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Instructor: Artem Cheprasov Show bio

Artem has a doctor of veterinary medicine degree.

Necrotizing fasciitis is the death of fibrous connective tissue in the body caused by flesh-eating bacteria. Learn its causes, progression, symptoms, signs, and treatments. Updated: 09/23/2021

Most everyone who is an omnivore, and certainly a carnivore, enjoys a nice steak every now and then. All sorts of things could be on the menu, from T-bone steak to rib steak. However, what's not enjoyable is when you are on the menu. And no, it's not because Hannibal Lecter is out to get you! It's because nearly invisible, tiny bacteria are eating you from the inside out.

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Necrotizing Fasciitis

The condition caused by these bacteria is known as 'necrotizing fasciitis.' This is more commonly called 'flesh-eating disease.' The reason it is called necrotizing fasciitis is relatively simple to explain. 'Fasciitis' comes from the word 'fascia,' a type of fibrous connective tissue in your body. This tissue surrounds things such as the muscles, blood vessels and nerves in your body. You can basically think of the fascia as the thin skin around a sausage you may be enjoying along with your steak.

In any case, the suffix 'itis' in 'fasciitis' implies an inflammatory process is occurring because our immune system is responding to the invasion of bacteria and their toxins with a defense mechanism called inflammation. Hence, we get fasciitis, or the inflammation of the fascia. In addition, our fasciitis is necrotizing because it causes necrosis, or the death of tissues and cells. That's not at all to say that only the fascial planes of your body are damaged; it's more of a generalization. Tissues such as muscle groups that are surrounded by the fascia are affected as well.

Basically, you can imagine that the inflammatory process, which generates a lot of heat in the area of inflammation, is like a fire on a grill. If you put a sausage on the grill, then the skin, or fascia, would begin to cook right away. It won't be long, however, before the rest of the sausage would begin to heat up as well, since the sausage skin is very thin.

Causes of Necrotizing Fasciitis

Regardless, there are many different bacteria that end up causing necrotizing fasciitis. They include:

Staphylococcus aureus

Clostridium perfringens

Aeromonas hydrophila

Bacteriodes fragilis

Streptococcus pyogenes

Since there are so many flesh-eating bacteria to recall, you can use the acronym 'SCABS' to help you remember everything. If a person is going to survive this condition, they will have a lot of scabs on their body as a result of the healing process that will be taking place. Therefore, the flesh-eating bacteria cause SCABS, or Staph, Clostridium, Aeromonas, Bacteriodes and Strep.

Another thing you need to know is that the term 'flesh-eating bacteria' is generally a misnomer the media came up with to generate ratings. In reality, the bacteria do not actually eat your flesh. Instead, they release powerful toxins, known as 'exotoxins,' that either directly or indirectly destroy the infected and surrounding tissue.

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1. The death of tissues and cells is known as:

1. Swelling

2. Cancer

3. Trauma

4. Oncogenesis

5. Necrosis

2. The layer of fibrous connective tissue that surrounds muscles is known as:

1. Marrow

2. Myocites

3. Viscera

4. Myelin

5. Fascia

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About This Quiz & Worksheet

The quiz will test you on definitions. The questions will ask you to complete the sentence with the correct term from the choices provided.

Quiz & Worksheet Goals

The quiz will cover the following definitions:

Flesh eating disease

Necrotizing fasciitis

Treatment for flesh eating disease

Skills Practiced

The quiz will help you practice the following skills:

Reading comprehension - ensure that you draw the most important information from the related flesh eating bacteria lesson

Critical thinking - apply relevant concepts to examine information about muscle tissue in a different light

Distinguishing differences - compare and contrast topics from the lesson, such as necrotizing fasciitis

Additional Learning

After the lesson ends, make sure to head over to our fun lesson Flesh Eating Bacteria: Causes, Progression & Treatments. The interesting partner lesson covers similar information. The lesson will help you review the following topics:

Defining necrotizing fasciitis

Analyzing the name of necrotizing fasciitis

Exploring the characteristics of necrosis

Describing the different types bacteria causing necrotizing fasciitis

Detailing an acronym to help you remember all the flesh eating bacteria

Explore our library of over 84,000 lessons

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The College of Family Physicians of Canada

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OBJECTIVE To describe the defining characteristics and treatment of necrotizing fasciitis (NF), emphasizng early diagnostic indications.

QUALITY OF EVIDENCE PubMed was searched using the terms necrotizing fasciitis and necrotizing soft tissue infections, paired with early diagnosis. Results were limited to human studies in English. Additional articles were obtained from references within articles. Evidence is levels II and III.

MAIN MESSAGE Necrotizing fasciitis is classified according to its microbiology (polymicrobial or monomicrobial), anatomy, and depth of infection. Polymicrobial NF mostly occurs in immunocompromised individuals. Monomicrobial NF is less common and affects healthy individuals who often have a history of trauma (usually minor). Patients with NF can present with symptoms of sepsis, systemic toxicity, or evidence of skin inflammation, with pain that is disproportional to the degree of inflammation. However, these are also present in less serious conditions. Hyperacute cases present with sepsis and quickly progress to multiorgan failure, while subacute cases remain indolent, with festering soft-tissue infection. Because the condition is rare with minimal specific signs, it is often misdiagnosed. If NF is suspected, histology of tissue specimens is necessary. Laboratory and radiologic tests can be useful in deciding which patients require surgical consultation. Once NF is diagnosed, next steps include early wound debridement, excision of nonviable tissue, and wide spectrum cover with intravenous antibiotics.

CONCLUSION Necrotizing fasciitis is an uncommon disease that results in gross morbidity and mortality if not treated in its early stages. At onset, however, it is difficult to differentiate from other superficial skin conditions such as cellulitis. Family physicians must have a high level of suspicion and low threshold for surgical referral when confronted with cases of pain, fever, and erythema.

A 62-year-old woman of Chinese descent was admitted to hospital with a 3-day history of fever, shortness of breath, and biochemical evidence of septicemia (raised total white blood cell count and C-reactive protein levels). No obvious source of sepsis could be identified at the time of admission, except for complaints of left lower leg pain. There was no evidence of inflammation of the leg at that time.

She had a history of left knee osteoarthritis, for which she had been undergoing a course of acupuncture for the past 6 weeks. Otherwise, her medical history was unremarkable.

Classification

Different terms and classifications have been used to describe necrotizing infections of the skin and subcutaneous tissue. These include necrotizing fasciitis, synergistic necrotizing cellulitis, s treptococcal myonecrosis, and gas gangrene. This variety of classifications and terminology has been based on affected anatomy, microbial cause, and depth of infection. Awareness of this helps to reduce confusion.

Terms like necrotizing fasciitis, myonecrosis, and necrotizing adipositis refer to classification by depth of infection. Type 1 and type 2 infections refer to classification based on microbial cause. Historically, necrotizing infections were classified according to anatomical sites. Fournier gangrene (involving the perineum) and Ludwig angina (involving submandibular and sublingual spaces) are examples. These infections were named after the physicians who first described them. 7, 8

Although these descriptive terms are useful, they cause much confusion. One recently proposed recommendation suggested that the term necrotizing soft tissue infections should be used to describe them all, as treatment is the same: early surgery and broad spectrum antibiotics. 9 For the purposes of this article, however, the more familiar term necrotizing fasciitis will be used.

Microbiology

Microbiologically, NF has been classified as either type 1 (polymicrobial) or type 2 (monomicrobial). 10 Polymicrobial infections are more common, with cultures yielding a mixture of aerobic and anaerobic organisms. 11 These infections typically occur in the perineum and trunk. The isolates reflect normal skin commensalism found adjacent to the site of infection. For example, in NF of the perineum, anaerobic bacteria are isolated. The etiologic isolates consist of Gram-positive organisms, such as Staphylococcus aureus, S pyogenes, and enterococci; Gram-negative aerobes, such as Escherichia coli and Pseudomonas species; and anaerobic organisms, such as Bacteroides or Clostridium species. 12, 13 Type 1 NF occurs in immunocompromised individuals, such as patients with diabetes mellitus or chronic renal failure.

Monomicrobial infections are less common than the polymicrobial variety. These typically occur in the limbs and afflict healthy patients with no implicative comorbidities. There is often a history of trauma, frequently trivial. As S pyogenes and S aureus are the usual pathogens, type 2 NF might be associated with toxic shock syndrome. 9 Community-acquired methicillin-resistant S aureus (MRSA) has increasingly been described in NF. A recent retrospective review of cases from 2000 to 2006 in Los Angeles, Calif, showed MRSA isolated in one-third of cases. 13

Pathology

Most cases commence with trauma to the skin surface (eg, from a penetrative injury or even acupuncture needles, as was the case with our patient), with seeding of bacteria. Infection starts in the deep tissue planes, and the epidermis might not be initially affected. The clinical disease is expressed when infective organisms spread through the tissue along the deep fascia. Bacteria rapidly multiply within viable tissue, although fibrous attachments between subcutaneous tissues and fasciae limit spread to areas like the hands, feet, and scalp. Lack of fibrous attachments in the trunk and limbs, however, can lead to widespread infection and tissue destruction. Infection also spreads to venous and lymphatic channels, leading to edema. The spread of bacteria results in thrombosis of blood vessels in dermal papilla, resulting in ischemia and gangrene of subcutaneous fat and dermis. 14 If the fascia is breached, infection of the muscle leading to myositis occurs. Gas-producing organisms such as Clostridium species can give rise to subcutaneous gas, from which stems the descriptive term gas gangrene.

