Necrotising Fasciitis: A Review Of The Clinical Presentation, Pathology, And Treatment

Necrotising Fasciitis: A Review of the Clinical Presentation, Pathology, and Treatment

Bhargava R.

Abstract

Necrotising Fasciitis (NF) is a rare bacterial infection which causes rapid and extensive necrosis of the fascia and subcutaneous tissue, which can lead to amputation, severe systemic toxicity, and even death. There are approximately 500 cases in the UK each year1, with mortality rates between 25 and 35%.2 Early diagnosis is often hindered by the fact the initial symptoms presented are similar to other, more common soft-tissue conditions such as cellulitis, and are thus often treated as such. Differential diagnoses can include cellulitis, gas gangrene, and pyomyositis. Most commonly affected areas are the limbs and the perineum. NF can be caused by many species of bacteria, most of which are naturally present in the human body in small amounts. Diagnosis can be made by examination, medical imaging or exploratory surgery (the third being the most accurate way of identifying NF). Broad-spectrum antibiotics are often prescribed when NF is suspected and once a definitive diagnosis has been made, an extensive surgical debridement must be performed to remove the necrotic tissue (the boundaries of which are at the surgeon`s discretion). During the surgery, biopsies are taken to identify the bacteria causing the infection and specific antibiotics are prescribed. Further treatments include hyperbaric oxygen (HBO) therapy, intravenous immunoglobulin (IVIG) therapy, and a novel drug known as AB103.

Clinical Presentation Diagnosis

The bacteria can enter the body through any break in the skin, even in patients with pre-existing skin conditions such as abscesses, psoriasis or pressure ulcers. Any situation where the integumentary system is compromised - such as trauma (lacerations or burns), surgery, or intravenous drug use - can permit the entry of the bacteria and subsequently cause NF.

There are a number of conditions which can cause a predisposition to NF, the most common being those which cause immunosuppression, such as diabetes mellitus, AIDS, cancer and C4 deficiency. Immunosuppressant drugs are also linked with cases of NF, such as Infliximab, a chimeric monoclonal antibody which has been shown to increase the risk of infection due to its effect on lymphocytes and cytokines (especially TNF- & - a cytokine which has a role in inflammatory response and regulation of leukocytes). Immunosuppressants used in post-transplant care to minimise organ rejection have also been linked to an increase in the risk of infection.3 Studies also show that patients with diabetes mellitus hold a high risk of amputation during surgery.4

NF initially presents with symptoms similar to cellulitis, and thus it is extremely difficult to differentiate between the two, which means that only 15 - 34% of patients get accurately diagnosed at admission, thus vastly increasing the amputation and mortality rates.5 However, the most common initial symptoms are erythema, severe and disproportionate pain which extends beyond the margins of the obvious visible infection, swelling, and a high fever, as well as edema which extends beyond the margins of the visible erythema. Several other symptoms are much more suggestive of NF, but occur much later in the course of the infection, which include the presence of large bullae, heavy bruising of the skin and the presence of subcutaneous emphysema found by radiological imaging or examination. One of the most important contrasts between cellulitis and NF is the chronology of the disease - symptoms of NF progress much more rapidly and thus early diagnosis is critical in order to reduce mortality. Systemic toxicity and/or ischemia is a sign that the infection has progressed further and must be dealt with quickly by surgical intervention. Despite the advancements in medical imaging and laboratory testing, surgical exploration remains the most accurate diagnostic method for NF. Subcutaneous emphysema, fascial thickening and edema may be seen on a computed tomography (CT) scan, but these symptoms are all nonspecific and thus a definitive diagnosis cannot be made. Laboratory tests are always conducted at admission and usually a white blood cell (WBC) count greater than 15,000 cells/mm3 and a serum sodium level greater than 135 mmol/L is one of the most common results for NF. However, there is a much more accurate system known as the laboratory risk indicator for necrotising fasciitis (LRINEC) score, which takes into account C-reactive protein level, WBC count, haemoglobin level, serum sodium level, serum creatinine level, and serum glucose level at admission. However, this score on its own is not sufficient to confirm the diagnosis. Therefore, exploratory surgery under high clinical suspicion is the best way of proceeding. A small incision can be made at the infection site, whereby the surgeon can assess the adherence of the fascia to the surrounding soft tissue. If the diseased fascia is no longer adherent to the surrounding tissue, and the surgeon can easily slide their finger along the fascial plane, the diagnosis is confirmed and surgical debridement should be performed.6

Classification Pathology

NF is classified into four types based on their microbiology and aetiology.

