Introduction Necrotizing fasciitis (NF) is a rare, life-threatening, soft-tissue infection characterized by rapidly spreading inflammation and necrosis of the skin, subcutaneous fat, and fascia.1 The incidence of NF in adults has been reported to be 0.40 cases per 100,000 population, while the incidence in children is 0.08 cases per 100,000 population.2,3 Despite the uncommon nature of this condition, over the last decade, there has been a five-fold increase in the incidence of NF.4 Although largely unexplained, the aging of the population and the increase in numbers of immunosuppressed individuals may be related. Rapid early intervention may prevent morbidity and mortality, but, left untreated, mortality rates as high as 73 percent have been reported.1 Mortality varies with age, with increasing mortality seen in older age groups. For example, patients over 50 years of age have a mortality rate of 37 percent, while those over 60 years of age have a mortality rate of 62 percent.5 The earliest reference to this condition was made by Hippocrates in the 15th century BC, who spoke of it as a complication of erysipelas.1,6 However, the term necrotizing fasciitis was not coined until 1952. Over the years, other terms have been used to refer to NF, including flesh-eating bacteria syndrome, suppurative fasciitis, hospital gangrene, and necrotizing erysipelas.2,7,8 Risk Factors While NF is rare, there are many underlying conditions that can predispose patients to develop NF (Table 1).1–3,6,7,9–19 Importantly, immunosuppression caused by a variety of conditions, such as diabetes mellitus, C4 deficiency, AIDS, and malignancy, are predisposing factors. Additionally, certain medications that can induce immunosuppression have been implicated in the development of NF. Newer medications have been added to the growing list of known immunosuppressive medications. Infliximab, an inhibitor of tumor necrosis factor-alpha (TNFa), has been linked to an increase in infections due to its effects on lymphocytes and cytokines and has also been associated with one case of NF.19 FK506, a macrolide immunosuppressant used primarily in post transplantation, has also been linked to an increase in infections due to its immunosuppressive qualities, as well as a case of NF.17 The portal of entry for bacteria causing NF is varied. Simply put, the entrance of bacteria can occur from any break in the skin, even in patients with pre-existing skin conditions, such as psoriasis, pressure ulcers, or perirectal abscesses.1 Any condition in which the integrity of the integument is compromised can permit the entrance of bacteria and subsequent development of NF. Often, NF may occur as a result of trauma (including burns and lacerations), post-surgical wounds, or needle sticks often from intravenous drug abusers (IVDA).18 NF arising in IVDA often presents with an abscess of the arm, while commonly other portals of entry more often present on the lower extremities and buttocks. Children, who possess similar risk factors for NF as adults, such as diabetes mellitus, post-surgical wounds, trauma, and minor lacerations, are at increased risk.3 However, children more often have other common risk factors, such as malnutrition, history of varicella, and immunosuppression. Types of NF Several classification systems, not mutually exclusive, exist to categorize NF. NF can be categorized based on the culprit microorganisms cultured from the wounds (Table 2).1,6,9,20,21 Two types exist. Type 1 NF is a polymicrobial infection consisting of infection with aerobic and anaerobic bacteria, such as Clostridium and Bacteroides species, which work synergistically in the progression of NF. Type 2 NF consists of group A Streptococcus (S. pyogenes) with or without a coexisting Staphylococcal infection. Also, NF is divided by the rapidity of presentation. In this schema, NF is divided into three groups (fulminant, acute, subacute) based on the initial clinical presentation of the patient, including length of infection and extent of the disease.22 Patients with fulminant disease present with rapid disease progression and shock. These patients will report having symptoms for only several hours with few blisters on a small area of skin. Patients with acute disease suffer from symptoms for several days often with large areas of their skin involved. Finally, patients with subacute disease may describe having worsening symptoms over the course of several weeks with only localized skin involvement. Signs and Symptoms Distribution. NF can affect any area of the body, but in adults it most commonly occurs on the extremities (Figures 1–4).23 