In addition, infections with toxin-producing bacteria ( S aureus and S pyogenes) can lead to a toxic shock-like syndrome. Therefore, seemingly limited infection can result in septic shock and multiorgan failure.

Risk factors

Often, patients presenting with NF have some predisposition to infection. Immunocompromise, advanced age, peripheral vascular disease, and obesity are some predisposing factors. Box 1 lists known risk factors. In a Singapore study, 70.3% of patients with NF had diabetes mellitus. 1 Most patients have a history of trauma, or there might be a history of surgery or penetrating injury. However, the injury can be quite trivial; eg, insect bites or scratches. As in the case we described, NF has even been reported after acupuncture. 15 This type of specific history (further examples of which are summarized in Table 2) is often only obtained if the physician directly questions the patient; otherwise, patients are likely to neglect or forget to mention it.

Nonsteroidal anti-inflammatory drug use has been implicated in severe necrotizing streptococcal infections. It is postulated that nonsteroidal anti-inflammatory drugs impair lymphocyte function. 16 However, it could also be that suppression of symptoms and signs of inflammation leads to later diagnosis, especially in patients presenting early with nonspecific symptoms. 17

Risk factors for NF in the pediatric population include malnutrition and skin infections such as varicella. 18, 19

It is important to emphasize that physicians should not rule out NF in normal healthy patients with minor dermatologic trauma. These are the cases that get missed, and which are often sensationalized.

Clinical features

Patients with NF can present with constitutional symptoms of sepsis (eg, fever, tachycardia, altered mental state, diabetic ketoacidosis) alone or with evidence of skin inflammation, which makes diagnosis a little more straightforward.

Limbs are among the most common sites of infection. According to a retrospective review of patients treated for NF in 3 tertiary hospitals in Canada, common sites of infection included the lower extremities (28%), upper extremities (27%), perineum (21%), trunk (18%), and the head and neck (5%). 20 As NF first starts in the deep tissue planes, at initial presentation there might be minimal epidermal involvement. This can make it difficult to differentiate from non-necrotizing skin infections and cellulitis.

Patients with NF are usually systemically toxic, initially presenting with fever (temperature greater than 38°C), tachycardia, diaphoresis, and possibly even an altered mental state or diabetic ketoacidosis. The physical examination should include all parts of the body to search for skin inflammation. This is especially necessary for patients who present with sepsis of which the source is not obvious. The perineum and oral cavity are areas that can be easily missed. 21

Most patients present with signs of skin inflammation (ie, pain, skin edema, and erythema). However, as these are also present in less serious conditions such as erysipelas and cellulitis, the degree of pain relative to the skin condition might provide the physician with clues-NF typically presents with pain out of proportion to the degree of skin inflammation.

Erysipelas, being an infection of the superficial dermis, has well-defined borders and might blister profoundly. With cellulitis, one can expect erythema with lymphangitis and minimal blistering.

Although crepitus and blistering are the most specific signs of necrotizing soft tissue infection, they are not sensitive. Two retrospective case series, by Wang et al 6 and Elliot et al, 25 reported an absence of crepitus in 62% to 63% of cases and an absence of blistering in 76% to 95% of cases upon initial presentation. As mentioned earlier, lymphangitis and lymphadenopathy are absent in necrotizing infections, but they remain features of cellulitis. 14, 22

A patch of anesthesia over the site of erythema is also sometimes described in NF. This is thought to be due to infarction of cutaneous nerves in necrotic subcutaneous fascia and soft tissue. 26

Disease progression

Necrotizing fasciitis can follow a hyperacute or a subacute course of progression. The patient with a hyperacute course presents with sepsis and rapidly progresses to multiorgan failure. Diagnosis of sepsis is obvious, and these patients are hospitalized.

Subacute NF can present a diagnostic dilemma, and the primary care physician, as the likely first point of contact, should be aware of this.

Hospitalization

Primary care physicians have to use clinical judgment to decide which patients who present with evidence of skin inflammation should be hospitalized or receive further evaluation. As mentioned earlier, only 15% to 34% of patients with a discharge diagnosis of necrotizing skin and subcutaneous infection had an admitting diagnosis of NF. 1, 2

Further, some patients with non-necrotizing soft tissue infections will require admission. Studies of patients with soft tissue infection showed that a history of diabetes mellitus, pyrexia, hand infections, and an area of inflammation greater than 70 cm ² are independent predictors of hospitalization. 30

Hospitalization is indicated for patients with soft tissue infections accompanied by signs and symptoms of systemic toxicity (fever, hypothermia, tachycardia [heart rate more than 100 beats/min]), hypotension (systolic blood pressure less than 90 mm Hg or more than 20 mm Hg below baseline), an altered mental state, severe infection (including those requiring formal operative intervention), intractable nausea and vomiting, immunocompromise, failure of outpatient therapy, and poor social support. The latest Infectious Diseases Society of America skin and soft tissue infection guidelines indicate that hospitalization should be considered in patients with "hypotension and/or an elevated creatinine level, low serum bicarbonate level, elevated creatine phosphokinase level (2-3 times the upper limit of normal), marked left shift, or a C-reactive protein level more than 13 mg/L." 31

In the early stages of NF, cutaneous manifestations are a continuum, but signs and symptoms evolve over time. 6 Even if, at first encounter, the physician might diagnose uncomplicated cellulitis, it is prudent to advise early review if symptoms or signs progress.

Diagnosis and decision for surgical exploration

The criterion standard for diagnosis of NF is histology of tissue specimens obtained during surgical exploration, which was demonstrated in our case description. During surgical exploration, tissue integrity and depth of invasion can be assessed. Fascial necrosis and loss of fascial integrity indicate a necrotizing infection. Muscle involvement and necrosis are indicative of an advanced stage.

To help decide which patients require surgical exploration, particularly in those with equivocal clinical signs, laboratory and radiologic tests might sometimes be useful.

Leukocytosis with neutrophilia, acidosis, altered coagulation profile, impaired renal function, raised creatinine kinase levels, and raised inflammatory markers, such as C-reactive protein levels, are all helpful if viewed within the whole of the clinical context.

Clinical scores like the laboratory risk indicator for NF (LRINEC) score are available to help diagnose NF and differentiate it from other skin and soft tissue infections ( Tables 3 14, 22- 26 and 4 9, 32). A score of 6 and above (intermediate or high risk) suggests NF. The patient in our case scored 7. In a study by Brogan et al, 19 an intermediate to high risk of NF had a positive predictive value of 92% and a negative predictive value of 96%. However, the LRINEC score was based on retrospective studies of patients with diagnosed or highly suspected NF. It has not been validated in patients for whom the diagnosis of NF is not apparent in the initial assessment. Further, certain tests, such as the C-reactive protein test, are not readily available in the primary care setting, where patients present with infection in the early stages and where laboratory support is limited; therefore, this score is not easily ascertained. Blood cultures are usually part of the workup in hospital and might yield up to 27.3% positive cultures in necrotizing infections, 11 compared with the mere 2% positive blood culture yield in patients with cellulitis. 33

Additional bedside tests include needle aspiration and incision biopsy. Negative results, however, cannot exclude NF. Surgical exploration is preferable.

It must be emphasized that diagnosis of NF is clinical, and the clinician should draw information from both the patient's condition and the aggregate of tests. Physicians should have a high index of suspicion and low threshold for surgical referral.

Macroscopic findings during surgical exploration include gray necrotic tissue, lack of bleeding, thrombosed vessels, "dishwater" pus, noncontracting muscle, and a positive "finger test" result, which is characterized by lack of resistance to finger dissection in normally adherent tissues. 9

Treatment

Once the diagnosis is made, treatment must begin on multiple fronts. First, surgical consultations should be urgently requested with the intention of early wound debridement for collection of tissue cultures, excision of all nonviable tissue, and delineation of the extent of the disease. (This is also important as tissue hypoxia limits the efficacy of intravenous antibiotics, which was demonstrated in our patient-her fever did not break despite intravenous antibiotics until the wound debridement and fasciotomy were complete.) Patients are often incredulous at the preoperative briefing when told they need an extensive operation for their skin infection; it is important to educate them about the gravity of their condition and the risk of increased mortality if surgical debridement is not performed.

Until blood culture results are available, wide spectrum coverage with intravenous antibiotics (with an awareness of resistance in the patient population being treated) is started. These antibiotics cover S pyogenes, S aureus (including community-acquired MRSA if indicated, according to local resistance patterns), and Gram-negative aerobes and anaerobes as clinically indicated. In particular, Gram-negative organisms would be suspected in perineal and abdominal wall wounds, necrotic diabetic foot ulcers, and in heavily contaminated wounds associated with devitalizing major trauma.

Hyperbaric oxygen has also been used as an adjunct to surgery and antibiotics. Its role is still ill-defined. Some authors have reported a reduction in mortality, morbidity, and need for repeated debridement in up to two-thirds of cases. 37, 38 Well-controlled randomized controlled trials are still lacking. Moreover, a retrospective review by Golger et al showed that morbidity associated with NF was higher in patients who underwent hyperbaric oxygen therapy. 20

In type 2 NF caused by streptococci resulting in streptococcal toxic shock syndrome, intravenous immunoglobulins might play a therapeutic role. Recently, a multicentre, randomized, double-blind, placebo-controlled trial evaluated the safety and efficacy of intravenous immunoglobulins in streptococcal toxic shock syndrome. The trial was prematurely stopped because of poor recruitment, but it showed 3.6-fold higher mortality in the placebo group compared with the treatment group. 39

Prognosis

There is also considerable postoperative morbidity, sometimes from extensive debridement resulting in muscle loss. Patients might have to undergo a period of rehabilitation to regain function of the affected areas. Scarring and disfigurement can also be substantial.

