Necrotizing fasciitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]

Necrotizing fasciitis or fasciitis necroticans, commonly known as “flesh-eating bacteria,” is a rare infection of the deeper layers of skin and subcutaneous tissues, easily spreading across the fascial plane within the subcutaneous tissue. Many types of bacteria can cause necrotizing fasciitis (eg. Group A streptococcus, Vibrio vulnificus, Clostridium perfringens, Bacteroides fragilis), of which Group A streptococcus (also known as Streptococcus pyogenes) is the most common cause. It is severe inflammation of the muscle sheath that leads to necrosis of subcutaneous tissue and adjacent fascia.^[1][2]

Narcotizing fasciitis was first described by Hippocrates in the fifth century B.C. as the complication of erysipelas.^[3][4] During the Civil War, necrotizing fasciitis was described as “hospital gangrene” by Confederate Army surgeon Joseph Jones.^[5][6] In 1924, Frank L. Meleney reported a series of 20 patients as having hemolytic streptococcal gangrene, later called Meleney’s gangrene.^[7] Necrotizing fasciitis of perineum was described in 1883 by the French physician Jean Alfred Fournier.^[8]

Necrotizing fasciitis may be classified according to International Classification of Diseases-10 (ICD-10) into M72.6 Necrotizing fasciitis.^[9] Based on microbiological findings, necrotizing fasciitis may be classified into four types: Type I, Type II, Type III, and Type IV. Necrotizing fasciitis is further classified based on anatomic location and severity of symptoms.^[10]

The pathophysiology of necrotizing fasciitis is common to all types, but the speed of development and associated clinical features differs depending on the causative organisms. Following transmission, the bacteria uses the entry site to invade the fascial planes which causes the wide spread necrosis of superficial fascia, deep fascia, subcutaneous fat, nerves, arteries, and veins. Necrotizing fasciitis can be a serious complication of omphalitis in the neonate. The pathogenesis of necrotizing fasciitis is the result of bacterial and host factors. The exact pathogenesis of type 1 necrotizing fasciitis is not fully understood but polymicrobial species work synergistically to enhance the spread of infection. Group A streptococcus is the most common causative agent of type 2 necrotizing fasciitis. Bacterial virulence factors, exotoxins, superantigens and host immune system plays a major role in the pathogenesis of type II necrotizing fasciitis. Recurrent necrotizing fasciitis is caused by MRSA. On gross pathology, the characteristic findings of necrotizing fasciitis include subcutaneous emphysema, skin sloughing, bulae and necrosis. Inflammatory changes are seen on microscopic histopathology.^[1]

The causative organisms vary depending on the type of necrotizing fasciitis: Type I (polymicrobial), Type II (monomicrobial), Type III (Gram negative monomicrobial, including marine related organisms) and Type IV (fungal).^[1]

Necrotizing fasciitis must be differentiated from other diseases that cause erythema, pain, edema and necrosis of soft tissues such as sunburn, cellulitis, erysipelas, diabetic myonecrosis and vasculitis.^[11]

The incidence of necrotizing fasciitis in adults is 0.40 cases per 100,000 people/year and the incidence in children is higher at 0.08 cases per 100,000 people/year.The overall mortality rate in the United states from 2003- 2013 was 4.8/1,000,000 per year. Patients from all age groups can develop necrotizing fasciitis but slightly more common among >50 years age and effects men and women equally.The incidence rate of necrotizing fasciitis is high in black, Hispanic, and American Indian individuals compared to Whites and low in Asian individuals.

Common risk factors in the development of necrotizing fasciitis include trauma, alcoholism, diabetes, intravenous drug abuse, immunosupression and burns.^[1]

According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for necrotizing fasciitis.

If left untreated, the acute inflammatory changes spread quickly, accompanied by high fever and extreme weakness leading to necrosis of soft tissue. Common complications of necrotizing fasciitis include limb loss, sepsis, toxic shock syndrome, disseminated intravascular coagulation (DIC). Depending on the extent of the necrotizing fasciitis at the time of diagnosis, the prognosis may vary. The prognostic factors associated with necrotizing fasciitis include diabetes mellitus, acute renal failure, admission serum creatinine >2mg/dl and admission white blood cells >30,000 cells mm3.

LRINEC is a diagnostic scoring system used to distinguish necrotizing fasciitis from other soft tissue infections.