Conversely, in very young children (3 Distribution of disease is important. There is a higher mortality rate when the head, neck, chest, or abdomen are involved. These areas are more difficult to treat, and critical structures reside within them. Involvement of the genitalia is referred to as Fournier’s gangrene (FG) and usually results from a polymicrobial infection. Typically, it occurs as a result of trauma, extension of a urinary tract infection, or an extension of an infection in the perianal or retroperitoneal areas.24 FG has an abrupt onset with rapid progression of disease, oftentimes without discovering the specific causative microorganism. Clinical course. Early on, patients often present with a clinical picture similar to and difficult to differentiate from cellulitis.4,23 However, one important clue can be used to distinguish NF from cellulitis. Patients will complain of severe pain, usually out of proportion to the clinical appearance of the skin affected. Early diagnosis is critical and may be life saving, as early diagnosis leads to early treatment. It is known that the sooner the diagnosis is made, the lower the mortality. NF may appear similar to cellulitis, with redness and edema, in addition to a spreading, diffuse inflammatory reaction that blends into the surrounding tissue. The overlying skin is shiny and tense without sharply demarcated borders. In acute cases, infection progresses for two to three days, causing the redness of the skin to turn purple or purple-black, thus heralding the beginning of devastating tissue necrosis.22 This process may take several weeks in subacute cases. Necrosis occurs presumably as a direct result of thrombosis of the skin’s underlying nutrient vessels.23 This necrotic tissue, in turn, supports the growth and migration of bacteria with subsequent unabated progression of tissue necrosis. If necrosis involves underlying cutaneous nerves, anesthesia may follow pain in the affected skin.22 Clear or hemorrhagic bullae may develop, but the fluid eventually transforms into a gray, foul-smelling fluid termed dishwater pus. When bullae rupture, a dry, black eschar may develop at the site of rupture. Over time, as bacterial invasion progresses, worsening infection and frank cutaneous gangrene can be seen.23 This gangrene extends beyond the skin and into the subcutaneous fat and fascial planes below. Characteristic of NF, a separation of the necrotic tissue along the fascial planes with suppuration occurs. Normal fascia surrounding muscle is thick and forms a protective barrier for the muscle against the overlying infection/necrosis. However, in cases of progressive disease, deeper involvement can develop with invasion of fascia and myonecrosis of the underlying muscle. Lymphadenitis, lymphangitis, crepitation, and venous thrombosis are less commonly seen. There have been some rare reports of metastatic abscesses developing within the liver, lung, spleen, brain, and pericardium in patients with NF.6 Metastatic abscesses may occur in the skin, as well as presenting as painless, subcutaneous fluctuant masses, often located over pressure points.25 During progression of disease, patients will suffer from systemic complications of NF, including a high fever, chills, and constitutional symptoms (Table 3).1,13,26–28 In fulminant cases, multiorgan system failure will occur, frequently resulting in death. Hemorrhagic cellulitis. Hemorrhagic cellulitis (HC) is a variant of NF.9 HC is characterized by an acute onset of painful erythema and hemorrhage localized to dependent areas of the body, such as the lower extremities, followed by blistering and sloughing of the necrotic areas. Pathogenesis of this condition is related to lipopolysaccharide-induced or bacterial mitogen-induced TNFa secreted by activated macrophages. TNFa injures endothelial cells and epidermal keratinocytes via neutrophil degranulation and DNAse activation. Therefore, effective treatment for this condition is the combination of antibiotics and corticosteroids, which inhibit secretion of and block cytotoxic effects of TNFa. Pathophysiology Bacteria are introduced into the skin through a decrease in tissue resistance often as a result of immunosuppression.12 Bacteria spread through the skin, subcutaneous tissue, and fascia aided by the release of bacterial toxins and enzymes, such as hyaluronidase, collagenase, streptokinase, and lipase. Uninhibited progression of bacterial penetration results in tissue necrosis and thrombosis of the vasculature. In NF type 2 caused by beta hemolytic streptococcal (BHS) infection, superantigens are thought to be involved in the pathogenesis