a break in the skin barrier. Organisms spread from the subcutaneous tissue along the superficial and deep fascial planes facilitated by bacterial enzymes and toxins. The infection spreads to involve the vascular supply to tissue causing vascular occlusion, ischemia, and tissue necrosis. Superficial nerves are often damaged producing localized anesthesia.

The development of NF is caused by interactions between virulence factors of pathogenic organisms and patient comorbidities, predisposing factors, and immune response. Toxins (ie, superantigens) are released by causative pathogens and initiate an endogenous cytokine reaction that ultimately results in hypotension and widespread tissue destruction. Bacteria rapidly multiply within viable tissue. Fibrous attachments between fascia and subcutaneous tissues limit the spread of bacteria (eg, in the feet and hands); however, there is a lack of fibrous attachments in the trunk and limbs, allowing the rapid spread of infection. Edema results from infection-induced cytokine release locally and from spread into venous and lymphatic channels. Breaching of the fascia can lead to infection of the muscle (myositis). Clostridium species can produce gas and lead to gas gangrene. With toxin-producing bacteria (ie, Streptococcus pyogenes and Staphylococcus aureus), toxic shock-like syndromes can occur.

MICROBIOLOGY

Necrotizing fasciitis is often divided into two classifications depending on the causative organism(s): type 1 and 2. Type 1 is more common and is caused by a mixture of aerobic and anaerobic bacteria. Causative pathogens are usually Gram-positive such as the Bacteroides,Clostridium, Staphylococcus, and Streptococcus species. Other less commonly reported causative organisms for type 1 NF include the Enterobacteriaceae and fungal species, specifically mucormycosis. Risk factors for type 1 disease include a history of diabetes, peripheral vascular disease, immune-compromised states, and recent surgery.

Type 2 NF is a monomicrobial infection caused by group A Streptococcus, Clostridium species, or S aureus.1,6 Group A Streptococcus and Clostridium species share the ability to infect all the compartments of the soft tissues, including fascia and muscle. They also cause a rapidly progressive and severe form of NF medicated through exotoxins (ie, secreted toxin).

Two lesser-known NF classifications are type 3 NF, which is generally caused by Vibrio vulnificus, Clostridium, and Klebsiella species, and type 4 NF, which has a fungal etiology, including Candida species and Zygomycetes.7 Neither of these classifications is well understood.

CLINICAL MANIFESTATIONS

Clinical manifestations of NF range from localized to systemic findings. Most studies show a predilection for infection of the extremities followed by perineal and truncal infections.5,8 Of note, truncal infections are more common in children than adults. Predictors of NF include having a history of recent surgery (past 90 days) or trauma at the affected site, IV drug use, alcoholism, comorbidities (ie, diabetes mellitus, obesity, and peripheral vascular disease), and the use of immunosuppressive drugs.9

The initial presentation of NF may vary: NF can follow a hyperacute presentation with sepsis and subsequent multiorgan failure, or, conversely, a subacute course of progression can occur, with a soft-tissue infection followed by sudden deterioration. Initial signs and symptoms of NF include localized swelling, erythema, and pain, as are seen with other types of skin and soft-tissue infections.10 Notably, pain and systemic symptoms can be disproportionate to physical findings in NF cases.

Individuals with NF will often be tachycardic at initial presentation. As the infection progresses, systemic symptoms such as diaphoresis, chills, and rigor can be observed. Hypotension and shock are common in advanced disease consistent with sepsis. Without intervention, patients with NF will develop severe sepsis and septic shock with altered mental status and cardiovascular and/or pulmonary collapse and will require intensive care and physiologic support. Other organ systems can also be compromised, including the renal system, as indicated by decreased urine output and acute kidney injury.

Locally, advanced infection will often manifest as tense edema outside of the area of compromised skin, pain disproportionate to the wound appearance, and a salmon-colored skin discoloration.6,11 Vascular thrombosis manifests as a blue discoloration resembling ecchymosis followed by bullae and necrosis of the skin. At this point in the infection progress, nerve damage also occurs, and physical examination may reveal areas of hyperesthesia combined with anesthetic portions of the skin.