Prophylaxis

As NF is a potentially lethal disease, the primary care physician might be asked whether those in close contact with the patient should be given chemoprophylaxis. Particular mention is made of type 2 infections caused by S pyogenes (group A streptococcus) as this organism is highly contagious and has been responsible for epidemics of scarlet fever, pharyngitis, and surgical wound infections. Recommendations are available: United Kingdom and Centers for Disease Control and Prevention recommendations for the management of close community contacts of those with invasive group A streptococcal disease both affirm that antibiotic prophylaxis is not warranted given currently available evidence. 43- 45 It is, however, recommended that health care workers routinely inform and educate household contacts of patients with invasive group A streptococcal infections, advising them to seek medical attention immediately if they develop symptoms.

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OBJECTIVE To describe the defining characteristics and treatment of necrotizing fasciitis (NF), emphasizng early diagnostic indications. QUALITY OF EVIDENCE PubMed was searched using the terms necrotizing fasciitis and necrotizing soft tissue infections, paired with early diagnosis. Results were limited to human studies in English. Additional articles were obtained from references within articles.

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LEON L. CHEN, DNP, AGACNP-BC, FCCP, FAANP, FNYAM, BRIAN FASOLKA, PhD, RN, CEN, and CAITLIN TREACY, MS, AGACNP-BC

Abstract

Necrotizing soft-tissue infections (NSTIs) are rare but rapidly progressive, life-threatening bacterial infections with high morbidity and mortality. NSTIs include necrotizing forms of fasciitis, myositis, and cellulitis. This article focuses on necrotizing fasciitis (NF) and discusses NF classifications, clinical features, diagnostic approaches, evidence-based treatments, and nursing interventions.

Keywords: bacterial infection, necrotizing fasciitis, necrotizing soft-tissue infections, NF, NSTIs, sepsis, toxic shock syndrome

NECROTIZING soft-tissue infections (NSTIs) are rare but rapidly progressive, life-threatening bacterial infections that can destroy the epidermis, dermis, subcutaneous tissue, fascia, and muscle.1-4 Patients with certain comorbidities such as diabetes are at a higher risk for NSTIs. Described as far back as Hippocrates, NSTIs continue to be associated with significant mortality.3,5 Prompt recognition of signs and symptoms, targeted diagnostic testing, and timely treatment are crucial to avoid poor patient outcomes, including sepsis, amputation, and death.2

Although NSTIs include necrotizing forms of fasciitis, myositis, and cellulitis, this article will focus on the most common type, necrotizing fasciitis (NF).

Epidemiology

NSTIs are relatively rare. The incidence of NF is estimated to be 0.3 to 15 cases per 100,000 population.1 However, due to difficulty in diagnosis and underreporting, this is likely an underestimation.6,7

Certain factors place patients at a higher risk for NF and other NSTIs, including any skin or mucosal breach and various surgical procedures. Patients with comorbidities such as immunosuppression, malignancy, vascular disease, diabetes, alcoholism, and obesity are at an increased risk of NSTIs with progression to severe sepsis and septic shock.6

NF classifications

NF is an infection of the deep soft tissues causing progressive destruction of the muscle fascia and overlying subcutaneous fat. Two major classifications of NF are generally accepted, and several new classifications have been proposed to create further subdivisions.1 The following classifications are based on the underlying bacteria that initiated the cascade of injury.1,8

Polymicrobial (type I) NF. Type I NF stems from polymicrobial infection identified via microbiological culture. This type of infection is caused by both aerobic and anaerobic bacteria. The complex microbiological profile of offending organisms leads to gaseous infiltration of subcutaneous tissue similar to gas gangrene.3,9 Type I NF accounts for most reported cases of NF and is more prevalent in older adults with chronic diseases.

Monomicrobial (type II) NF is most commonly associated with Gram-positive organisms such as group A Streptococcus (GAS) and methicillin-resistant Staphylococcus aureus (MRSA). Endotoxins released by type II NF organisms are responsible for some clinical presentations, including toxic shock syndrome.3,6,9 Type II NF is not associated with a specific age group. Some patients do not have comorbidities or an obvious portal of entry that predisposes them to severe infection.3,6

Several other species of organisms have been implicated in NF, including Pseudomonas, Klebsiella, Clostridium, Aeromonas, and Vibrio vulnificus. These organisms, while rare, are more virulent and produce more severe clinical manifestations. The identification of these microbes has led some experts to propose a third type classification of NF, but no consensus has been reached.3,10

The two forms of NF are also differentiated by the site of the infection. Necrotizing microbial infiltration into the submandibular space fascia leading to tissue damage is called Ludwig angina. An oropharyngeal infection leading to secondary septic thrombophlebitis of the internal jugular vein is termed Lemierre syndrome. Fournier gangrene, described as bacterial infiltration into the gastrointestinal or urethral mucosa, can progress rapidly into the perineal region.6,11 These alternate classifications and nomenclatures may not have significant impact on immediate clinical management of NF but are important nevertheless for epidemiologic purposes.

Pathophysiology

The pathophysiology characteristic of both types of NF is widespread. Diffuse damage to superficial tissue extends to the deep muscular plane and fascia, with certain unique features depending on the offending organism.11 Due to its complex poly-microbiological profile, Type I NF is likely to be especially severe in older adults with existing comorbidities. The presence of both aerobic and anaerobic organisms causes extensive tissue necrosis and hemodynamic compromise. Some organisms of the Clostridium species produce alpha toxins that further degrade tissue. It is not unusual for the organisms of Type I NF to have synergistic effects, producing more profound local and systemic damage.6,7,9,11

Type II NF associated with GAS causes tissue damage by releasing exotoxins, which often initiate a complex cascade of immune-related responses including cytotoxic T-cells, cytokine release, and toxic shock syndrome. Microvascular damage or thrombosis may lead to tissue ischemia and subsequent necrosis.12

Signs and symptoms

Many patients with NF present to the ED exhibiting signs and symptoms of an infection. Superficial findings may not be distinct beyond erythema and edema.1 Clinicians must quickly recognize the distinction between cellulitis manageable with antimicrobial therapy and NF requiring surgical intervention. Delays in appropriate management of NF can have devastating consequences, including limb loss, organ damage, and a significantly increased risk of death.3,13

Unfortunately, the critical diagnostic distinction between cellulitis and NF is typically difficult to discern, as the initial clinical presentation of NF is often vague.3 Presentation can be further distorted by factors such as the use of nonsteroidal anti-inflammatory drugs, which can mask signs such as fever and classic symptoms of NF such as crescendo-like pain. Severe pain that is disproportionate to the degree of apparent injury is considered a classic symptom of NF, but patients with diabetic neuropathy may not experience the same level of pain as those without preexisting neuropathy.2,5,10

In NF, the site of injury impacts the severity of clinical manifestations due to local bacterial flora and proximity to vital organs. For example, NF of the head and neck region are more likely to have polymicrobial infection and progress to mediastinitis.1

At early stages, patients can be largely asymptomatic or have only mild localized signs and symptoms that can be attributed to benign disorders such as skin irritation or self-limiting inflammation.9,11 If the initial presentation is mild, the patient may not be alarmed enough to seek immediate help.11

Most patients experience superficial erythema, edema, tenderness or pain, and fever regardless of the extent of the infection into deep fascia. With Type II NF, patients' initial superficial injury may be undetectable and severe signs and symptoms may not manifest until the underlying tissue damage has progressed extensively and the patient is already at extreme risk for a poor outcome.8,9,11,12 Patients with extensive comorbidities who develop NF caused by organisms that release exotoxins tend to have more severe systemic signs and symptoms consistent with severe sepsis and septic shock, such as hemodynamic instability and lactic acidosis.6

Organisms that are gas-producing may cause subcutaneous crepitus that can be detected upon palpation of the affected region. Skin lesions such as bullae and blisters occur when the infection is in advanced stages. While these may help clinicians differentiate the disease from relatively benign disorders such as cellulitis, they do not have a high diagnostic sensitivity. The clinician should remain suspicious of a more severe underlying infection even if these overt signs are not present.2,5,8,9,11,12

Despite the various classifications of NF and subtle differences in etiology and microbiology, the overall diagnostic and treatment approach is similar.3,13

Diagnosis

No specific lab studies have been proven to be reliable for the diagnosis of NF.14 Wong and colleagues developed the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) to help clinicians screen for NF using serum levels of the total white blood cell count, hemoglobin, sodium, glucose, creatinine, and C-reactive protein.15 LRINEC scores of 6 or more were thought to be associated with NF. However, in subsequent reports LRINEC scores failed to accurately predict NF.16,17

Lab studies should include a complete blood cell count, complete metabolic panel, coagulation profile, lactate level, creatine kinase, C-reactive protein, and erythrocyte sedimentation rate. Confirmatory diagnosis of the causative bacteria is based upon a culture and Gram stain of specimens collected from deep tissue, or by positive blood cultures. Cultures collected from superficial sites may not have clinical value if the causative organism is within the deep tissue.13

Medical management

Initial pharmacotherapy should include empiric broad-spectrum antibiotics until soft tissue Gram stain, culture, and sensitivity results are available.3 The most recent Infectious Disease Society of America guideline recommends either vancomycin or linezolid in combination with piperacillin-tazobactam, a carbapenem, or ceftriaxone-metronidazole. Clindamycin should also be included in empiric therapy due to its effect on toxins released by certain organisms, including S. aureus and GAS.3,13 Penicillin plus clindamycin is recommended to treat documented GAS necrotizing infections.13 As soon as the sampled specimen's microbiology is determined, the clinician can tailor therapy to the specific organism while utilizing local antibiograms in order to determine local resistance patterns. Additional medical management includes supportive measures such as aggressive I.V. fluid resuscitation and vasopressor support for septic shock.4

Surgical management

Surgery is the gold standard treatment when NF is either suspected or diagnosed. Surgical exploration and debridement of the affected tissue should be performed promptly. Initial tissue findings may include discoloration, gross edema or ecchymosis, and signs of necrosis. Specimens for Gram stain and culture should be obtained during surgical exploration.