of disease.12 BHS secrete superantigens that have the ability to activate T-helper cell lymphocyte clones. T-helper cells secrete various cytokines, such as TNFa and -b, clotting factors, and complement.1,8,11,28 This initiates thrombosis and inflammation. Oxygen-free radicals and nitrous oxide are produced. This leads to shock, worsening immunosuppression, depression of myocardial function, and multiorgan failure. BHS may also produce other virulence factors, such as M proteins types 1, 3, 4, 6, 12, and 28. These virulence factors act to depress neutrophilic phagocytosis, thus limiting the body’s ability to rid itself of the bacteria. Sharkawy, et al., showed that patients infected with serotype M3 have greater mortality.4 Several reports in the literature have implicated nonsteroidal, anti-inflammatory agents (NSAIDS) in the progression of NF; however, this remains controversial.4 NSAIDS are postulated to potentiate tissue damage by decreasing granulocyte adhesion and phagocytosis and increasing cytokine production. However, even if this occurs, there have been no reports of increased severity of systemic findings of NF. Diagnosis Because of the rapid progression inherent in NF, it is important to recognize and treat NF quickly to reduce mortality.1 The clinician should have a high index of suspicion and begin therapy immediately based on the clinical findings, such as appearance of the skin and extreme pain out of proportion to the clinical exam. This coupled with fever and a patient’s toxic appearance is highly suggestive of NF. Laboratory, radiologic, and histopathologic testing should be ordered to confirm the diagnosis (Table 4).1,2,9,13,25,27,28,30,31 A positive gram stain and blood cultures can guide antibiotic therapy. If BHS is causal, a rapid strep screen is a fast, noninvasive, inexpensive test that can detect the presence of antigens to group A Streptococcus. Radiologic testing may detect air within the tissue, highly suggestive of NF.2,27,28,30,31 Plain x-rays and ultrasound can be used; however, MRI and CT scans produce better quality images. MRI is superior to CT since it is less invasive; however, the images are equal in resolution quality. Fine needle aspiration, frozen section of tissue biopsy, fascial biopsy, and skin biopsy for histopathology are all useful in diagnosis of NF.16,23 The advantage of frozen section is speed, as results can be obtained relatively quickly. Surgical exploration can be of both diagnostic and therapeutic value. Pathognomonic for NF is a positive “finger” test.23 The finger test can be used to delineate the extent of infection into the adjacent normal appearing skin. It requires a 2cm vertical incision be made into the skin to the deep fascia. Lack of bleeding may be seen or a murky dishwater pus exudate may ooze from the incision site. An index finger, or hemostat, is gently pushed forward into the normal appearing tissue and the level of the junction of the subcutaneous tissue and the deep fascia. Normally, subcutaneous tissue adheres tightly to the deep fascia. If the subcutaneous tissue is easily dissected off the fascia, the finger test is positive. Liquefactive necrotic tissue or pus can also be found in between the fascial planes in NF. Treatment The most effective treatment found to decrease mortality is early diagnosis and prompt surgical debridement.23 The gold standard of treatment for NF includes intravenous antibiotics with broad-spectrum antibacterial coverage, prompt surgical debridement, and supportive care in an intensive care unit (ICU). ICU care involving hemodynamic support, wound care, and nutritional support is critical.1,2,6–13,22,25–28 A combination of broad spectrum antibiotics, such as a penicillin, an aminoglycoside or third generation cephalosporin, and clindamycin or metronidazole, are typically employed to provide broad bacterial coverage. Once the gram stain and culture and sensitivity results are obtained, the antibiotic regimen can be adjusted. If a diagnosis of NF is made, emergent surgical debridement and/or fasciotomy should be considered.1,2,6–13,22,25–28 Debridement beyond the visible margin of infection is necessary. Repeated debridements may be required and should continue until the subcutaneous tissue can no longer be separated from the deep fascia.2,6,9,11 Fasciotomy may be performed at the time of debridment.11,32 If infection progresses despite serial debridements and antibiotics, amputation may be life saving. Supportive care in an ICU is critical to survival. This involves fluid resuscitation, cardiac monitoring, aggressive wound care, and adequate nutritional