DIFFERENTIAL DIAGNOSIS

Diagnosing NF can be challenging because early disease may be difficult to differentiate from a simple cellulitis.12 Clinicians must have a high index of suspicion for NF as a result.13 Distinguishing manifestations in NF include sites of infection displaying pain out of proportion with examination findings, skin necrosis, crepitus, and ischemia (with hemorrhagic bullae). In addition, the presence of the following systemic signs and symptoms can indicate NF: tachycardia, fever, hypotension, and tachypnea.

The laboratory risk indicator for NF and finger tests are important tools for NF diagnosis. The former is based on laboratory markers, and the latter is a surgical assessment that can be performed at the bedside or in the OR. In rare cases where diagnosis is still not clear, a fascial biopsy can confirm the diagnosis but should not delay definitive management in cases of NF.

Particularly at the early stages, NF may be mistaken for other soft-tissue infections such as cellulitis or erysipelas. Cellulitis is a soft-tissue infection characterized by inflammation extending to the subcutaneous tissues, whereas erysipelas extends to the dermis. The progression, clinical symptoms, and systemic signs of illness can help to differentiate these infections from NF. Other forms of necrotizing infections with varying depths include necrotizing cellulitis and myositis. However, the former tends to have a less severe presentation than NF, and the latter is quite rare and tends to have fewer overlying skin changes.

In subacute presentations, other entities may be considered on the differential diagnosis, but these disorders are rare, primarily occur in different clinical contexts, and do not have the rapid onset and progression seen with NF. Nonnecrotizing fasciitis has an absence of necrosis but otherwise may have similar symptoms as NF. Eosinophilic fasciitis, another mimic of NF, involves infiltration of superficial muscle fascia collagen by lymphocytes, plasma cells, and eosinophils14 and can be distinguished based on clinical and radiographic features. Proliferative fasciitis is thought to originate from local stress reactions that result in eventual fibrous proliferation. Follow-up imaging is helpful to evaluate for tissue destruction and support the diagnosis.15 Graft-versus-host disease, which occurs in persons who have undergone stem-cell transplants, is a noninfectious entity that presents with subcutaneous perimuscular/intramuscular edema and involves donor T lymphocytes damaging the epithelial cells that line the recipient target organ.16

THERAPY

Treating NF includes the principles of management of all surgical infections: source control, antimicrobial therapy, and physiologic support as needed (see Table). Early and complete surgical debridement is essential for reducing amputation rates and mortality; antimicrobial therapy is an adjunct to source control in the treatment of NF. Mortality estimates for NF range from 25% to 35%, largely due to delays in treatment, and may be even greater in low-resource settings.17,18 As such, the importance of early recognition and initiation of treatment cannot be overemphasized.

Table.

Emergent NF treatment involves surgical debridement of necrotic and infected tissue.19 Necrotic tissue located on extremities may require amputation based on joint involvement and rapidly progressing infection. Repeat debridement is often required at frequent intervals to ensure source control is achieved. Physiologic support includes adequate fluid resuscitation and oxygenation. In advanced stages, organ failure may necessitate intensive care with mechanical ventilation and pressor support with or without renal replacement therapies.

Antimicrobial therapy should be started early and include broad empiric coverage for Gram-positive, Gram-negative, and anaerobic species. Therapy targeting methicillin-resistant S aureus may also be used empirically based on local rates, risk factors, and clinical presentation. Specific antimicrobial therapy will differ based on whether the infection is monomicrobial (type 2) or polymicrobial (type 1). For polymicrobial infections, initial therapy can include vancomycin plus piperacillin-tazobactam or a carbapenem such as meropenem.11 For patients with penicillin allergies, clindamycin is an acceptable replacement for piperacillin-tazobactam. Clinicians should perform blood cultures but not delay the initiation of antimicrobial therapy or surgical intervention. High-dose IV clindamycin may be added to therapy initially because it can help to reduce toxin production in cases of group A Streptococcus-associated NF (type 2). Intravenous immunoglobulin therapy can bind exotoxins and decrease inflammatory response in NF but is currently recommended only for critically ill patients who have streptococci as causative agents.19 Hyperbaric oxygen therapy is not currently recommended in guidelines for NF management.