Discrete pus is generally absent, but surgical wounds often drain copious volumes of tissue fluid. Consequently, patients may need aggressive fluid volume replacement after surgery.13

Nursing considerations

Given the subtlety in presentation and lack of confirmatory physical findings, timely diagnosis of NF may be difficult. It is crucial for nurses to maintain a high index of suspicion for NF, especially in patients who are at high risk. In particular, nurses should assess for localized erythema, warmth, tenderness disproportionate to the affected area, skin sclerosis, and signs of sepsis and septic shock including fever and hemodynamic instability.6

Nurses who suspect NF should promptly notify a provider and prepare for additional workup and management. This may include further imaging and lab studies.

Nurses should also be prepared to initiate treatment for NF in a timely manner. Interventions include administration of I.V. antimicrobials and fluids and correction of metabolic derangements. For some patients, transfer to the ICU may be indicated for frequent assessments and invasive hemodynamic monitoring.

Given the risk for septic shock, the nurse must frequently monitor vital signs and other the physical assessment findings for signs of decompensation. The nurse must immediately notify the provider and/or call the rapid response team of signs and symptoms of impending shock and be prepared to administer I.V. fluids, both crystalloids and colloids, and possibly vasoactive agents such as I.V. norepinephrine, as prescribed.1 Given the severe pain often associated with NF, nursing care includes frequent pain assessments and appropriate pain management interventions.

Pre-op care should include medication reconciliation and the patient's informed consent. Intraoperatively, nurses must be prepared to assist with the collection of deep tissue culture specimens according to institutional protocol.

Nurses who care for patients in the post-op setting will have to carefully monitor them for surgical wound integrity, bleeding, and electrolyte imbalances. Nurses must be diligent about administering prescribed antimicrobials as scheduled to maintain serum drug levels.

In the post-op setting, nursing care also includes hemodynamic monitoring, pain management, and nutritional support. Due to the large surgical wounds and increased metabolic demand experienced by patients with NF, the expected caloric requirement may be twice that of a typical patient in order to replace protein and fluid loss.6 The nurse should anticipate that multiple surgical procedures will be performed as definitive NF treatment.

Along with standard precautions, nurses caring for patients with invasive GAS infection with soft tissue involvement should initiate droplet and contact precautions. Droplet and contact precautions may be discontinued after 24 hours of antimicrobial therapy.1,18

Patient education and support

The nurse should assess the patient's understanding of NF and provide additional teaching as necessary. Additional elements of patient teaching include pain management, antimicrobial therapy, surgical procedures, and wound care. As the patient prepares for discharge from acute care, the nurse must provide patient education regarding home medications, follow-up care, and signs and symptoms of normal healing versus those suggesting possible complications.

The patient should also receive targeted rehabilitation from the physiatry team to increase functional status. Given the severity of the condition, the nurse should prepare the patient and family for a prolonged hospital stay. If partial or full amputation was required to treat NF, the patient may experience significant disfigurement and associated psychological distress. In addition, patients who survive to hospital discharge are at increased risk for morbidity and mortality due to functional decline and impaired wound integrity. Nurses must provide patients and their families emotional support services, including social work and counseling if possible.5

Timely care improves outcomes

Despite advances in understanding, diagnosis, and treatment, NF still causes significant morbidity and mortality. Its microbiological profile remains complex and its classification may evolve as our understanding of NSTI increases. Vague and nonspecific presentations can make diagnosis difficult. Clinical judgment and a high index of suspicion for NF will ultimately expedite recognition. Timely diagnosis and supportive therapies, including antimicrobials and timely referral to surgery, are crucial to improve patient outcomes.

​

A healthy man, age 60, developed NF after scratching his hand on a piece of metal.

Footnotes

The authors and planners have disclosed no potential conflicts of interest, financial or otherwise.

REFERENCES

1. Stevens DL, Baddour LM. Necrotizing soft tissue infections. UpToDate. 2020. www.uptodate.com.

4. Wessels MR. Streptococal infections . In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2012:1176. [ Google Scholar]

6. Misiakos EP, Bagias G, Patapis P, Sotiropoulos D, Kanavidis P, Machairas A. Current concepts in the management of necrotizing fasciitis. Front Surg. 2014;1:36. [[ PubMed] PMC free article] [ Google Scholar]

8. Jabbour G, El-Menyar A, Peralta R, et al. Pattern and predictors of mortality in necrotizing fasciitis patients in a single tertiary hospital. World J Emerg Surg. 2016;11:40. [[ PubMed] PMC free article] [ Google Scholar]

# data[].attributes.attachment_link.title
Necrotizing fasciitis: A comprehensive review

# data[].attributes.attachment_link.description
LEON L. CHEN, DNP, AGACNP-BC, FCCP, FAANP, FNYAM, BRIAN FASOLKA, PhD, RN, CEN, and CAITLIN TREACY, MS, AGACNP-BC Necrotizing soft-tissue infections (NSTIs) are rare but rapidly progressive, life-threatening bacterial infections with high morbidity and mortality. NSTIs include necrotizing forms of fasciitis, myositis, and cellulitis.

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Necrotizing fasciitis (NF) is a rare, fulminant, and life-threating infection of fascia and subcutaneous tissue [1–4]. The incidence rate based on insurance claims data is 4 per 100,000 person-years [5]. The causative pathogens are evidenced to be changing over time, infection is typically polymicrobial, however, monomicrobial infection with β-hemolytic streptococci and methicillin-resistant Staphylococcus aureus (MRSA) have increasingly been reported [1,2,4]. Infection usually develops after an inciting event such as perirectal infection, trauma, intravenous drug abuse, chronic diabetic ulcerations, and surgical site infections [4,6]. Early identification and intervention are paramount for survival of patients presenting with NF [1]. Treatment often requires multiple and extensive surgical debridement, prolonged polymicrobial antibiotic coverage, and systematic support to prevent vital organs failure [1,4].

Because of the low incidence, previous investigations lacked reproducibility, and most studies were statistically underpowered to assess factors associated with the risk of mortality [1,2]. The aim of this study is to use nationally representative data to examine the clinical and demographic profile of patients admitted with NF and the risk of their mortality.

Patients and Methods

This study is a retrospective cross-sectional analysis using the Nationwide Readmissions Database (NRD) for the years 2010–2014. The NRD is part of the Healthcare Cost and Utilization Project (HCUP), sponsored by the Agency for Healthcare Research and Quality. The NRD is a unique and powerful database designed to support various types of analyses of national re-admission rates for all payers and the uninsured. The database includes discharge data from 27 geographically dispersed states, accounting for 57.8% of the total U.S. resident population and 56.6% of all U.S. hospitalizations. Additionally, the database allows for weighted analysis that has been utilized in this project to provide a better estimation of national outcomes. The NRD tracks patient across the sampled hospitals within a calendar year for any re-admission. This database addresses a large gap in health care data, namely the lack of nationally representative information on hospital re-admissions for all ages. The NRD consists of publicly available de-identified data that is exempt from purview of the Institutional Review Board [7].

The NRD contains records of diagnoses and procedures developed during admission using the International Classification of Disease, 9th Revision (ICD-9). The database utilizes Clinical Classification Software and Elixhauser Comorbidity Software to categorize ICD-9 codes into broader clinical groups. Categorization generated by those software programs were used in this study to define the study parameters unless otherwise specified. Further information regarding the categorization scheme is available on the HCUP website [7].

The first objective of the study is to examine the clinical and demographic profile of patients who presented emergently with NF. The second objective of the study is to identify factors associated with the risk of mortality.

The study population included patients who were admitted emergently with NF. The NRD reports the principal diagnosis of admission. In certain cases, patients presented with compounded clinical picture and NF might be part of the presentation such as in trauma. This study included all patients with either NF as the principal diagnosis or a secondary diagnosis as illustrated in Figure 1. Patient with NF were identified by surveying the database for the ICD-9 code: 728.86. The code is limited because it does not include the site of infection, nonetheless, it has been previously used with good validity by other studies that reported NF [2,5,8].

FIG. 1. Principal diagnosis of admission in patients presented emergently either with necrotizing fasciitis (NF) as the primary diagnosis or a secondary diagnosis.

The included patients were followed for 30 days for re-admission. The study sample was divided into two groups based on the presences of history of diabetes mellitus. Necrotizing fasciitis in patients with diabetes has been demonstrated to be distinctly different from that in patients without diabetes [2]. For this reason, we examined the difference in presentation and outcomes between both groups and assessed the mortality risk in each group separately. All records were checked for completeness of data; records with missing values for the study parameters were excluded.

