Chapter VI.14. Necrotizing Fasciitis
Michelle V. Stafford
June 2022

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The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Chad S.D. Sparks. This current third edition chapter is a revision and update of the original author’s work.


An 11 year old, previously healthy boy, presents to the office with a chief complaint of extreme pain from a 3 day old puncture wound on his right calf. He reports fever, redness, and swelling for one day. His temperature was not measured, but he felt very hot. He was treated with acetaminophen which reduced his fever, but not his pain.

Exam: T39, P132, R26, BP 105/78. He is alert and in obvious pain. Heart auscultation is significant for tachycardia. Lungs are clear on auscultation, but he is tachypneic. A round puncture wound measuring 0.3 cm in diameter is noted on his right lateral calf with erythema and edema extending distally for 3 cm. Palpation of this area results in severe tenderness. The capillary refill of the skin overlying this region is slightly delayed. There is no popliteal or groin tenderness on the right. The rest of his exam is normal.

A surface wound culture is obtained. A CBC is normal. His CRP and ESR are elevated. A blood culture is spending. Intravenous (IV) acetaminophen, ceftriaxone, and clindamycin are administered. An ultrasound is negative for an abscess but shows some soft tissue abnormalities in a much larger area than was anticipated. He is admitted to the hospital for suspected necrotizing fasciitis. The next day, the skin near his wound progressively develops bluish discoloration, blisters, and bullae. An MRI scan demonstrates fluid in a fascial plane of the lateral compartment of the lower leg. The wound culture grows group A beta hemolytic streptococci (Streptococcus pyogenes). Surgical debridement is performed confirming the diagnosis of necrotizing fasciitis (NF). Brown serous fluid is removed and cultured. S pyogenes grows from the serous fluid the next day. Ceftriaxone is discontinued, replaced by IV penicillin, but clindamycin is continued. He continues to require daily surgical debridement until the sixth day of hospitalization, with slow and progressive improvement. He is discharged after 10 days of hospitalization. Follow-up the next month shows good recovery.


Necrotizing fasciitis (NF) is a group of infections, presenting in any age group as an abrupt, rapidly advancing soft tissue infection with systemic toxicity and high mortality. It is characterized by microbial spread along the superficial fascia, which comprises all the tissue between the skin and underlying muscles (1).

The classification of NF is challenging because of its similarity to other syndromes, its numerous etiologies, and the use of different terms to define different types of NF. The diagnoses will often overlap with other entities as the infection spreads to adjacent tissues For example, necrotizing cellulitis may extend and secondarily involve the fascial planes, or vice versa (1,2). Several studies have tried to classify NF based on anatomic location, bacteriology, presence or absence of crepitance, and clinical progression.

NF falls under the general category of necrotizing soft tissue infection (NSTI), which are defined as infections associated with necrotizing changes of any of the layers within the soft tissue (dermis, subcutaneous tissue, superficial fascia, deep fascia, or muscle) (2). There are three types of NSTI: 1) NF, 2) necrotizing cellulitis, and 3) myonecrosis; however, in the clinical context NF is often used as a broadly inclusive term for overlapping types of NSTI.

There are three types of NF that are often described and easy to conceptualize: Type I is polymicrobial (aerobes and anaerobes) and occurs more often in adults, postoperatively or with co-morbidities such as diabetes mellitus or peripheral vascular disease. Type II is commonly caused by S pyogenes (also known as group A beta hemolytic streptococcus (GABHS or GAS)), and less frequently other Streptococci or Staphylococci. Type III is the rarest and results from infection with Vibrio vulnificus (marine vibrio that should be suspected with the ingestion of or exposure to contaminated seafood or wounds from marine species/objects such as fish spines, oyster shells, or other sharp marine objects), Aeromonas hydrophila, and possibly Clostridium species (3,4,5,6).

Type I NF infection involves at least one anaerobic species (e.g., Bacteriodes or Peptostreptococcus) in combination with one or more facultative anaerobic or aerobic organisms (3). Depending on the population, some studies report polymicrobial infections to be more common than monomicrobial causes of NF (types II and III), while others report the opposite or a similar incidence rate (4). The most common bacteria in type I NF is Bacteroides species, which are gram-negative anaerobic bacilli. Fournier's gangrene is a variant of polymicrobial NF usually found in the scrotum or penis of older, often immunocompromised individuals (1). This variant is rare in children.