Type I is the most common, accounting for around 70 - 80% of cases, and are generally polymicrobial, composed of a mixture of Gram-positive cocci such as S. aureus, S. pyogenes, and enterococci, Gram-negative rods such as E. coli, and P. aeruginosa, as well as anaerobes such as the Bacteroides or Clostridium genus. 5 Patients with type I NF are typically elderly and have comorbidities such as diabetes mellitus, obesity, or vascular diseases, and often do not have a history of trauma. The infection can occur due to the breakdown of tissue integrity from abscesses or due to perforations which lead to bacterial translocation. Type I infections usually occur in the perineal and genital area. Some members of Clostridium genus are naturally occurring in the human gastrointestinal microbiota, as well as in the genital tract, but can cause NF when translocated to the subcutaneous area. Various clostridial species have been associated with NF, such as C. perfringens, C. sordellii, and C. septicum. C. perfringens is perhaps the most common pathogen of the clostridial species, and is found in the GI tract.6 It produces the toxin phospholipase C ( &-toxin), which causes severe damage to the cell membrane by hydrolysing phospholipids such as phosphatidylcholine into phosphocholine and diglycerides, which then leads to cell lysis. Furthermore, the &-toxin also acts as a platelet agonist, initiating platelet aggregation which can result in thrombosis and subsequently severe ischemia, which causes an overall decrease in tissue pH and thus enhances bacterial proliferation, as well as tissue necrosis due to lack of perfusion. The platelets can also impair phagocyte function by adherence and thus interfere with diapedesis. There are two other toxins that are produced by C. perfringens which are &-toxin and &-toxin, the former being much less common in NF-causing strains.7 The &-toxin is a pore-forming toxin which exerts a cytotoxic effect by causing the swelling of cells and creating pores in the lipid raft.8 The &-toxin is responsible for impairing leukocyte function by inhibiting chemotaxis and damaging capillary endothelium, causing fluid to leak into the surrounding tissue.9 C. sordellii infections have been identified in many cases of intravenous drug use (predominantly heroin). It produces two toxins known as lethal toxin (TcsL) and haemorrhagic toxin (TcsH). They are glycosyltransferases, which act by glycosylating small GTPases in the cytosol, which can have adverse effects on the cell cycle, apoptosis, and transcri ption. Furthermore, TcsH is also able to induce a haemorrhagic response, but is less prevalent than TcsL.10 C. septicum produces an &-toxin (different to that of C. perfringens), which is a pore-forming cytolysin, secreted as an inactive protoxin, activated by a protease enzyme in the skin causing lysis and vacuolation.11

Type II is much less common, accounting for only about 20-30% of cases, and involves group A &-haemolytic streptococcus (GAS or S. pyogenes) either on its own or in combination with S. aureus. Patients with type II NF are generally younger and healthier but have a history or trauma, surgery or intravenous drug use. This infection typically affects the limbs and extremities.6 One of the most common symptoms of GAS NF infections is toxic shock syndrome (TSS) which is caused by a group of proteins known as superantigens (SAgs), the most common SAg in GAS being M-protein. SAgs are able to bypass the antigen presenting pathway used by regular antigens and bind directly to the major histocompatibility complex (MHC) class II on antigen presenting cells (APCs) and, where regular antigens stimulate 0.01% of T-cells for a limited, highly specific immune response, SAgs can stimulate around 20-30%. This triggers a massive cytokine storm, including TNF- &, interleukin (IL)-1, IL-2, and IL-6. All of which are responsible for a huge immune and inflammatory response and TSS, characterised by a high fever, tachycardia, excessive pain, and eventually circulatory shock and multisystem organ failure. Once shock has been established, mortality exceeds 50%. GAS also secretes a potent pore-forming exotoxin known as streptolysin S (SLS), which is cytolytic and targets erythrocytes, platelets, subcellular organelles and leukocytes and causes irreversible osmotic lysis. S. aureus also secretes a pore-forming toxin known as &-toxin (or Haemolysin- &), which is much more prevalent in methicillin resistant strains and is most commonly associated with hospital/community-acquired infections.12 The mechanism for Type II GAS and staphylococcal infections is very similar to the Type I GAS and staph infections, with the major difference being the patient group.