Comparing the presentation and outcomes of patients with diabetes with those without diabetes the following factors were considered: age: <18, 18–40, >40 to <60, ≥60 years; gender: male, female; obesity; current tobacco use, ICD-9 code: 305.1; history of alcohol abuse; history of drug abuse; trauma admission; development of septicemia; development of disseminated intravascular coagulopathy, ICD-9: 286.6; development of septic shock, ICD-9: 785.52.; development of cardiovascular, pulmonary, and renal complications during admission, ICD-9 codes adopted from previous study [9]; surgical intervention other than amputation; amputation, ICD-9 codes: 84.01–09, 84.10–19; utilization of hyperbaric oxygen therapy (HBOT), ICD-9: 939.5; utilization of hemodialysis, ICD-9: 399.5; received blood and blood component transfusion, ICD-9: 990.4, 990.5, 990.6, V58.2; received intravenous immunoglobulin (IVIG) therapy, ICD-9 code: 991.4; length of hospital stay in days, the total length of hospital stay of the first admission and re-admission if occurred; and cost of health services (the database includes hospital charges associated with each admission as well as cost-to-charge ratio determined for each hospital that allows conversion of charges values to cost values, all cost values were adjusted for inflation rate to reflect 2017 U.S dollar value using Bureau of Labor Statistics inflation calculator) [7,10].

Factors that were assessed for their association with mortality, in addition to the factors in the previous paragraph, include a history of: complications from diabetes; chronic lung diseases; congestive heart failure; hypertension; peripheral vascular diseases; paralysis; rheumatoid arthritis/collagen vascular diseases; chronic liver diseases; chronic renal failure; malignancy without metastasis; malignancy with metastasis; and human immunodeficiency virus (HIV) infection.

Characteristics of patients who did not undergo surgical intervention were investigated. Factors examined included: age: <65, ≥65 years; gender: male, female; Charlson comorbidity index score: 0–1, 2–3, ≥4 [11]; trauma admission; development of septicemia; and insurance type: private, Medicare, Medicaid, self-pay.

Statistical analysis used weighted data reflecting a national estimate in calculating percentages and odds ratios. The records' weights are available in the NRD and calculated based on the stratification variables that were used in sampling methodology [7].

Statistical methods used in the analysis included χ² tests to examine the association between each of the independent factors and the outcomes of interest. Factors that demonstrated association with the outcomes were considered possible confounders and were included in multivariable logistic regression models. Multivariable logistic regression models were used to calculate the odds ratio (OR) and 95% confidence interval (CI). Linear regression model was used to compare means of length of hospital stay and cost of health services. Significance level was set as (α = 0.05). All data analyses were performed using SAS 9.4 for Windows (SAS Institute Inc., Cary, NC).

Results

A total of 4,178 patients were identified who were admitted emergently with NF in the United States between 2010 and 2014 (Table 1). Septicemia was the most common diagnosis at presentation (39.5%). Necrotizing fasciitis was a primary admission diagnosis in 23.3% of the sample. Trauma was the main presentation in 5.7% of the patients, whereas 9.2% initially were diagnosed as cellulitis or abscess cases (Fig. 1). The average age of the study population was 53.5 ± 0.3 years. Necrotizing fasciitis was statistically equally represented in both genders (p = 0.08). Almost half of the patients (n = 2,061, 48.9%) had a history of diabetes mellitus. Overall mortality risk was 12.6% (95% CI = 11.5–13.7%). There was no annual change in the risk of mortality throughout the study period (Fig. 2). Compared with patients who did not have diabetes, patients with diabetes who developed NF were more likely to be older than 40 years, obese, a non-smoker, and with no history of alcohol or drug abuse (p < 0.001 each). Patients with diabetes were less likely to present with trauma and septicemia (p < 0.001 each) and less likely to develop disseminated intravascular coagulopathy and septic shock (p < 0.001 each). Amputation risk was higher in patients with diabetes (18.1% vs. 9.3%, p < 0.001). Mortality risk in patients with diabetes was substantially lower in the multivariable logistic regression model (8.5% vs. 16.5%, OR: 0.44, 95% CI = [0.34, 0.56], p < 0.001), the model controlled for factors that demonstrated significant association with mortality in the univariable analysis, those factors are: age, gender, obesity, history of congestive health failure, history of peripheral vascular diseases, history of chronic liver diseases, history of chronic renal failure, history of non-metastatic and metastatic malignancies, trauma admission, septicemia, septic shock, disseminated intravascular coagulopathy, undergoing surgical intervention, whether cardiovascular, pulmonary, and renal complications reported during admission; and whether hemodialysis and blood transfusion were performed during admission.

FIG. 2. Annual mortality risk in a study population of patients admitted emergently with necrotizing fasciitis (NF).

Table 1. Characteristics of Patients Admitted Emergently with Necrotizing Fasciitis in Relation to Diabetes Mellitus, 2010–2014

| Sample population, (%) (N = 4,178) | History of diabetes mellitus, (%)
Not reported (n = 2,117) | Reported (n = 2,061) | pa
Age (y) | | | |
<18 | 1.57 | 3.05 | 0.00 |
18 to <40 | 16.96 | 22.73 | 10.85 |
40 to <60 | 45.76 | 39.93 | 51.93 |
≥60 | 35.71 | 34.29 | 37.22 | < 0.001b
Gender | | | |
Male | 58.41 | 59.86 | 56.87 |
Female | 41.59 | 40.14 | 43.13 | 0.08
Obesity | | | |
Not reported | 70.93 | 80.73 | 60.56 |
Reported | 29.07 | 19.27 | 39.44 | < 0.001
Current tobacco use | | | |
Not reported | 75.67 | 73.06 | 78.43 |
Reported | 24.33 | 26.94 | 21.57 | < 0.001
History of alcohol abuse | | | |
Not reported | 93.36 | 91.21 | 95.63 |
Reported | 6.64 | 8.79 | 4.37 | < 0.001
History of drug abuse | | | |
Not reported | 90.40 | 85.83 | 95.23 |
Reported | 9.60 | 14.17 | 4.77 | < 0.001
Trauma admission | | | |
Not reported | 59.33 | 55.85 | 63.01 |
Reported | 40.67 | 44.15 | 36.99 | < 0.001
Septicemia | | | |
Not reported | 43.30 | 42.77 | 43.87 |
At presentation | 39.59 | 37.22 | 42.09 |
During admission | 17.11 | 20.01 | 14.04 | < 0.001
Disseminated intravascular coagulopathy | | | |
Not reported | 97.04 | 95.59 | 98.58 |
Reported | 2.96 | 4.41 | 1.42 | < 0.001
Septic shock | | | |
Not reported | 72.48 | 67.89 | 77.35 |
Reported | 27.52 | 32.11 | 22.65 | < 0.001
Cardiovascular complications during admission | | | |
Not reported | 97.05 | 97.16 | 96.92 |
Reported | 2.95 | 2.84 | 3.08 | 0.71
Pulmonary complications during admission | | | |
Not reported | 68.27 | 65.88 | 70.80 |
Reported | 31.73 | 34.12 | 29.20 | 0.001
Acute renal failure during admission | | | |
Not reported | 56.74 | 59.31 | 54.02 |
Reported | 43.26 | 40.69 | 45.98 | < 0.001
Hyperbaric oxygenation utilization | | | |
Not reported | 98.73 | 98.96 | 98.47 |
Reported | 1.27 | 1.04 | 1.53 | 0.07
Hemodialysis | | | |
Not reported | 92.02 | 93.13 | 90.86 |
Reported | 7.98 | 6.87 | 9.14 | 0.010
Blood and blood components transfusion | | | |
Not reported | 75.44 | 76.35 | 74.47 |
Reported | 24.56 | 23.65 | 25.53 | 0.19
Immunoglobulin infusion | | | |
Not reported | 99.68 | 99.43 | 99.95 |
Reported | 0.32 | 0.57 | 0.05 | 0.006
Surgical intervention other than amputation | | | |
Not reported | 30.23 | 27.53 | 33.08 |
Reported | 69.77 | 72.47 | 66.92 | 0.003
Amputation | | | |
Not reported | 86.43 | 90.74 | 81.87 |
Reported | 13.57 | 9.26 | 18.13 | < 0.001
Thirty-day re-admission | | | |
Not reported | 87.68 | 88.72 | 86.59 |
Reported | 12.32 | 11.28 | 13.41 | 0.06
In-hospital death within 30 d of initial admission | | | |
Not reported | 87.38 | 83.47 | 91.51 |
Reported | 12.62 | 16.53 | 8.49 | < 0.001
Length of total hospital stay per case, day, mean (SEM) | 17.99 (0.32) | 17.57 (0.43) | 18.44 (0.43) | 0.17
Cost of total health-services per case, U.S.$, mean (SEM) | 50,523.00 (1,218.76) | 51,604.00 (1,521.03) | 49,377.00 (1,598.90) | 0.005

Considering patients without diabetes separately, factors that demonstrated association with mortality in the univariable analysis are shown in Table 2. Those factors were included in the multivariable analysis that demonstrated the following factors to be with a higher risk of mortality in patients who do not have diabetes (Table 3): age ≥40 years; history of congestive heart failure; history of peripheral vascular diseases; history of chronic liver diseases; history of malignancy without metastasis; septicemia; disseminated intravascular coagulopathy; septic shock; pulmonary complications during admission; acute renal failure during admission; not undergoing surgery with or without amputation; and receiving hemodialysis.