Type II infection is probably the most extensively studied type of NF and the most common in children (7). It is usually caused by S. pyogenes, and less frequently by Staphylococcus aureus, anaerobic Streptococci and others (2). S pyogenes has been increasing in frequency since 1990. The reason for this increase is unknown, but it parallels the increasing incidence of other types of invasive streptococcal infections since 1985 (7,8). It should be noted that S. pyogenes only rarely causes NF, compared to its less virulent and much more common non-necrotizing infections of cellulitis, erysipelas, intertrigo, and impetigo. The invasive nature of some S pyogenes infections has been linked to several virulence factors. The M protein inhibits complement activation and protects the bacteria from phagocytosis by polymorphonuclear leukocytes. There are over 80 distinct M proteins; the two most commonly isolated in NF are the M-1 and M-3 subtypes of S. pyogenes (1). Other important virulence factors are the exotoxins. There are five different exotoxin proteins: A, B, C, D, and E. Most noted in NF are the streptococcal pyrogenic exotoxins types A, B, and C. Exotoxins recruit T cells and increase production of tumor necrosis factor alpha, interleukin 1-beta, and interleukin 6. These pro-inflammatory molecules lead to fever, shock, edema, and multiple organ failure (1). The so-called streptococcal superantigen may also play a role in this process. Although these proteins are unique to the Streptococcal species, the clinical picture is often difficult to distinguish from other types of NF.

Invasive S. pyogenes NF may present as an infection with a defined portal of entry, or an infection of deep tissues without an overt wound or lesion (4). Superficial cutaneous lesions (such as varicella vesicles, insect bites, abrasions, or lacerations), breaches to mucosal integrity (such as surgical incision or childbirth), or penetrating trauma are common portals of entry. The initial lesion may be only mildly erythematous; however, within the next 24 to 72 hours, the inflammation becomes extensive overlying the necrotizing tissue. The skin subsequently becomes dusky and discolored and develops blisters and bullae over the next 7 to 10 days. This progression is both faster and more severe than that seen in cellulitis or erysipelas. Bacteremia is frequently present and ensuing mortality is high. 50% of patients with S pyogenes NF may initially present at sites of nonpenetrating trauma, such as a muscle strain or bruise (4), with fever and escalating pain. Other symptoms may include malaise, myalgias, diarrhea, and anorexia within the first 24 hours. This presentation of NF is frequently occult leading to a misdiagnosis or a delayed diagnosis, resulting in mortality greater than 70% (4). Thus, an early diagnosis of NF is essential and should be suspected when the pain is more severe that what the visible infection suggests.

The differential diagnosis of severe pain and inflammation of the skin is broad, including entities such as cellulitis, erysipelas, acute febrile neutrophilic dermatosis, acute hemorrhagic edema of infancy, drug reactions, and vasculitis. NF is frequently confused with cellulitis because the early clinical presentation of pain, erythema, and edema is common to the two. Factors that may aid in differentiating NF from cellulitis are recent surgery, pain out of proportion to clinical findings, hypotension, skin necrosis, and hemorrhagic bullae (4). Definitive diagnosis requires surgical exploration and probing. If any question remains after probing, a biopsy should be obtained (2,7). Erysipelas is red, slightly raised, well-demarcated areas of induration and usually involves only the superficial cutaneous tissue. Ecthyma gangrenosum due to Pseudomonas species may also present similarly to NF but appears ulcerated rather than bullous.

Although there are several distinct etiologies of NF, the clinical presentations are very similar. The clinical picture of NF is significant for severe pain, erythema with ill-defined borders, and swelling that progressively extends from the site of trauma, surgery, or other provoking insult (7). The clinician's history should include questions regarding any inciting event such as a small wound or traumatic occurrence at the site of infection. Conversely, the absence of an initiating event does not exclude the possibility of NF.

Common initiating events depend on the age group as well as the patient's immune status. In the newborn, NF can be a serious complication of omphalitis (7). It may begin as erythema and induration around the umbilicus and progress to a purplish discoloration and periumbilical necrosis during the subsequent hours or days (1). In older children, NF may present after trauma, surgery, or resolving varicella lesions (7). The history frequently reveals fever persisting after the third day of rash, associated with severe, localized pain, over an area of swelling, erythema, and possibly necrotic skin (1,7). The mechanism of how varicella increases the risk for NF is unknown, but varicella is known to frequently be secondarily infected with GABHS and S. aureus.

In the 1990s, an association between NF and non-steroidal anti-inflammatory drug (NSAID) use was proposed. Numerous studies examined this relationship, and the results have been mixed. Most believe these studies do not prove a causal relationship, but caution is advised, and physicians may consider recommending acetaminophen instead of ibuprofen for children with varicella (1,7). Varicella infections are currently less common due to varicella and zoster immunizations.

Although the diagnosis of NF is primarily clinical, laboratory testing and imaging may be helpful. Surgical probing and frozen section biopsy are used for diagnosis of NF (2). There must be a high index of suspicion for NF to move straight to surgery. Cultures of the blood and wound should be obtained. This will help guide antibiotic therapy over the course of the disease. Routine blood work such as a complete blood count and chemistry panels may be helpful.