During early stages, the symptoms of necrotizing fasciitis are non-specific. Symptoms include fever, nausea, and fatigue.^[12][13]

Physical examination of patients with necrotizing fasciitis is usually remarkable for local soft tissue signs such as warmth, tenderness beyond margins of erythema, swelling, erythema with ill defined margins, blistering/bullae, skin discoloration, foul discharge (greyish or brown discharge), fluctuance, crepitus, skin sloughing or necrosis, absence of lymphangitis or lymphadenopathy (lymphangitis is rarely observed in necrotizing fasciitis patients), sensory and motor deficits (e.g. localized anesthesia).^[14][12] Finger probe test is useful in the diagnosis of necrotizing fasciitis.^[12]

Laboratory findings consistent with the diagnosis of necrotizing fasciitis include positive blood and tissue culture, elevated inflammatory markers, leukocytosis and elevated serum creatinine.

There are no electrocardiogram findings associated with necrotizing fasciitis. Electrocardiogram may be helpful in the diagnosis and management of complications of necrotizing fasciitis.

On x ray of affected area, necrotizing fasciitis is characterized by subcutaneous gas or soft tissue swelling (specific x-ray finding) and increased soft tissue thickness and opacity. Chest x-ray findings associated with necrotizing fasciitis include early changes of fluid overload and adult (acute) respiratory distress syndrome (ARDS).

On CT scan, necrotizing fasciitis is characterized by subcutaneous emphysema, asymmetrical fascial thickening associated with fat stranding, edema and abscesses.

On MRI, necrotizing fasciitis is characterized by features such as loss of muscle texture and high signal intensity compatible with intramuscular hemorrhage in T1 weighted image. On T2-weighted images, subcutaneous and intramuscular edema in a reticulated pattern and subfascial and interfascial crescentic fluid collection are seen.

Ultrasound is more useful in children (with raising incidence after primary varicella infection). On ultrasound, necrotizing fasciitis is characterized by distorted and thickened fascial planes with turbid fluid accumulation in the fascial layers, subcutaneous edema and soft tissue gas.

On frozen section biopsy, histologic criteria for diagnosis of necrotizing fasciitis include necrosis of superficial fascia, fibrinous thrombi of arteries and veins, polymorphonuclear infiltration of the dermis and fascia, and presence of microorganisms within the destroyed fascia and dermis.

Necrotizing fasciitis is a medical and surgical emergency. The mainstay of therapy for necrotizing fasciitis includes surgical exploration and debridement along with antimicrobial therapy. Initial pharmacologic therapy often includes a combination of intravenous antibiotics including penicillin, vancomycin, and/or clindamycin.

Surgery is the mainstay of treatment for necrotizing fasciitis. Immediate surgical referral remains the only method of reducing mortality and morbidity.

Effective measures for the primary prevention of necrotizing fasciitis include prevention of trauma/breaks in skin integrity, treatment of underlying infections, hand washing, proper wound care and proper management of underlying co-morbidities.

Secondary prevention strategies following necrotizing fasciitis include early diagnosis and prompt treatment with either antibiotics or surgery. This strategy prevents or slows the progression and complications of the disease.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]

Narcotizing fasciitis was first described by Hippocrates in the fifth century B.C. as the complication of erysipelas.^[1][2] During the Civil War, necrotizing fasciitis was described as “hospital gangrene” by Confederate Army surgeon Joseph Jones.^[3][4] In 1924, Frank L. Meleney reported a series of 20 patients as having hemolytic streptococcal gangrene, later called Meleney’s gangrene.^[5] Necrotizing fasciitis of perineum was described in 1883 by the French physician Jean Alfred Fournier.^[6]

• Necrotizing fasciitis was first described by Hippocrates in the fifth century B.C. as the complication of erysipelas.^[1][2]
• During the Civil War, necrotizing faciitis was described as “hospital gangrene” by Confederate Army surgeon Joseph Jones.^[3][4][7]
• In 1924, Frank L. Meleney reported a series of 20 patients as having hemolytic streptococcal gangrene, later called Meleney’s gangrene.^[5]
• The association between bacterial infection and necrotizing fasciitis was made in 1918.
• In 1952, the disease was named as necrotizing fasciitis by Wilson.^[3]
• Necrotizing fasciitis of perineum was described in 1883 by the French physician, Jean Alfred Fournier.^[6]
• Guiliano and colleagues divided the necrotizing fasciitis into type I and type II.^[8]
• In 1989, Stevens and colleagues were the first to characterize unique clinical characteristics associated with GASNF.^[9]
• The soft tissue infections were first classified as either local or spreading by Smith et al.^[10]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]

