This is an 11 year old, previously healthy male who presents to the office with a chief complaint of extreme pain from a 3 day old puncture wound on his right calf. He also reports fever, redness, and swelling for one day. The height of his fevers is not measured. He was given acetaminophen for fever and pain. The fever improved, but the pain has worsened.
Exam: VS T 39 degrees C, HR 132, RR 26, BP 105/78. He is alert and in obvious pain. HEENT exam is negative. Lungs are clear. Breathing is tachypneic. Heart is tachycardic, without murmurs or extra sounds. Abdomen is soft and non-tender. 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.
A wound culture is obtained. A CBC and blood culture are drawn. IV ceftriaxone is administered and he is admitted to the hospital. Over the next 36 hours, the skin near his wound progressively develops a bluish discoloration, blisters, and bullae. Group A-beta hemolytic streptococci (GABHS) is isolated from the wound culture and blood culture. Ceftriaxone is discontinued and he is started on IV penicillin G and clindamycin for necrotizing fasciitis (NF). On the second day of hospitalization, an MRI finds fluid in a fascial plane of the lateral compartment of the lower leg. Surgical debridement is performed and brown serous fluid is removed and cultured. The surgeon confirms the diagnosis of NF. GABHS grows from the serous fluid the next day.
He continues to require daily surgical debridement until the sixth day of hospitalization, but he slowly improves. He is discharged on day ten. Follow-up for the next month shows good recovery.
Necrotizing fasciitis (NF) is a group of infections that present in any age group as an abrupt, rapidly advancing soft-tissue infection with systemic toxicity and high mortality (1). It is characterized by microbial spread along the fascial planes into deep tissue, which results in necrosis of the superficial tissue.
The classification of NF is ambiguous because of its similarity to other syndromes and its numerous etiologies. Often, the diagnoses will overlap as infection spreads to adjacent tissue. For example, necrotizing cellulitis may involve the fascial planes secondarily or vice versa. Several studies have tried to classify NF based on anatomic location, bacterial flora, presence or absence of crepitance, and clinical progression.
NF falls under the general category of necrotizing soft tissue infection (NSTI). There are three types of NSTI: 1) NF, 2) necrotizing cellulitis, and 3) myonecrosis. However, NF is often used in clinical settings as a broadly inclusive term for overlapping types of NSTI. Clinically, there are three syndromes of NF that are often described and easy to conceptualize: Type I is polymicrobial and includes saltwater NF due mainly to marine Vibrio species. Type II is group A streptococcal NF. Type III is clostridial myonecrosis or gas gangrene (2). The most common form of NF is the polymicrobial Type I. In one pediatric study, 75% of children developed NF with polymicrobial etiology (Type I) (3). The most common species of bacteria cultured from a study of 182 subjects in Maryland were Streptococcal species, Staphylococcal species, Enterococcal species, and Bacteroides species. Anaerobes such as Clostridia were also common in type I NF and could be differentiated by gas production visible on imaging studies. The most common bacteria in type I NF is Bacteroides, which is a gram-negative anaerobic bacillus. Fournier's gangrene is a variant of polymicrobial NF usually found in the scrotum or penis of older, often immunocompromised individuals. This variant is rare in children.
Type II infection with GABHS is probably the most extensively studied type of NF and is common in children (4,5). However, Type II NF has received extra attention in the lay press recently and is referred to as the "flesh-eating" bacterial infection (6). In cases where only one bacterium was present on culture, group A beta hemolytic streptococcus (GABHS) was the most common. In addition, GABHS (also known as Strep pyogenes) has been increasing in frequency since 1990 (7,8). The reason for this increase is unknown, but it may be related to the increasing incidence of other types of invasive streptococcal infections since 1985 (9).
The invasive nature of some GABHS infections and their increasing prevalence has been linked to several virulence factors. It should be noted that NF is rare compared to the total number of non-NF GABHS cellulitis infections which are much more common. The M protein has been found responsible for protecting the bacteria from phagocytosis by polymorphonuclear leukocytes (10). There are over 80 distinct M proteins, but the two most often isolated in NF are the M-1 and M-3 subtypes of S. pyogenes (8). Another important virulence factor is the exotoxin. There are five different exotoxin proteins: A, B, C, D, and E. Most commonly noted in NF are the streptococcal (scarlatina) pyrogenic exotoxins (SPE) types A, B, and C. Exotoxins recruit T cells and increase production of tumor necrosis factor alpha, interleukin 1-beta, and interleukin 6. The effects are characterized by fever, shock, edema, and multiple organ failure (11). The streptococcal superantigen (SSA) can 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 (4).