The LRINEC (laboratory risk indicator for necrotizing fasciitis) score is often cited in discussions of NF. Score calculation is facilitated with an online calculator. LRINEC scores have sensitivities and specificities of 68% and 85% (at score of ≥6); and 41% and 95% (≥8), respectively (9).

Imaging can also be useful in differentiating NF from cellulitis. Crepitus on physical exam, or soft tissue gas on plain radiographs are considered pathognomonic for NSTI and are recommended as an initial approach. Ultrasound is useful to confirm or rule out an abscess, and it has been advocated by some to demonstrate NF, but its use requires special expertise (10).

Computed tomography (CT) scans and MRI studies are more definitive and are better at demonstrating soft tissue swelling and gas in the tissues, but these studies should not delay intervention. Evidence of gas, or crepitus, should prompt immediate surgical consultation (2). MRI contrast enhanced images may show asymmetric thickening and hyperintensity of the deep fascia, which is sensitive but not specific for NF. On CT scan, the absence of fascial enhancement is considered specific for NF (4,9,11).

The mainstays of treatment for NF are surgical intervention and intravenous antibiotics. Surgical exploration is essential for NF to determine the extent of infection, to assess the need for debridement or amputation, and to obtain specimens for culture. Surgical debridement is recommended every day until the patient is stable and without signs of infection or sepsis, which may take several days. Debridement should cover the infected area as well as a margin of healthy tissue to prevent reoccurrence of infection. As a result of the extensive debridement, the patient may need skin grafting. In addition, physical therapy and rehabilitation will be needed for those with extensive muscle debridement (2).

For initial empiric therapy, broad antibiotic coverage is recommended, including agents effective against both aerobes (including MRSA), and anaerobes. Medications may include vancomycin, linezolid, or daptomycin combined with one of the following: piperacillin-tazobactam, a carbapenem, ceftriaxone plus metronidazole, or a fluoroquinolone plus metronidazole (2). Doxycycline and quinolones have activity against Vibrio vulnificus (5). Specific, narrow antibiotic therapy can be employed once cultures return and bacterial susceptibilities are known.

In cases of NF caused by S pyogenes, the recommended antibiotic treatment is penicillin plus clindamycin. Penicillin is bactericidal and highly effective against S pyogenes. Clindamycin inhibits ribosome function and hence the production of streptococcal virulence factors (2,7). The duration of treatment is not well established, but since NF is a severe infection, antimicrobial therapy for NF should be continued until the patient no longer manifests signs of systemic inflammation and is improving (2), a process that often may require a 14-day course.

The addition of intravenous immune globulin (IVIG) has been advocated, specifically for cases of streptococcal toxic shock syndrome. The rationale is its possible ability to neutralize extracellular toxins. Clear supporting evidence is lacking. The Infectious Diseases Society of America (IDSA) does not currently support the routine use of IVIG for these cases and, instead, recommends further efficacy studies (2). Similarly, hyperbaric oxygen has been suggested as an adjunctive therapy for NF, specifically for the treatment of gas gangrene and myonecrosis. IDSA considers the available studies of low quality and recommends against the routine hyperbaric oxygen use which could delay more definitive surgical therapy (2).

In general, NF has a poor prognosis often resulting in either severe residual morbidity (due to extensive surgical debridement and amputations) or mortality. Mortality is high (probably close to 100%) if untreated, or if treatment is delayed. Age is an important factor in mortality (with older adults faring worse), as well as the number of comorbidities (especially diabetes) and presence of bacteremia, shock or hypotension. Early and aggressive use of antibiotics and surgical debridement are positive prognostic factors. The mortality associated to NF is cited as 25% to 75% (2,7).


Questions
1. The most common species of bacteria isolated from Type I NF is:
. . . . a. Staphylococcus aureus
. . . . b. Streptococcus pyogenes (GABHS)
. . . . c. Bacteroides species
. . . . d. Clostridium species

2. An early diagnosis of NF is essential to reduce mortality and amputation risk. Which early clinical factor is highly suggestive of NF?
. . . . a. Leukocytosis
. . . . b. Severe pain out of proportion to what is visible
. . . . c. Necrotic skin
. . . . d. Poor distal circulation

3. Which imaging modality is most useful in initially differentiating cellulitis from NF?
. . . . a. Plain radiograph
. . . . b. MRI
. . . . c. CT
. . . . d. Ultrasound

4. The most important virulence factor that protects GABHS from phagocytosis is:
. . . . a. Streptokinase
. . . . b. M protein
. . . . c. Streptococcal pyrogenic exotoxins
. . . . d. Streptolysin O
. . . . e. Hyaluronidase

5. Type II NF is most often caused by:
. . . . a. Clostridium perfringens
. . . . b. Streptococcus pyogenes (GABHS)
. . . . c. Bacteroides
. . . . d. Campylobacter