Table 3. Factors Associated with Mortality in Adult Patients without a History of Diabetes Mellitus Admitted Emergently with Necrotizing Fasciitis

| In-hospital death within 30 d of initial admission, (%) | ORa | 95% CI | p
Age (y) | | | |
18 to <40 | 4.62 | Reference | |
40 to <60 | 14.47 | 2.10 | 1.30, 3.38 | 0.003
≥60 | 28.29 | 3.90 | 2.37, 6.41 | < 0.001
Gender | | | |
Male | 15.46 | Reference | |
Female | 19.40 | 1.11 | 0.82, 1.50 | 0.50
Current tobacco use | | | |
Not reported | 19.91 | Reference | |
Reported | 9.62 | 0.73 | 0.50, 1.06 | 0.10
History of congestive heart failure | | | |
Not reported | 15.16 | Reference | |
Reported | 34.96 | 1.53 | 1.02, 2.30 | 0.042
History of peripheral vascular diseases | | | |
Not reported | 15.99 | Reference | |
Reported | 33.91 | 2.06 | 1.20, 3.53 | 0.009
History of chronic liver diseases | | | |
Not reported | 14.51 | Reference | |
Reported | 33.59 | 2.35 | 1.45, 3.83 | < 0.001
History of chronic renal failure | | | |
Not reported | 15.60 | Reference | |
Reported | 36.24 | 1.17 | 0.76, 1.79 | 0.48
History of malignancy without metastasis | | | |
Not reported | 15.84 | Reference | |
Reported | 39.70 | 1.88 | 1.09, 3.22 | 0.022
Trauma admission | | | |
Not reported | 13.98 | Reference | |
Reported | 20.93 | 1.15 | 0.84, 1.58 | 0.37
Septicemia | | | |
No reported | 2.69 | 0.32 | 0.18, 0.57 | < 0.001
At presentation | 29.83 | Reference | |
During admission | 22.63 | 0.92 | 0.66, 1.28 | 0.60
Disseminated intravascular coagulopathy | | | |
Not reported | 14.73 | Reference | |
Reported | 65.81 | 2.78 | 1.39, 5.55 | 0.004
Septic shock | | | |
Not reported | 5.78 | Reference | |
Reported | 40.12 | 2.47 | 1.69, 3.62 | < 0.001
Cardiovascular complications during admission | | | |
Not reported | 16.38 | Reference | |
Reported | 39.38 | 1.20 | 0.61, 2.36 | 0.59
Pulmonary complications during admission | | | |
Not reported | 6.04 | Reference | |
Reported | 37.71 | 3.39 | 2.32, 4.95 | < 0.001
Acute renal failure during admission | | | |
Not reported | 6.79 | Reference | |
Reported | 31.23 | 1.99 | 1.43, 2.77 | < 0.001
Surgical intervention other than amputation | | | |
Not reported | 24.55 | Reference | |
Reported | 14.13 | 0.37 | 0.26, 0.54 | < 0.001
Amputation | | | |
Not reported | 16.04 | Reference | |
Reported | 26.65 | 0.49 | 0.30, 0.81 | 0.005
Hemodialysis | | | |
Not reported | 14.47 | Reference | |
Reported | 50.81 | 1.68 | 1.06, 2.67 | 0.028
Blood and blood components transfusion | | | |
Not reported | 13.53 | Reference | |
Reported | 28.02 | 1.11 | 0.77, 1.60 | 0.59

Table 2. Characteristics of Adult Patients without a History of Diabetes Mellitus Admitted Emergently with Necrotizing Fasciitis in Relation to Mortality Risk, 2010–2014

| Sample population, (%) (N = 2,117) | In-hospital death within 30 d of initial admission, (%)
Not reported (n = 1,760) | Reported (n = 357) | pa
Age (y) | | | |
18 to <40 | 23.44 | 26.96 | 6.36 |
40 to <60 | 41.19 | 42.47 | 34.96 |
≥60 | 35.37 | 30.57 | 58.68 | < 0.001
Gender | | | |
Male | 59.75 | 60.90 | 54.20 |
Female | 40.25 | 39.10 | 45.80 | 0.017
Obesity | | | |
Not reported | 80.38 | 80.03 | 82.08 |
Reported | 19.62 | 19.97 | 17.92 | 0.42
Current tobacco use | | | |
Not reported | 72.22 | 69.73 | 84.32 |
Reported | 27.78 | 30.27 | 15.68 | < 0.001
History of alcohol abuse | | | |
Not reported | 90.94 | 91.03 | 90.50 |
Reported | 9.06 | 8.97 | 9.50 | 0.80
History of drug abuse | | | |
Not reported | 85.39 | 84.76 | 88.42 |
Reported | 14.61 | 15.24 | 11.58 | 0.06
History of chronic lung diseases | | | |
Not reported | 84.93 | 85.23 | 83.50 |
Reported | 15.07 | 14.77 | 16.50 | 0.48
History of congestive heart failure | | | |
Not reported | 90.47 | 92.53 | 80.47 |
Reported | 9.53 | 7.47 | 19.53 | < 0.001
History of hypertension | | | |
Not reported | 60.50 | 60.91 | 58.53 |
Reported | 39.50 | 39.09 | 41.47 | 0.37
History of peripheral vascular diseases | | | |
Not reported | 94.10 | 95.30 | 88.27 |
Reported | 5.90 | 4.70 | 11.73 | < 0.001
History of paralysis | | | |
Not reported | 96.56 | 96.53 | 96.68 |
Reported | 3.44 | 3.47 | 3.32 | 0.88
History of rheumatoid arthritis/collagen vascular diseases | | | |
Not reported | 96.75 | 97.12 | 94.95 |
Reported | 3.25 | 2.88 | 5.05 | 0.07
History of chronic liver diseases | | | |
Not reported | 92.99 | 94.61 | 85.10 |
Reported | 7.01 | 5.39 | 14.90 | < 0.001
History of chronic renal failure | | | |
Not reported | 88.35 | 89.88 | 80.92 |
Reported | 11.65 | 10.12 | 19.08 | < 0.001
History of malignancy without metastasis | | | |
Not reported | 94.91 | 96.30 | 88.15 |
Reported | 5.09 | 3.70 | 11.85 | < 0.001
History of malignancy with metastasis | | | |
Not reported | 97.65 | 97.75 | 97.16 |
Reported | 2.36 | 2.25 | 2.84 | 0.53
History of HIV infection | | | |
Not reported | 99.81 | 99.83 | 99.71 |
Reported | 0.19 | 0.17 | 0.29 | 0.65
Trauma admission | | | |
Not reported | 55.83 | 57.90 | 45.77 |
Reported | 44.17 | 42.10 | 54.23 | < 0.001
Septicemia | | | |
No reported | 41.79 | 49.02 | 6.60 |
At presentation | 38.18 | 32.29 | 66.80 |
During admission | 20.03 | 18.68 | 26.59 | < 0.001
Disseminated intravascular coagulopathy | | | |
Not reported | 95.45 | 98.13 | 82.45 |
Reported | 4.55 | 1.87 | 17.55 | < 0.001
Septic shock | | | |
Not reported | 67.19 | 76.32 | 22.80 |
Reported | 32.81 | 23.68 | 77.20 | < 0.001
Cardiovascular complications during admission | | | |
Not reported | 97.08 | 97.86 | 93.24 |
Reported | 2.92 | 2.14 | 6.76 | < 0.001
Pulmonary complications during admission | | | |
Not reported | 65.23 | 73.89 | 23.11 |
Reported | 34.77 | 26.11 | 76.89 | < 0.001
Acute renal failure during admission | | | |
Not reported | 58.03 | 65.21 | 23.11 |
Reported | 41.97 | 34.79 | 76.89 | < 0.001
Surgical intervention other than amputation | | | |
Not reported | 28.03 | 25.49 | 40.35 |
Reported | 71.98 | 74.51 | 59.65 | < 0.001
Amputation | | | |
Not reported | 90.45 | 91.55 | 85.07 |
Reported | 9.55 | 8.45 | 14.93 | < 0.001
Hyperbaric oxygenation utilization | | | |
Not reported | 99.08 | 98.89 | 100.00 |
Reported | 0.92 | 1.11 | 0.00 | NAc
Hemodialysis | | | |
Not reported | 92.91 | 95.80 | 78.87 |
Reported | 7.09 | 4.20 | 21.13 | < 0.001
Blood and blood components transfusion | | | |
Not reported | 75.70 | 78.91 | 60.06 |
Reported | 24.30 | 21.09 | 39.94 | <0.001
Immunoglobulin infusion | | | |
Not reported | 99.41 | 99.29 | 100.00 |
Reported | 0.59 | 0.71 | 0.00 | NAc

Univariable and multivariable analyses of risk factors of mortality in patients with diabetes are shown in Tables 4 and 5, respectively. Factors that retained substantial association with mortality risk in patients with diabetes included: age ≥60 years; history of chronic liver diseases; history of chronic renal failure; disseminated intravascular coagulopathy; septic shock; pulmonary complications during admission; acute renal failure during admission; and not undergoing surgery.