Type III NF is most often associated with crepitus due to growth of clostridium perfringens. This is often referred to as gas gangrene. The gas produced can often be seen on various imaging modalities such as x-ray, MRI, or CT.
The differential diagnosis of severe pain and inflammation of the skin includes cellulitis, erysipelas, acute febrile neutrophilic dermatosis, acute hemorrhagic edema of infancy, drug reactions, and vasculitis. NF is regularly confused with cellulitis because its early clinical presentation is also pain, erythema, and edema. However, cellulitis extends only to the subcutaneous tissue and is poorly demarcated. An experienced clinician is usually able to make an accurate diagnosis. Definitive differentiation from necrotizing cellulitis is generally established with surgical incision and probing. If any question remains after probing, a biopsy should be obtained (12). Erysipelas is red, raised, well-demarcated areas of induration and usually involves only the superficial cutaneous tissue. Ecthyma gangrenosum may also present as NF, but is due to Pseudomonas and appears ulcerated rather than bullous (13).
Although there are several distinct etiologies of NF, the clinical presentations are very similar. The clinical picture of NF is significant for pain, erythema, and swelling that progressively extends from the site of trauma, surgery or other provoking insult. The clinician's history should include questions regarding any inciting event such as a small wound or traumatic occurrence at the site of infection. On the other hand, the absence of an initiating event does not rule out 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. It may begin as swelling and erythema around the umbilicus and progress to a purplish discoloration and periumbilical necrosis during the subsequent hours or days (13). In older children, NF may present after trauma, surgery, or with resolving varicella lesions. In a study, almost 50% of pediatric cases were superimposed upon varicella in its 3rd-4th day of progression (8). The history frequently reveals a persistent fever after the third day of rash, associated with severe, localized pain, over an area of swelling, erythema, and possibly necrosing skin (14). The mechanism of how varicella increases the risk for NF is unknown. An association has been shown between NF and NSAID use with varicella. Numerous studies examined this relationship, but the results have been mixed. Most believe these studies do not prove a causal relationship. However, physicians may consider recommending acetaminophen instead of ibuprofen for children with varicella (15).
Pain in an extremity is usually the presenting symptom. It is extreme and often out of proportion with the physical findings. NF has a propensity for the extremities, but can occur anywhere there is deep fascia (16). In the first 24-48 hours, it is associated with edema, erythema, and warmth of the skin overlying the necrotizing tissue. After that point, the skin will become dusky and discolored. It will develop blisters and bulla over the next seven to ten days. During that time, the discoloration will become sharply demarcated. Its tenderness will also disappear as the superficial nerves experience ischemia (17). This progression is both faster and more severe than that seen in cellulitis or erysipelas (18). If not addressed, NF can quickly progress to multi-organ failure, acute respiratory distress syndrome, renal impairment, coagulopathy, liver abnormalities, and generalized erythroderma (19).
Although the diagnosis of NF is primarily clinical, laboratory workup and imaging may be helpful. Surgical probing and frozen section biopsy are used for diagnosis of NF, but they are invasive and take time to complete. There must be a high index of suspicion for NF to move straight to surgery. Therefore, the most important first steps of medical management are probably the gram stain and cultures of both the blood and the wound, if one is present. This will help guide antibiotic therapy over the course of the disease. In addition, routine blood work such as a CBC and chemistry panels may be helpful.
Imaging can also be very useful in differentiating NF from cellulitis. Crepitus or soft tissue gas on plain x-rays are pathognomonic for NSTI. However, they are only found in 37%-57% of the cases (20). More recently, MRI and CT scans have been investigated to identify NF. Contrast enhanced images may show asymmetric thickening of the deep fascia and/or gas bubbles in the deep tissue. However, MRI may overestimate the extent of disease and intravenous contrast may be contraindicated in some patients in shock or with renal failure. In most cases, however, empiric treatment should be initiated as soon as possible, even prior to obtaining imaging results (21).
The mainstays of treatment for NF are intravenous antibiotics and surgical debridement. Generally, broad antibiotic coverage is necessary for empiric therapy. A study by Elliot suggested a combination of ampicillin, gentamicin, and clindamycin or ampicillin/sulbactam for broad coverage (4). Penicillin covers GABHS and most anaerobes. Clindamycin covers all anaerobes and it inhibits bacterial protein (toxin) synthesis in organisms that are not multiplying. However, anaerobic infections are frequently polymicrobial necessitating broad spectrum coverage. Specific antibiotic therapy can be employed after cultures return and bacterial sensitivities are known. Recent studies indicate clindamycin treatment produces better outcomes and decreases mortality in streptococcal disease. In fact, a combination of the two drugs is currently advocated in the literature (3,22). In the pediatric setting, there is no current recommendation for length of antimicrobial treatment, but it should be continued as long as there are signs of infection. Treatment for cellulitis is continued for at least three days after the acute inflammation has subsided (22). Therapy for NF should be continued for at least as long as for severe cellulitis.