Type III infections are extremely rare and are caused by gram-negative marine organisms (most commonly Vibrio vulnificus) found in warm saltwater environments. The number of cases of type III is gradually increasing due to the rise in sea surface temperatures. Similar to type II, TSS occurs in many patients and there is usually a large amount of dishwater fluid and pus found at the wound site. It is usually very rapidly progressing due to the fast-acting exotoxins secreted by V. vulnificus, such as metalloprotease VvpE and cytolysin/haemolysin VvhA which can induce changes in vascular permeability, septic shock and inflammatory responses which can lead to multisystem organ failure.13

Type IV is an even rarer form of NF, which some studies have described as being fungal in nature. Some fungi known to cause type IV NF are from the Apophysomyces genus (A. variabilis and A. elegans). It is an extremely aggressive infection which & invades blood vessels, leading to thrombosis and infarction, causing necrotic lesions.14

Initial Treatment

Broad-spectrum antibiotics are prescribed as soon as NF is suspected, and once diagnosis is confirmed, surgical debridement is performed. Given the aggressive nature of the infection, the time from admission to debridement must be kept to an absolute minimum and as soon as NF is suspected, & the diagnostic and treatment processes have to be performed quicker. Multiple studies show that mortality was drastically reduced due to early diagnosis and treatment (one study showed that out of 42 patients, 30 were diagnosed and treated early and two died, and of the 12 that were transferred from other hospitals and treated later, 9 died15& another showed that cases in which surgery was performed more than 24 hours after recognition resulted in 70% mortality compared to 36% for cases with surgery within 24 hours16). The debridement is completely in the hands of the surgeon, who can choose to conserve more tissue or perform a wide and radical debridement, and even amputation if necessary. Ideally debridement should be performed past the boundaries of necrosis and over into healthy bleeding tissue, which could potentially be a large operation, and the surgeon must be ready and willing to debride en masse tissue and organs to reduce the risk of spread. Patients almost always require multiple procedures (generally 3-4 - with the second usually within 24 hours of the initial operation), and the extent of the initial debridement can have a large impact on the requirements and success of further procedures.6 Studies show that conservative or inadequate debridements have a much higher mortality rate than those which are radical and excessive (smaller, conservative operations had a mortality of 71% compared to initial radical surgery which had a mortality of 43%16). Amputation may be necessary in the extremities, particularly when a joint is involved, or if the infection is rapidly spreading despite multiple debridements. However, the patient s autonomy must be respected and their preferences must be taken into account when determining whether amputation is the correct way to proceed. After the procedure, the wound is covered and dressings are changed regularly to preserve wound cleanliness and hygiene. In some perineal cases, a colostomy may also be performed in order to divert faecal matter away from the wound site in order to maintain cleanliness, & but this is not always necessary as long as the dressings are changed regularly and the faecal matter can be managed through liquid stools and a faecal management system. Reconstructive surgery is also performed on the wound site in the form of various levels of skin grafts, tissue expansion or flaps in order to cover the soft tissue and achieve definitive wound closure.

When NF is suspected, empirical antibiotics are prescribed, which cover Gram-positive, Gram-negative, and anaerobic bacteria. During the initial debridement, tissue biopsies are taken to determine precisely which pathogens are present, which can be used to narrow down the antibiotic therapy to increase specificity.6 This is extremely important due to the polymicrobial nature of the disease. The antibiotic therapy helps to reduce the spread of the infection and thus minimises the number of debridements required. For type I, metronidazole (which disrupts nucleic acid synthesis), clindamycin (which hinders &-toxin production) or carbapenems (which inhibit bacterial cell wall synthesis) are effective against the clostridial species.17 For type II, clindamycin is effective against GAS, due to its inhibition of SAgs production, and vancomycin, linezolid or daptomycin are effective against MRSA, with linezolid damaging exotoxins, and daptomycin disrupting bacterial membrane integrity.12 Type III can be treated with tetracycline (which inhibits protein synthesis and toxin production by binding to the ribosomes) and cephalosporins (which inhibit the formation of the peptidoglycan layer on bacterial cell walls).18 Type IV is treated with antifungals such as posaconazole and terbinafine, which are effective against A. variabilis and work by inhibiting the synthesis of ergosterol in fungal cell membranes and thus impairing its growth.14

Blood pressure is also constantly monitored and maintained to keep up perfusion of the wound site.