6. Initial empiric treatment for streptococcal NF should include:
. . . . a. Erythromycin
. . . . b. Gentamicin
. . . . c. Doxycycline
. . . . d. Penicillin

7. Which wound clinical factor suggests that doxycycline should be added to the initial empiric antibiotic treatment for NF?
. . . . a. Fecal wound contamination
. . . . b. Bee sting
. . . . c. Pinched by a crab
. . . . d. Injury from a fish fin
. . . . e. A splinter from a canoe

8. Necrotizing fasciitis has a significant clinical risk for which of the following outcomes?
. . . . a. Death
. . . . b. Amputation
. . . . c. Limb dysfunction
. . . . d. Antibiotic allergy


References
1. Pasternack MS, Swartz MN. Chapter 93. Cellulitis, Necrotizing Fasciitis, and Subcutaneous Tissue Infections. In: Bennett JE, Dolin R, Blaser MJ (eds). Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 9th edition. 2020. Elsevier. pp 1282-1306.
2. Stevens DL, Bisno AL, Chambers HF, et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America. Clin Infect Dis 2014;59(2):e10–e52.
3. Noor A, Krilov LR. Necrotizing Fasciitis. Pediatr Rev 2021;42(10): 573-575.
4. Stevens DL. Bryant AE. Necrotizing Soft-Tissue Infections. N Engl J Med. 2017;377(23):2253-2265.
5. Coerdt KM, Khachemoune A. Vibrio vulnificus: Review of Mild to Life-threatening Skin Infections. Cutis. 2021;107:E12-E17. doi:10.12788/cutis.0183
6. Tsai Y, Huang T, Chen J, et al. Bacteriology and mortality of necrotizing fasciitis in a tertiary coastal hospital with comparing risk indicators of methicillin-resistant Staphylococcus aureus and Vibrio vulnificus infections: a prospective study. BMC Infect Dis. 2021:21:771. https://doi.org/10.1186/s12879-021-06518-5
7. Creech CB. Chapter 75. Myositis, Pyomyositis, and Necrotizing Fasciitis. In: Long SS, Prober CG, Fischer M (eds). Principles and Practice of Pediatric Infectious Diseases, 5th edition. 2018. Elsevier. pp 473-479.
8. Gaensbauer J, Nomura Y, Ogle JW. Infections: Bacterial & Spirochetal. In: Hay Jr. WW, Levin MJ, Abzug MJ, Bunik M (eds). Current Diagnosis & Treatment: Pediatrics, 25e. McGraw Hill; 2020. Accessed June 30, 2022. https://accessmedicine.mhmedical.com/content.aspx?bookid=2815§ionid=244269175
9. Fernando SM, Tran A, Cheng W, et al. Necrotizing Soft Tissue Infection: Diagnostic Accuracy of Physical Examination, Imaging, and LRINEC Score. Ann Surg. 2019;269(1):58-65.
10. Lahham S, Shniter I, Desai M, et al. Point of Care Ultrasound in the Diagnosis of Necrotizing Fasciitis. Am J Emerg Med 2022;51:397-400.
11. Carbonetti F, Cremona A, Carusi V, et al. The role of contrast enhanced computed tomography in the diagnosis of necrotizing fasciitis and comparison with the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC). Radiol Med 2016;121(2):106-121.


Answers to questions
1. c. Bacteroides is the most common bacteria isolated in type I or polymicrobial NF. Staphylococcus, streptococcus, and clostridium are also commonly found.
2. b. Severe pain out of proportion to what is visible. The CBC is often non-specific. The other clinical factors listed are late findings.
3. a. Plain radiographs are routinely used to differentiate cellulitis and NF. MRI and CT are more definitive. Answers b and c could be correct, but ultrasound (answer d) is less definitive, although it is useful to rule out an abscess. If NF is suspected, surgical exploration is necessary.
4. b. The M protein inhibits the activation of complement and prevents phagocytosis. The other virulence factors listed belong to streptococcal species, but have different roles in causing infection.
5. b. Streptococcus pyogenes is the most common cause of type II NF. This type of NF is particularly common in children.
6. d. First line therapy for streptococcal NF is penicillin, which is active against S pyogenes and other Streptococci. Adding clindamycin may be useful even if the organism is penicillin sensitive since it may inhibit protein synthesis (toxin production).. For other organisms, anti-microbial therapy should be based on culture and susceptibility results once they are obtained.
7. d. An injury from a fish fin suggests NF due to a marine vibrio. Similarly, choices c and e are likely correct as well since a pinch from a crab and a splinter from a canoe (or a pier/dock, paddle, ocean debris, etc.) could suggest a marine vibrio as well.
8. a,b,c are all correct (death, amputation, limb dysfunction). Antibiotic allergy is less common.


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