Necrotizing fasciitis may be classified according to International Classification of Diseases-10 (ICD-10) into M72.6 Necrotizing fasciitis.^[1] Based on microbiological findings, necrotizing fasciitis may be classified into four types: Type I, Type II, Type III, and Type IV. Necrotizing fasciitis is further classified based on anatomic location and severity of symptoms.^[2]

Based on microbiological findings, necrotizing fasciitis may be classified into four types.^{[3][4][5][6][7][8][9]}

• Based on anatomic location, necrotizing fasciitis may be classified into:^[2]

• Fournier’s gangrene (necrotizing fasciitis of perineum)
• Craniofascial necrotizing fasciitis
• Cervical fasciitis
• Ludwig’s angina (submandibular and sublingual spaces)^[10]

• Based on severity of disease, necrotizing fasciitis is classified into:^[11]

• Hyperacute
• Sub-acute

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]

The pathophysiology of necrotizing fasciitis is common to all types, but the speed of development and associated clinical features differs depending on the causative organisms. Following transmission, the bacteria uses the entry site to invade the fascial planes which causes the wide spread necrosis of superficial fascia, deep fascia, subcutaneous fat, nerves, arteries, and veins. Necrotizing fasciitis can be a serious complication of omphalitis in the neonate. The pathogenesis of necrotizing fasciitis is the result of bacterial and host factors. The exact pathogenesis of type 1 necrotizing fasciitis is not fully understood but polymicrobial species work synergistically to enhance the spread of infection. Group A streptococcus is the most common causative agent of type 2 necrotizing fasciitis. Bacterial virulence factors, exotoxins, superantigens and host immune system plays a major role in the pathogenesis of type II necrotizing fasciitis. Recurrent necrotizing fasciitis is caused by MRSA. On gross pathology, the characteristic findings of necrotizing fasciitis include subcutaneous emphysema, skin sloughing, bulae and necrosis. Inflammatory changes are seen on microscopic histopathology.^[1]

The pathophysiology of necrotizing fasciitis is common to all types of necrotizing fasciitis, but the speed of development and associated clinical features differs depending on the causative organisms.^[1]

• The transmission of pathogens occurs through the following routes:^[2][3]

• External trauma (e.g., laceration, abrasion, burn, insect bite)
• Direct spread from a perforated viscus (particularly colon, rectum, or anus) or another surgical procedure (e.g., vasectomy, hemorrhoidectomy)
• Urogenital organ
• Perirectal abscess
• Decubitus ulcer

• Following transmission, the bacteria uses the entry site to invade the fascial planes which causes the wide spread necrosis of superficial fascia, deep fascia, subcutaneous fat, nerves, arteries, and veins.
• Superficial skin and deeper muscles are typically spared.
• In late stages, lesions develop liquefactive necrosis at all tissue levels.

Necrotizing fasciitis in neonate

• Necrotizing fasciitis can be a serious complication of omphalitis in the neonate.
• The omphalitis may progress resulting in purplish discoloration and periumbilical necrosis.
• The necrosis may extend to the flanks and even onto the chest wall.

The pathogenesis of necrotizing fasciitis is the result of bacterial and host factors.^[4][5]

Type 1 NF

• The exact pathogenesis of type 1 necrotizing fasciitis is not fully understood.
• It is thought that type 1 NF is caused by polymicrobial species that work synergistically to enhance the spread of infection.
• Synergistic NF is comparatively slow process evolving over days.
• It usually develops in the area where gut flora breaches the mucosa, entering the tissue planes.

Type 2 NF

• Group A streptococcus is the most common causative agent of type 2 NF.^[6][7]
• Type 2 NF is initially insidious in onset but progress more rapidly.^[8]
• The disease may appear spontaneously with no obvious focus. Hematogenous infection from many foci such as skin, throat, ascending vaginitis, primary peritonitis reaches the fascial layer or seeds vimentin exposed by muscle damage.
• Direct inoculation of GAS through wounds or associated surgery is less common.
• The pathogenesis of type 2 NF is the result of the following process:

• Inhibition of phagocytosis of bacteria by hyaluronic acid capsule and M protein
• Adherence of bacteria to host cell through adherence factors such as M protein, protein F and lipoteichoic acid^[9]
• Release of exotoxins (streptococcal pyogenic exotoxins and superantigen) into blood produce massive proliferation of T cells and cascading release of cytokines activating inflammatory process
• Activation of inflammatory process which begins to kill bacteria
• The streptococci release massive amounts of enzymes, hemolysins, DNAase, proteases and collagenases which destroy the normal skin and surrounding tissue with progressive coagulative necrosis
• The inflamed cells release more cytokines that stimulate more inflammatory cells
• The massive release of cytokines result in systemic inflammatory response syndrome resulting in shock, organ failure, depression of myocardial function and immune suppression
• Stimulation of T-cells by superantigen causes activation of complement pathway, the bradykinin–kallikrein system, and the coagulation cascade, worsening small vessel thrombosis and tissue ischemia. Tissue ischemia impedes oxidative destruction of bacteria by polymorphonuclear cells and prevents adequate delivery of antibiotics.
• The blood flow to local tissue is compromised due to thrombosis of large number of dermal capillaries by the local hypercoaguable state, platelet–neutrophil plugging of vessels and increased interstitial pressure

• Nerves supplying the necrotizing areas of skin die, the central areas become anaesthetic and peripheral areas remain tender
• In later stages, infection from deeper layers ascends, producing edema of epidermal and dermal layers (peau d’orange) and a woody firmness of the tissues
• The fascial and nerve destruction results in sensory and motor deficits, which causes progression of hemorrhagic bulae to cutaneous gangrene

Recurrent necrotizing fasciitis

Recurrent NF is seen in following conditions:^[10]

• Methicillin resistant staphylococcus aureus (MRSA)
• Complement C4 deficiency

On gross pathology the characteristic findings of necrotizing fasciitis include:^[11]

• Subcutaneous emphysema
• Edema
• Erythema
• Bulae
• Skin sloughing
• Dull grey discoloration

• 
  By Nephron – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19107063

On microscopic histopathological analysis, the characteristic findings of necrotizing fasciitis are^[11]

• Early stages

• Obliterative vasculitis with microangiopathic thrombosis
• Acute inflammation of subcutaneous tissue
• Superficial hyaline necrosis along with edema and inflammation of the dermis and subcutaneous fat
• Dense neutrophil-predominant inflammatory infiltrate

• Late stages

• Noninflammatory intravascular coagulation and hemorrhage
• Myonecrosis

• 
  By Piotr Smuszkiewicz, Iwona Trojanowska and Hanna Tomczak – Late diagnosed necrotizing fasciitis as a cause of multiorgan dysfunction syndrome: A case report. Cases Journal 2008, 1:125. doi:10.1186/1757-1626-1-125, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=5639655
• 
  By Piotr Smuszkiewicz, Iwona Trojanowska and Hanna Tomczak – Late diagnosed necrotizing fasciitis as a cause of multiorgan dysfunction syndrome: A case report. Cases Journal 2008, 1:125. doi:10.1186/1757-1626-1-125, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=5639655

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]

The causative organisms vary depending on the type of necrotizing fasciitis: Type I (polymicrobial), Type II (monomicrobial), Type III (Gram negative monomicrobial, including marine related organisms) and Type IV (fungal).^[1]

Necrotizing fasciitis may be caused by the following organisms:^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]

Necrotizing fasciitis must be differentiated from other diseases that cause erythema, pain, edema and necrosis of soft tissues such as sunburn, cellulitis, erysipelas, diabetic myonecrosis and vasculitis.^[1]

Necrotizing fasciitis must be differentiated from:^{[1] [2][3]}

Early stage

• Muscle strains
• Viral illness
• Thrombosis
• Sprain or exacerbation of gout
• Sunburn or an allergic rash

Late stage

• Non-necrotizing fasciitis (eosinophilic fasciitis, paraneoplastic fasciitis, nodular fasciitis, and proliferative fasciitis)
• Cellulitis
• Dermatomyositis
• Erysipelas
• Vasculitis (Lupus myofasciitis, Churg-Strauss Vasculitis and others)
• Graft-versus-host disease (GVHD)
• Diabetic myonecrosis
• Compartment syndrome
• Lymphedema
• Phlegmasia cerulea dolens
• Myxedema
• Gastroenteritis
• Necrotizing pyoderma gangrenosum

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]

The incidence of necrotizing fasciitis in adults is 0.40 cases per 100,000 people/year and the incidence in children is higher at 0.08 cases per 100,000 people/year.The overall mortality rate in the United states from 2003- 2013 was 4.8/1,000,000 per year. Patients from all age groups can develop necrotizing fasciitis but slightly more common among >50 years age and effects men and women equally.The incidence rate of necrotizing fasciitis is high in black, Hispanic, and American Indian individuals compared to Whites and low in Asian individuals.