Table 5. Factors Associated with the Risk of Mortality in Adult Patients with a History of Diabetes Mellitus Admitted Emergently with Necrotizing Fasciitis

| In-hospital death within 30 days of initial admission, (%) | ORa | 95% CI | p
Age (y) | | | |
18 to <40 | 1.77 | Reference | |
40 to <60 | 5.57 | 2.99 | 0.95, 9.43 | 0.06
≥60 | 14.52 | 6.01 | 1.87, 19.34 | 0.003
Current tobacco use | | | |
Not reported | 9.41 | Reference | |
Reported | 5.15 | 0.84 | 0.49, 1.42 | 0.50
History of congestive heart failure | | | |
Not reported | 7.43 | Reference | |
Reported | 15.83 | 1.11 | 0.71, 1.75 | 0.65
History of chronic liver diseases | | | |
Not reported | 7.26 | Reference | |
Reported | 31.48 | 6.67 | 4.29, 10.38 | < 0.001
History of chronic renal failure | | | |
Not reported | 6.50 | Reference | |
Reported | 15.41 | 1.84 | 1.24, 2.73 | 0.003
History of malignancy with metastasis | | | |
Not reported | 8.35 | Reference | |
Reported | 27.36 | 4.80 | 0.98, 23.53 | 0.05
Trauma admission | | | |
Not reported | 6.94 | Reference | |
Reported | 11.13 | 1.02 | 0.70, 1.49 | 0.91
Septicemia | | | |
No reported | 3.06 | 0.59 | 0.34, 1.02 | 0.06
At presentation | 12.85 | Reference | |
During admission | 12.38 | 0.66 | 0.41, 1.07 | 0.09
Disseminated intravascular coagulopathy | | | |
Not reported | 7.98 | Reference | |
Reported | 43.82 | 3.43 | 1.40, 8.41 | 0.007
Septic shock | | | |
Not reported | 3.61 | Reference | |
Reported | 25.13 | 3.96 | 2.42, 6.48 | < 0.001
Cardiovascular complications during admission | | | |
Not reported | 8.24 | Reference | |
Reported | 16.32 | 1.14 | 0.53, 2.48 | 0.73
Pulmonary complications during admission | | | |
Not reported | 3.47 | Reference | |
Reported | 20.65 | 2.74 | 1.77, 4.24 | < 0.001
Acute renal failure during admission | | | |
Not reported | 4.23 | Reference | |
Reported | 13.49 | 1.52 | 1.03, 2.26 | 0.037
Surgical intervention other than amputation | | | |
Not reported | 16.82 | Reference | |
Reported | 7.01 | 0.31 | 0.20, 0.50 | < 0.001
Amputation | | | |
Not reported | 9.08 | Reference | |
Reported | 5.80 | 0.74 | 0.45, 1.24 | 0.26
Hemodialysis | | | |
Not reported | 6.99 | Reference | |
Reported | 23.35 | 1.34 | 0.82, 2.20 | 0.24
Blood and blood components transfusion | | | |
Not reported | 7.46 | Reference | |
Reported | 11.49 | 0.98 | 0.66, 1.47 | 0.93

Table 4. Characteristics of Adult Patients with a History of Diabetes Mellitus Admitted Emergently with Necrotizing Fasciitis in Relation to Mortality Risk, 2010–2014

| Sample population, (%) (N = 2,061) | In-hospital death within 30 days of initial admission, (%)
Not reported (n = 1,887) | Reported (n = 174) | Pa
Age (yr.) | | | |
18 to <40 | 10.85 | 11.64 | 2.26 |
40 to <60 | 51.93 | 53.59 | 34.08 |
≥60 | 37.22 | 34.77 | 63.66 | < 0.001
Gender | | | |
Male | 56.87 | 57.48 | 50.33 |
Female | 43.13 | 42.52 | 49.67 | 0.09
Obesity | | | |
Not reported | 60.56 | 60.53 | 60.89 |
Reported | 39.44 | 39.47 | 39.11 | 0.92
Current tobacco use | | | |
Not reported | 78.43 | 77.64 | 86.91 |
Reported | 21.57 | 22.36 | 13.09 | 0.003
History of alcohol abuse | | | |
Not reported | 95.63 | 95.70 | 94.90 |
Reported | 4.37 | 4.30 | 5.10 | 0.57
History of drug abuse | | | |
Not reported | 95.23 | 95.09 | 96.82 |
Reported | 4.77 | 4.91 | 3.18 | 0.28
History of diabetes mellitus related complications | | | |
Not reported | 59.65 | 59.28 | 63.66 |
Reported | 40.35 | 40.72 | 36.34 | 0.24
History of chronic lung diseases | | | |
Not reported | 84.02 | 84.12 | 82.88 |
Reported | 15.98 | 15.88 | 17.12 | 0.67
History of congestive heart failure | | | |
Not reported | 87.45 | 88.46 | 76.60 |
Reported | 12.55 | 11.54 | 23.40 | < 0.001
History of hypertension | | | |
Not reported | 32.97 | 33.35 | 28.84 |
Reported | 67.03 | 66.65 | 71.16 | 0.20
History of peripheral vascular diseases | | | |
Not reported | 86.94 | 86.92 | 87.09 |
Reported | 13.06 | 13.08 | 12.91 | 0.94
History of paralysis | | | |
Not reported | 98.23 | 98.22 | 98.33 |
Reported | 1.77 | 1.78 | 1.67 | 0.93
History of rheumatoid arthritis/collagen vascular diseases | | | |
Not reported | 97.75 | 97.73 | 97.97 |
Reported | 2.25 | 2.27 | 2.03 | 0.83
History of chronic liver diseases | | | |
Not reported | 94.93 | 96.20 | 81.19 |
Reported | 5.07 | 3.80 | 18.81 | < 0.001
History of chronic renal failure | | | |
Not reported | 77.64 | 79.33 | 59.42 |
Reported | 22.36 | 20.67 | 40.58 | < 0.001
History of malignancy without metastasis | | | |
Not reported | 97.28 | 97.51 | 94.81 |
Reported | 2.72 | 2.49 | 5.19 | 0.07
History of malignancy with metastasis | | | |
Not reported | 99.29 | 99.44 | 97.72 |
Reported | 0.71 | 0.56 | 2.28 | 0.008
History of HIV infection | | | |
Not reported | 99.70 | 99.77 | 98.99 |
Reported | 0.30 | 0.23 | 1.01 | 0.06
Trauma admission | | | |
Not reported | 63.01 | 64.08 | 51.49 |
Reported | 36.99 | 35.92 | 48.51 | 0.001
Septicemia | | | |
No reported | 43.87 | 46.47 | 15.81 |
At presentation | 42.09 | 40.09 | 63.70 |
During admission | 14.04 | 13.44 | 20.48 | < 0.001
Disseminated intravascular coagulopathy | | | |
Not reported | 98.58 | 99.13 | 92.66 |
Reported | 1.42 | 0.87 | 7.34 | < 0.001
Septic shock | | | |
Not reported | 77.35 | 81.47 | 32.92 |
Reported | 22.65 | 18.53 | 67.08 | < 0.001
Cardiovascular complications during admission | | | |
Not reported | 96.92 | 97.18 | 94.08 |
Reported | 3.08 | 2.82 | 5.92 | 0.035
Pulmonary complications during admission | | | |
Not reported | 70.80 | 74.68 | 28.97 |
Reported | 29.20 | 25.32 | 71.03 | < 0.001
Acute renal failure during admission | | | |
Not reported | 54.02 | 56.54 | 26.91 |
Reported | 45.98 | 43.46 | 73.09 | < 0.001
Surgical intervention other than amputation | | | |
Not reported | 15.09 | 13.71 | 29.90 |
Reported | 84.91 | 86.29 | 70.10 | < 0.001
Amputation | | | |
Not reported | 90.45 | 91.55 | 85.07 |
Reported | 9.55 | 8.45 | 14.93 | < 0.001
Hyperbaric oxygenation utilization | | | |
Not reported | 99.08 | 98.33 | 100.00 |
Reported | 0.92 | 1.67 | 0.00 | NAc
Hemodialysis | | | |
Not reported | 90.86 | 92.34 | 74.85 |
Reported | 9.14 | 7.66 | 25.15 | < 0.001
Blood and blood components transfusion | | | |
Not reported | 74.47 | 75.31 | 65.44 |
Reported | 25.53 | 24.69 | 34.56 | 0.003
Immunoglobulin infusion | | | |
Not reported | 99.95 | 99.94 | 100.00 |
Reported | 0.05 | 0.06 | 0.00 | NAc

It should be noted that in both groups no mortality was reported among patients who were <18 years, received HBOT, or received IVIG. For this reason, those factors were not assessed for their association with mortality in the univariable analysis.

Patients who did not undergo surgery were more likely to be >65 years, have multiple comorbidities, and with Medicare insurance (p < 0.05 each; Table 6). They also were less likely to have been admitted because of trauma or have developed septicemia (p < 0.001 each).