support.1,11,23,26 Patients with NF are in a catabolic state and require increased caloric intake to combat infection.1 Nutritional supplementation can be delivered orally or via nasogastric tube, peg tube, or intravenous hyperalimentation. Nutritional support should begin immediately (within the first 24 hours of hospitalization).26 Prompt and aggressive nutritional support has been shown to lower complication rates.1 Baseline and repeated monitoring of albumin, prealbumin, transferrin, blood urea nitrogen, and triglycerides should be performed to ensure the patient is receiving adequate nutrition. Wound care is also an important concern.23 Advanced wound dressings have replaced wet-to-dry dressings. These dressings promote granulation tissue formation and speed healing. Advanced wound dressings may lend to healing or prepare the wound bed for grafting. A healthy wound bed increases the chances of split-thickness skin graft take. Vacuum-assisted closure (V.A.C., KCI International Inc., San Antonio, Texas) was recently reported to be effective in a patient whose cardiac status was too precarious to undergo a long surgical reconstruction operation.33 With the V.A.C., the patient’s wound decreased in size, and the V.A.C. was thought to aid in local management of infection and improve granulation tissue. Biologic debridement with maggots has been used in a number of chronic wounds, as well as osteomyelitis, burns, and traumatic wounds.34 One report highlighted maggot therapy in a patient with a NF wound of the neck. This patient suffered from severe coronary artery disease and a delicate cardiac status, which prohibited a long surgical debridement procedure. Additionally, the neck has many important structures, and complete surgical debridement is more difficult. In light of these circumstances, the patient underwent a prompt but abbreviated debridement of the necrotic tissue in the neck wound under general anesthesia. Post-operatively, maggots were placed in the wound. After 48 hours, the slough was decreased and the wound had improved clinically without need for further debridement. After two more days, the maggots were removed since new granulation tissue and reepithelialization had begun. The maggots not only cleansed the wound of necrotic tissue but also prevented and controlled infection and odor. The role of adjunctive hyperbaric oxygen (HBO) in the treatment of NF has been controversial.1,6,8,9,11,23,27,28,32,35,36 HBO works by increasing the partial pressure of oxygen in tissues. This increases leukocyte function and may increase destruction of anaerobic bacteria, reduce tissue edema, stimulate fibroblast proliferation, increase collagen formation, reduce ischemia, enhance the action of antibiotics, stimulate angiogenesis, and promote granulation tissue.8,11,28,32 Several series suggest that HBO significantly reduced mortality in NF patients. These cases reported a mortality reduction of 66 to 23 percent, 35 to 16 percent, and 43.5 to 20.7 percent.11,28,35,37 However, Brown, et al., did not find a decrease in mortality of NF patients treated with HBO (30 vs. 42%).11,28 Intravenous immunoglobulins (IVIG) have been shown to be an effective adjunctive treatment for patients with Streptococcal toxic shock syndrome (STSS).2,38,39 IVIG contains many antibodies, which neutralize the exotoxins/superantigens secreted by the Streptococcus and are involved in the pathogenesis of STSS.2 By inhibiting the binding of the superantigen to the T-cell receptor, certain cytokines, like TNFa and IL-1, which are involved in tissue destruction and organ failure, are inhibited. IVIG has been shown to decrease the hyperproliferation of T cells by binding Streptococcal toxin as well as opsonizing bacteria.1,28 Since STSS and NF are mediated by the Streptococcal toxins and inflict their tissue destruction via some of the same cytokines, it was postulated that IVIG would be as effective a treatment in NF as it was in STSS. While prospective trials on the use of IVIG for treatment of NF are lacking, there have been sporadic reports on their benefit.1,2,6,8,28 Kaul, et al., reported a significant increase in survival in the group of patients receiving IVIG, 34 vs. 67 percent.28 Conclusion NF is a rare, rapidly progressive, soft-tissue infection characterized by extensive necrosis of the skin and subcutaneous tissue. In order to decrease the mortality rate of this life-threatening condition, rapid diagnosis, immediate surgical intervention, and broad-spectrum antibiotics are critical. However, other adjuvant therapies have been considered, such as hyperbaric oxygen and intravenous immunoglobulin.