Adjunctive Treatment

While surgery and antibiotic therapy are the universally accepted treatments for NF, there are a number of add-on therapies which have been employed with varying degrees of success.

Hyperbaric oxygen therapy (HBOT) has been widely used in cases of NF post-operatively in order to promote wound healing and decrease mortality by reducing the risk of further infection. In some hospitals, it is part of the standard treatment plan, whereas in others, it is hardly used. It consists of a patient being placed in a pressurized chamber which can deliver oxygen at up to 2-3 times the atmospheric pressure, which can result in a tissue oxygen tension of up to 4 times the level of breathing pure oxygen at normal atmospheric pressure.6 Studies have shown that this intensive oxygenation has a vastly positive effect on the proliferation of fibroblasts, which are a key component in wound healing and synthesis of collagen and the extracellular matrix in connective tissue.19 Other reported beneficial effects of HBOT include an enhancement of the respiratory burst in macrophages and neutrophils, resulting in increased phagocytic action, as well as increased cytotoxicity to some anaerobes, and increased antibiotic efficacy.20 However, the use of HBOT in a clinical setting to treat NF is widely debated, with some studies reporting positive outcomes and decreased mortality, and others reporting no significant changes in mortality (23% with, 66% without21& 8.3% with, 13.3% without22& 11.9% with, 34.9% without23& 17% with, 26% without24).

Intravenous immunoglobulin (IVIg) therapy has also been used in some cases of NF, mainly to treat TSS in type II and decrease mortality by minimizing the risk of multisystem organ failure. It consists of & intravenously injecting human plasma, taken from plasma donors, which contains antibodies specific to the SAgs of GAS and S.aureus, which can inhibit the stimulation of T-cell proliferation and the cytokine storm and thus reduce the inflammatory response25 Theoretically, this should be an extremely effective treatment against type II NF, but once again, results are extremely varied, and thus there is not enough evidence to come to a definitive conclusion (27.3% with, 23.6% without26& 13% with, 50% without27).

A new drug, known as AB103, is in a phase III clinical trial to determine its efficacy in treating NF. AB103 is a synthetic peptide mimetic of the CD28 octapeptide receptor, which is a receptor on the surface of T-cells involved in the binding of SAgs and subsequently the mass stimulation of T-cells. AB103 is designed to inhibit the binding of the SAgs to the CD28 receptor and thus reduce the risk of TSS and decrease mortality. Preclinical studies showed that AB103 and similar mimetic peptides caused a decrease in mortality in animal models of TSS, and the phase I trial ensured that there were no toxic effects of the drug on healthy volunteers. The phase II double-blind trial determined that the drug was safe to use in a clinical setting, with varying effects on TSS, and therefore the phase III trial needs to determine the optimum dosage and efficacy.28 This is a promising new treatment for type II NF, and could potentially vastly reduce mortality and improve patient care.

Conclusion

Necrotising fasciitis is a rare and acute disease which needs to be approached with high clinical suspicion and quick decision making in order to effectively diagnose and treat the patient, and lower the risk of mortality. Early intervention has been shown to vastly improve treatment success rates. There are patient groups who are more susceptible, but NF can affect healthy patients as well. As of now, the most definitively effective treatment is aggressive surgical debridement combined with specific antibiotic therapy, with other add-on treatment methods displaying inconclusive results to prove their efficacy. However, AB103 shows potential for use in the treatment of type II NF, and therefore could be used as part of the standard treatment plan in the future.

References

Hasham S, Matteucci P, et al. Necrotising fasciitis. BMJ. 2005.

Rajput A, Waseem, et al. Mortality in necrotizing fasciitis. J Ayub Med Coll Abbottabad. 2008.

Trent J Kirsner R. Diagnosing necrotizing fasciitis. Advances in skin wound care. 2002.