Surgical debridement is recommended every day until the patient is stable and without signs of infection or sepsis. Debridement should cover the infected area as well as a margin of healthy tissue to prevent reoccurrence of infection. As a result, the patient may need extensive skin grafting to cover the debridement area. During recovery, frequent dressing changes are necessary. Unfortunately, scarring and disfigurement are very common after NF debridement and grafting. In addition, physical therapy and rehabilitation will be needed for those with extensive skin grafts (20).
Mortality is always worse if there is significant delay in therapy or inadequate surgical debridement. Unfortunately, NF is often diagnosed at a very late stage because the clinical presentation initially appears to be an ordinary cellulitis or wound infection. Therefore, management should begin as soon as possible with intravenous antibiotics and surgical debridement.
Hyperbaric oxygen (HBO) therapy has been evaluated as an adjunctive therapy. Treatment with HBO has not been examined adequately in randomized trials, but some studies have shown benefit in preventing the extension of NF. It may accomplish this by increasing the oxygen tension in the surrounding tissue (23). In fact, HBO has become standard treatment in clostridial myonecrosis (24). Unfortunately, HBO is difficult to obtain and is rarely utilized. Other management concerns are the systemic effects of NF. Organ system problems that need to be addressed may include respiratory insufficiency, transient renal failure, and blood pressure support.
Mortality in the literature ranges from 12% with early, aggressive treatment (1) to nearly 100% for those without surgical debridement (8). Prognosis depends most heavily on the patient's age. In one study, NF patients younger than age 35 had no fatalities. In contrast, mortality was 61% in the age group above 65 years. This difference may be explained by the various predisposing factors in the older group, such as diabetes mellitus. In fact, 62% of all NF patients had predisposing factors, but none were present in the younger group. However, the younger group was also more likely to have undergone surgery, which may indicate more intense therapy for the younger group. Other important factors impacting disease outcomes are the development of bacteremia, shock or hypotension, use of antibiotics other than clindamycin, or lack of adequate surgical debridement (8). Complications with toxic shock syndrome occurred in 50% of cases in one study (25). However, there was no correlation between increased mortality and specific M-serotype or the presence of SPE (streptococcal pyrogenic exotoxins) A or C (8).
1. The most common species of bacteria isolated from Type I NF is:
. . . . . a. Staphylococcus
. . . . . b. Streptococcus
. . . . . c. Bacteroides
. . . . . d. Clostridium
2. Which imaging modality is most useful in differentiating cellulitis from NF?
. . . . . a. Plain radiograph
. . . . . b. MRI
. . . . . c. CT
. . . . . d. Ultrasound
3. The virulence factor which has been found to protect streptococcal species from phagocytosis is:
. . . . . a. Streptokinase
. . . . . b. M-protein
. . . . . c. Streptococcal pyrogenic exotoxins
. . . . . d. Streptolysin O
. . . . . e. Hyaluronidase
4. Type III NF is most often caused by:
. . . . . a. Clostridium perfringens
. . . . . b. Group A beta-hemolytic streptococcus
. . . . . c. Bacteroides
. . . . . d. Campylobacter
5. First line treatment for streptococcal NF is:
. . . . . a. Erythromycin
. . . . . b. Gentamicin
. . . . . c. Doxycycline
. . . . . d. Penicillin
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Answers to questions
1.c. Bacteroides is the most common bacteria isolated in polymicrobial NF. Staphylococcus, streptococcus, and clostridium are also commonly found.
2.a. Plain films are routinely used to differentiate cellulitis and NF. MRI and CT are currently under investigation for utility, however, they are costly and time consuming. Answers b and c could be correct, but ultrasound (answer d) is not useful. If NF is suspected, surgical exploration is necessary and will yield the same information.
3.b. The M protein inhibits the activation of complement and prevents phagocytosis. The other virulence factors listed belong to the streptococcal species, but have different roles in causing infection.
4.a. Clostridium causes gas gangrene and crepitus, which characterizes Type III NF. The other bacteria listed are causes of Type I or Type II NF.
5.d. First line therapy for streptococcal NF is penicillin according to current guidelines. Unfortunately, one does not initially know that the NF is due to GABHS. Most anaerobes are penicillin sensitive. Adding clindamycin may be useful even if the organism is penicillin sensitive since it may inhibit protein synthesis (toxin production) in non-replicating organisms. For other organisms, anti-microbial therapy should be based on culture and sensitivity results when they are obtained.