Table 6. Characteristics of Patients with Necrotizing Fasciitis Who Were Less Likely to Undergo Surgical Intervention

| Risk of not undergoing surgery, (%) | ORa | 95% CI | P
Age (yr) | | | |
< 65 | 14.74 | Reference | |
≥ 65 | 23.92 | 1.40 | 1.09, 1.80 | 0.009
Gender | | | |
Male | 16.63 | Reference | |
Female | 17.32 | 1.01 | 0.84, 1.21 | 0.95
Charlson comorbidity index score | | | |
0 - 1 | 13.48 | Reference | |
2 - 3 | 19.81 | 1.48 | 1.16, 1.89 | 0.002
≥ 4 | 31.55 | 2.42 | 1.77, 3.31 | <0.001
Trauma admission | | | |
Not reported | 19.91 | Reference | |
Reported | 12.55 | 0.61 | 0.50, 0.73 | <0.001
Septicemia | | | |
Not reported | 20.37 | Reference | |
Reported | 14.27 | 0.65 | 0.53, 0.80 | <0.001
Insurance type | | | |
Private | 14.11 | Reference | |
Medicare | 22.61 | 1.37 | 1.08, 1.74 | 0.010
Medicaid | 15.29 | 1.08 | 0.83, 1.41 | 0.56
Self-pay | 12.51 | 0.90 | 0.64, 1.26 | 0.53

Discussion

This study provides an overall picture of NF and associated outcomes in the United States by utilizing the NRD for the years 2010–2014. The database is unique because it provides a large nationally representative sample of a relatively rare condition. The study identified 4,178 cases of NF, with an overall mortality risk of 12.6% (95% CI = 11.5–13.7%). In a review of 67 studies published between 1980 and 2008, the author observed the pooled mortality risk was 23.5% with a slight annual downward trend [4]. However, those studies included heterogeneous populations with small sample sizes (range, 7–198 cases), pooling the mortality risk as opposed to more advanced statistical methods that would control for variations in sampled populations that could result in a misleading information. The large sample of this study and the application of weighted analysis are likely to have produced a more reliable estimate of mortality risk in the United States.

The mortality risk among patients without diabetes was 16.5%, whereas the mortality risk among patients with diabetes was substantially lower, 8.5%. Diabetes mellitus is a common comorbidity in patients who presented with NF, the prevalence of diabetes has been reported to be between 44.5% and 72.3% [2]. The association of diabetes with NF is believed to be related to poor capacity of wound healing and increased susceptibility of infection in patients with diabetes [2]. The microbiologic profile of NF in patients with diabetes has been reported to be different from that of patients who do not have diabetes [2]. Patients with diabetes are more susceptible to NF caused by polymicrobial infection [2]. For those reasons, we decided to analyze patients with diabetes separately from patients without diabetes.

In a retrospective study from Taiwan by Cheng et al. [2] that used similar ICD-9 code to identify cases and reported 165 patients with NF, 51% had diabetes mellitus. Cheng et al. [2] reported no statistically significant difference in mortality between patients with and without diabetes, however, similar to this study patients with diabetes had a higher risk of undergoing amputation. Cheng et al. [2] also examined factors associated with mortality in patients with and without diabetes. Despite the multiple risk factors investigated, factors that were associated with a higher risk of mortality in patients with diabetes only included dyspnea at presentation and septicemia, whereas in patients without diabetes the risk factors identified were the functional status of the patient, pus at infection site, and systemic inflammatory response syndrome (SIRS) [2]. It is likely that the small sample size rendered the study underpowered to detect substantial differences in mortality associated with the examined factors [2].

There are conflicting results in the literature regarding the association of diabetes and mortality risk. Some studies failed to identify association with diabetes whereas others reported a negative prognosis [12,13]. The main limitation of all previous studies is the small sample size that rendered them underpowered to detect meaningful association and left room for random error. In a meta-analysis by Turner et al. [14] that examined the risk of mortality in patients who developed invasive fungal sinusitis, conflicting results regarding the association of diabetes with mortality risk were also found. Nonetheless, the final outcome of the meta-analysis demonstrated diabetes to be a good prognosis factor [14]. Although this is not well understood, it is believed that patients with diabetes are liable to develop infection. However, by controlling blood glucose levels, the infection is less likely to progress, thus blood glucose is hypothesized to be a modifiable risk factor that would improve survival; this is still to be proven [14]. Notably, the study demonstrated that septicemia was a risk factor of mortality only in patients who did not have diabetes, whereas septic shock was a risk factor of mortality in both groups. This might indicate that patients with diabetes are more likely to recover from septicemia than those without diabetes and it is probably for this reason that patients with diabetes had a lower mortality risk.

Patients who had chronic liver disease were at a higher risk of mortality in both studies groups. In a study by Liu et al. [15] that included 118 patients with liver cirrhosis who were admitted with soft tissue infection, 22 (18.6%) patients had proven NF, 8 (36.3%) of whom died. Infection in patients with chronic liver disease triggers excessive proinflammatory cytokines response, which in addition to pre-existing hemodynamic derangement, has been attributed to poor infection consequences in this population.16

Early identification of NF is a major determinant of survival.¹⁷ However, studies have demonstrated NF is often misdiagnosed as cellulitis or abscess approximately 50% of the time, which resulted in a delayed intervention [4,8,15,17,18]. In this study, 9.2% of patients were admitted initially as cases of cellulitis or abscess. However, it is unclear from data whether this was an initial misdiagnosis of NF or cellulitis that developed into NF during admission. Given the aggressive nature of NF, the subpopulation at high risk of mortality based on the risk factors identified here, especially those pertaining to comorbidities, should give a sign and raise a differential diagnosis of NF when encountering patient of this group presenting with soft tissue infection.

Surgical debridement and antibiotic agents are the mainstay treatment of NF [1,4].

Hyperbaric oxygen therapy has been proposed as adjunct therapy [19]. In this study the utilization of HBOT was reported in 1.3% of the sample. Hyperbaric oxygen therapy was not reported among patients who died, which prevented statistical evaluation of HBOT impact on mortality risk. There is a lack of evidence supporting the use of HBOT in patients with NF. In a retrospective study by Massey et al. [19] that included 80 patients with NF, 32 (40%) patients received HBOT as part of their treatment. They reported no statistically significant difference in number of operations performed, amputations, and mortality risk comparing patients who received HBOT to those who did not. Massey et al. [19] calculated the statistical power in their study to be only approximately 0.25 to detect a 10% absolute reduction in mortality associated with HBOT. To have a statistical power of 0.8, they would have needed an additional 261 patients.

Similar to HBOT, IVIG was used in a small proportion of patients (0.3%) and with no reported use among patients who died. Intravenous immunoglobulin as a treatment of NF is still theoretical, partially supported by its efficacy in other type of infection [20]. In a randomized, blinded, placebo-controlled trial at Copenhagen University Hospital that included 100 patients with NF admitted to the intensive care unit, no apparent effects of adjuvant IVIG on self-reported physical functioning was observed at six months [20]. In another retrospective study by Kadri et al. [21] that involved 164 patients, reported adjunctive IVIG had no apparent impact on mortality or hospital length of stay compared with debridement and antibiotic agents alone.

The NRB does not provide information regarding the reasons behind not undergoing surgery in 16.9% of the study sample. However, those patients might not have been fit to undergo general anesthesia because statistically they were more likely to be >65 years and to have multiple comorbidities. Paradoxically, controlling for age and comorbidities, it appears that patients who had a less severe presentation—a non-traumatic presentation or without septicemia—were less likely to undergo surgery. It is alarming that septicemia was a factor to undergo surgery in patients who presented emergently with NF because development of septicemia was an independent risk factor of mortality; this might reflect a delay in diagnosis. Nevertheless, this was reported in a small proportion of the study population and the circumstances behind not undergoing surgery cannot be fully elucidated using this database, further investigation is warranted using a more detailed clinical data.

The study has multiple limitations. Causality cannot be established because the data were collected cross-sectionally. The NRD is an administrative database that lacks clinical details such as culture and sensitivity reports, laboratory values, utilization of antibiotic agents, surgical details, number of procedures, severity of condition, and site of NF because the ICD-9 code used to identify cases lacks information regarding site; however, this ICD-9 code has been used previously by other studies that allowed for comparison with previous outcomes [2,5,8]. The lack of the above factors hinder elucidating the underlying factors behind the observed outcomes in the study. The study period is also relatively short to demonstrate meaningful trend analysis. Despite these limitations, the database provides a large sample size of a relatively rare condition. The data is suitable for assessment of overall national prevalence of NF and the associated burden in terms of mortality, length of hospital stay, and cost. The NRD includes a wide array of factors that were considered for their potential confounding effect. Additionally, the application of weighted analysis generates more accurate national estimates of the outcomes in the United States.

Conclusions

To our knowledge, this is the largest study to examine the outcomes and risk factors of NF. Septicemia is present at the time of admission in 40% of patients. Mortality risk appears to be lower than reported previously by smaller scale studies and remains stable throughout the study period, however, it was higher in patients who did not have diabetes. This study identified multiple risk factors associated with mortality. A high index of suspicion should be practiced when soft tissue infection develops in patients with chronic comorbidities. Comorbidities observed to be associated with a higher risk of mortality included congestive heart failure, peripheral vascular diseases, chronic liver diseases, and malignancy. The mainstay treatment is surgery and antibiotic ageents; HBOT and IVIG are currently being investigated as adjunctive therapy. In this study both modules were used infrequently with no reported use among patients who died, which prevented statistical evaluation of their impact on survival. Future studies with larger sample size and more detailed clinical information are warranted as well as studies aimed at understanding the complex and changing microbiology profile of NF that would guide antimicrobial therapy.

Funding Information

Al-Qurayshi is supported by National Institutes of Health-Institutional National Research Award: T32. None of the other authors have anything to disclose.

Author Disclosure Statement

All authors of this work declare no conflict of interest.

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Necrotizing Fasciitis - All You Need To Know - Dr. Pramil Cheriyath MD

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Flesh Eating Bacteria (Necrotizing fasciitis)