CASE REPORTS

Case 1

W.M. is a 26-year-old homeless man with amphetamine/opiate/IV drug use and hepatitis C virus who presented to the ED with redness and swelling of his left arm and erratic, confused behavior. His temperature was 38.3 [degrees]C with a heart rate of 140 beats per minute; other vital signs were stable. Blood tests revealed a white blood count of 19.9 x 10⁹/L (reference range, 4.5-11 x 10⁹/L), C-reactive protein level of 152.5 mg/L (reference range, 0.3-1.0 mg/L), blood glucose concentration of 5.0 mmol/L (reference, <6.9 mmol/L), and creatinine levels of 106 mmol/L (reference range for men, 61.9-114.9 mmol/L). X-ray imaging of his left forearm identified two small areas of gas in the tissues, and he was urgently taken for surgery based on the medical team's suspicion of necrotizing infection (Figure 1).

Figure 1.

Intraoperatively, the surgeon noted an approximately 10-cm abscess at the patient's left proximal forearm underlying the brachioradialis, proximally tracking to the distal lateral and volar forearm. Incision and debridement of the necrotic tissues and a volar fasciotomy were performed. Repeat debridement was performed 24 hours later (Figure 2). Gram stain revealed Gram-positive cocci and Gram-negative bacilli with tissue culture growing Streptococcus anginosus and an anaerobic Gram-positive bacillus.

Figure 2.

Broad empiric treatment was prescribed with piperacillin/tazobactam and vancomycin with delayed primary wound closure. Subsequently, antibiotics were narrowed to ceftriaxone and metronidazole. The patient received a total of 10 days of antibiotic therapy prior to being discharged with ongoing wound care.

Case 2

S.P. is a 59-year-old male smoker who presented with fever (temperature of 38.5 [degrees]C) and a draining left foot wound of 3 days' duration (Figures 3 and 4). Left foot X-ray demonstrated diffuse soft-tissue prominence with subcutaneous gas but no bony changes. He had an elevated white blood cell count of 22.2 x 10⁹/L, C-reactive protein level of 202 mg/L, blood glucose concentration of 15.8 mmol/L, and normal creatinine.

Figure 3.

Figure 4.

Urgent surgery was performed with debridement of the near-circumferential eschar and necrotic soft tissue, which extended proximally toward the lateral malleolus. Gram stain revealed Gram-negative coccobacilli and Gram-positive cocci, and tissue cultures grew S aureus, Peptostreptococcus species, and Prevotella species.

The patient was admitted to the ICU for postoperative care and treated empirically with piperacillin/tazobactam and clindamycin for his polymicrobial infection. Follow-up CT imaging revealed progression of the infection to the distal lower leg and posterior compartment with significant occlusive peripheral vascular disease. Because of a lack of reconstructive options for the left foot, the patient underwent a below-knee amputation. Following his amputation, he received a new diagnosis of type 2 diabetes and was transferred to the rehabilitation unit.

CONCLUSIONS

Necrotizing fasciitis is an uncommon but rapidly progressive soft-tissue infection with associated mortality. Early recognition of NF is crucial to implement appropriate management and improve outcomes.

PRACTICE PEARLS

* Necrotizing fasciitis is a rapidly progressive soft-tissue infection that can lead to death and disability.

* Risk factors for NF include older age, male sex, immunosuppression, and a history of trauma or surgery to an affected site.

* A high index of suspicion is needed to diagnose NF based on its nonspecific clinical presentation.

* Early surgical debridement of the infected site is essential in cases of NF to improve outcomes.

REFERENCES