Cheng NC, Tai HC, et al. Necrotizing fasciitis in patients with diabetes mellitus: clinical characteristics and risk factors for mortality. BMC Infect Dis. 2015.

Paz Maya S, Dualde Beltr n D, et al. Necrotizing fasciitis: an urgent diagnosis. Skeletal Radiol. 2014.

Hakkarainen T, Kopari N, et al. Necrotizing soft tissue infections: review and current concepts in treatment, systems of care, and outcomes. Curr Probl Surg. 2014.

Paasch C, Wilczek S, et al. Liver abscess and sepsis caused by Clostridium perfringens and Klebsiella oxytoca. Int J Surg Case Rep. 2017.

Nagahama M, Ochi S, et al. Recent insights into Clostridium perfringens beta-toxin. Toxins (Basel). 2015.

Stevens D, Mitten J, et al. Effects of alpha and theta toxins from Clostridium perfringens on human polymorphonuclear leukocytes. J Infect Dis. 1987.

Carter G, Awad M, et al. TcsL is an essential virulence factor in Clostridium sordellii ATCC 9714. Infect Immun. 2011.

Rimawi BH, Graybill W, et al. Necrotizing Fasciitis and Toxic Shock Syndrome from Clostridium septicum following a Term Cesarean Delivery. Case Rep Obstet Gynecol. 2014.

Shumba P, Mairpady Shambat S, et al. The Role of Streptococcal and Staphylococcal Exotoxins and Proteases in Human Necrotizing Soft Tissue Infections. Toxins (Basel). 2019.

Koh THB, Tan JHJ, et al. Early clinical manifestations of vibrio necrotising fasciitis. Singapore Med J. 2018.

Chander J, Stchigel A, et al. Fungal necrotizing fasciitis, an emerging infectious disease Caused by Aphophysomyces (Mucorales). Iberoamerican Journal of Mycology. 2013.

Voros D, Pissiotis C, et al. Role of early and extensive surgery in the treatment of severe necrotizing soft tissue infection. Br J Surg. 1993.

Freischlag J, Ajalat G, et al. Treatment of necrotizing soft tissue infections. The need for a new approach. Am J Surg. 1985.

Misiakos E, Bagias G, et al. Current concepts in the management of necrotizing fasciitis. Front Surg. 2014.

Wong K, Brown A, et al. Antibiotic use for Vibrio infections: important insights from surveillance data. BMC Infect Dis. 2015.

Kendall R, Feghali-Bostwick C. Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol. 2014.

Memar M, Yekani M, et al. Hyperbaric oxygen therapy: Antimicrobial mechanisms and clinical application for infections. Biomedicine Pharmacotherapy. 2018.

Riseman J, Zamboni W, et al. Hyperbaric oxygen therapy for necrotizing fasciitis reduces mortality and the need for debridements. Surgery. 1990.

George M, Rueth N, et al. Hyperbaric oxygen does not improve outcome in patients with necrotizing soft tissue infection. Surg Infect (Larchmt). 2009.

Escobar S, Slade J Jr, et al. Adjuvant hyperbaric oxygen therapy (HBO2) for treatment of necrotizing fasciitis reduces mortality and amputation rate. Undersea Hyperb Med. 2005.

Hassan, Z, Mullins R, et al. Treating necrotizing fasciitis with or without hyperbaric oxygen therapy. Undersea and Hyperbaric Medicine. 2010.

Takei S, Arora Y, et al. Intravenous immunoglobulin contains specific antibodies inhibitory to activation of T cells by staphylococcal toxin superantigens. J Clin Invest. 1993.

Kadri S, Swihart B, et al. Impact of Intravenous Immunoglobulin on Survival in Necrotizing Fasciitis With Vasopressor-Dependent Shock: A Propensity Score-Matched Analysis From 130 US Hospitals. Clin Infect Dis. 2017.

Linn r A, Darenberg J, et al. Clinical efficacy of polyspecific intravenous immunoglobulin therapy in patients with streptococcal toxic shock syndrome: a comparative observational study. Clin Infect Dis. 2014.

Bulger E, Maier R, et al. A Novel Drug for Treatment of Necrotizing Soft-Tissue Infections: A Randomized Clinical Trial. JAMA Surg. 2014.