Necrotizing fasciitis pathophysiology

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

Overview

“Flesh-eating bacteria” is a misnomer, as the bacteria do not actually eat the tissue. They cause the destruction of skin and muscle by releasing toxins (virulence factors). These include streptococcal pyogenic exotoxins and other virulence factors. S. pyogenes produces an exotoxin known as a superantigen. This toxin is capable of activating T-cells non-specifically. This causes the over-production of cytokines that over-stimulate macrophages. The macrophages cause the actual tissue damage by releasing oxygen free radicals that are normally intended to destroy bacteria but are capable of damaging nearly any macromolecule they contact in the body.

Pathophysiology

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

• The transmission of pathogens occurs through the following routes:

• External trauma
• Direct spread from a perforated viscus (particularly colon, rectum, or anus)
• Urogenital organ

• 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 liquefaction necrosis at all tissue levels.

Pathogenesis

The pathogenesis of necrotizing fasciitis is the result of bacterial and host factors.

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 together to enhance the spread of infection (Synergistic).
• 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.
• Type 2 NF is initially insidious in onset but progress more rapidly.
• 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
• Release of exotoxins (streptococcal pyogenic exotoxins and superantigens) 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 superantigens 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 oedema 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 bullae to cutaneous gangrene.

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  Virulence Factors of Group A Streptococcus

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  Inhibition of phagocytosis

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  Adherance to host cell and release of exotoxins

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  Activation of host immune response

Recurrent necrotizing fasciitis

Recurrent NF is seen in following conditions:

• Methicillin resistant staphylococcus aureus MRSA
• Complement C4 deficiency

Gross pathology

On gross pathology the characteristic findings of necrotizing fasciitis include:

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

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  Beginning of necrotizing fasciitis

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  Necrotizing fasciitis of left leg

Microscopic histopathological analysis

On microscopic histopathological analysis, the characteristic findings of necrotizing fasciitis are

• 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

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