• Since 2010, on average, there are between 700-1100 cases of necrotizing fasciitis caused by group A streptococcus annually in the United States.^[1]
• The incidence of necrotizing fasciitis in adults is approximately 0.40 per 100,000 individuals. The incidence of necrotizing fasciitis in children is approximately 0.08 per 100,000 individuals.^[2][3]

• Early intervention remains the only method of reducing mortality and morbidity in necrotizing fasciitis patients.
• The overall mortality rate of necrotizing fasciitis related deaths in the United States from 2003-2013 was 4.8/1,000,000 per year.^[4]
• The mortality rate in necrotizing fasciitis is approximately between 24-34%.^[5][6]
• The mortality rate of necrotizing fasciitis increases from 9% to 63% if associated with mysositis and streptococcal toxic shock syndrome.

Patients of all age groups may develop necrotizing fasciitis, however, it is slightly more common among patients >50 years age.^[7]

Necrotizing fasciitis effects men and women equally.^[8]

• The incidence rate of necrotizing fasciitis is higher in Black, Hispanic, and American Indian individuals compared to Whites.^[4]
• The incidence rate is low in Asian populations.

Necrotizing fasciitis is more common in developing countries because of low socioeconomic status and poor standards of hygiene.^[8]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]

Common risk factors in the development of necrotizing fasciitis include trauma, alcoholism, diabetes, intravenous drug abuse, immunosupression and burns.^[1]

Common risk factors in the development of necrotizing fasciitis include:^{[1][2][3][4][5][6]}

• NSAIDS mask the signs and symptoms leading to delay in diagnosis of existing infection.^[1][7][8]
• NSAIDS potentiate the development of renal failure by inhibiting renal prostaglandin synthesis and prevent the respiratory burst necessary for phagocytes to kill intracellular organisms leading to impairment of natural host defense mechanisms.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Yamuna Kondapally, M.B.B.S[2]

According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for necrotizing fasciitis.

According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for necrotizing fasciitis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]

If left untreated, the acute inflammatory changes spread quickly, accompanied by high fever and extreme weakness leading to necrosis of soft tissue. Common complications of necrotizing fasciitis include limb loss, sepsis, toxic shock syndrome, disseminated intravascular coagulation (DIC). Depending on the extent of the necrotizing fasciitis at the time of diagnosis, the prognosis may vary. The prognostic factors associated with necrotizing fasciitis include diabetes mellitus, acute renal failure, admission serum creatinine >2mg/dl and admission white blood cells >30,000 cells mm3.

• If left untreated, the acute inflammatory changes spread quickly, accompanied by high fever,extreme weakness and may progress to death.^[1]
• The overlying skin becomes smooth, tense and shiny. Diffuse erythema without distinct borders is seen.
• First 1 or 2 days, the lesions develop with progressive color changes from red to purple to blue and then becomes frankly gangrenous, first turning black, then greenish-yellow.
• If the patient has survived, a line of demarcation between viable and necrotic tissue would become sharply defined from days 7 to 10.
• Sloughing of necrotic skin would reveal the underlying pus and extensive liquefactive necrosis of subcutaneous tissues, which will be significantly more extensive than would be suspected with the overlying area of necrotic skin.
• Metastatic abscesses and pulmonary distress may develop as well.

Common complications of necrotizing fasciitis include:^[2]

• Limb loss
• Sepsis
• Kidney failure
• Compartment syndrome
• Extensive scarring and disfigurement
• Toxic shock syndrome
• Rapid advancement of disease resulting in death
• Disseminated intravascular coagulation

• Most of Type 2 NF cases are associated with streptococcal toxic shock syndrome which increases the mortality of streptococcal NF alone from <40% to 67% with up to half of patients needing amputation.
• The superantigens cause massive activation of T-cell, cytokine release, tissue damage, and toxic shock-like syndrome

Depending on the extent of the necrotizing fasciitis at the time of diagnosis, the prognosis may vary.^[3]

• The prognostic factors associated with necrotizing fasciitis include:

• Timing to operative intervention (most important prognositic factor)
• Age older than 60 years
• Female gender
• Number of comorbidities
• Acute renal failure
• Underlying malignancy
• Coagulopathy or acidosis on admission
• Clostridial or group A streptococcal infection
• Vibrio vulnificus infection
• Admission white blood cells >30,000 cells/mm3
• Diabetes mellitus
• Shock on admission
• Admission serum creatinine >2mg/dl
• Associated streptococcal toxic shock syndrome
• Over expression of cytokines in host
• Immunodeficiency
• High APACHE (Acute physiology, Age, and chronic health evaluation) II scores (>13)
• Use of NSAIDs