Abstract
Necrotizing fasciitis (NF) represents a rapidly progressive, life-threatening infection involving skin, soft tissue, and deep fascia. An early diagnosis is crucial to treat NF effectively. The disease is generally due to an external trauma that occurs in predisposed patients: the most important risk factor is represented by diabetes mellitus. NF is classified into 3 different subtypes according to bacterial strains responsible: type 1 associated to polymicrobial infection, type 2 NF, generally associated to Streptococcus species, often associated to Staphylococcus aureus and, eventually, Type 3, due to Gram-negative strains, such as Clostridium difficile or Vibrio. NF is usually characterized by the presence of the classic triad of symptoms: local pain, swelling, and erythema. In daily clinical practice immune-compromised or neuropathic diabetic patients present with atypical symptomatology. This explains the high percentage of misdiagnosed cases in the emergency department and, consequently, the worse outcome presented by these patients. Prompt aggressive surgical debridement and antibiotic systemic therapy are the cornerstone of its treatment. These must be associated with an accurate systemic management, consisting in nutritional support, glycemic compensation, and hemodynamic stabilization. Innovative methods, such as negative pressure therapy, once the acute conditions have resolved, can help fasten the surgical wound closure. Prompt management can improve prognosis of patients affected from NF reducing limb loss and saving lives.
Necrotizing fasciitis (NF) represents a rapidly progressive, life-threatening infection involving skin, soft tissue, and deep fascia. It requires prompt surgical treatment, which is the mainstay of therapy and which has to be associated with appropriate antibiotic therapy. The condition progresses very rapidly if not treated, until septic shock, and is associated with a very high mortality rate. 1
Historical Roots
Hippocrates described the clinical presentation of an erysipelas disease complication. The description that he made reminds the framework for NF. 2 Only more than a thousand years later we would talk again about the disease: in 1783 a French physician, Claude Colles, described a condition quite similar to NF. 3 But the modern idea of fasciitis was born in 1871, when an American surgeon reported more than 2000 cases of gas gangrene, observed during American Civil War. Those patients presented a mortality rate of about 40%. 4
During the 20th century there were many reports of NF not just on limbs but also in abdominal wall or perineum.5,6 The term “necrotizing fasciitis” was, however, reported for the first time only in 1952 by Wilson et al, taking into account the clinical evolution of the disease. 7
Since the introduction of antibiotic therapy, NF occurrence as a complication of general surgery or traumas greatly reduced, while it became a rather frequent issue in the management of severe cases of diabetic foot (DF), especially when ischemia was present.8,9
Epidemiology
The Centers for Disease Control and Prevention estimates a prevalence of NF in the United States of about 500 to 1000 cases per year, and also in Europe the numbers are quite similar. 10 Throughout the world the reported prevalence is 0.40 cases per 100 000 population. 11 Elderly patients are usually more likely to be affected, and the male-to-female ratio is about of 3 to 1 and diabetes constitutes a major risk factor. 12 Despite the disease affecting different parts of the body, the lower extremity have been recognized to be the most common site of NF. Less affected are abdomen, perineum, and upper limbs. 13
Etiology
In the vast majority of cases NF occurs after a trauma. This generally consists of external injuries and, less commonly, surgical wounds. Abdominal NF can be subsequent to hernias, complicated diverticulitis of enteric perforation. Surgical wounds determine the appearance of NF usually at chest while limb diseases are generally due to external trauma. 14 External limb injuries, such as chest wounds, for its closeness to bone structures, are very frequently associated with osteomyelitis, further worsening the prognosis of these patients. 14
In Asia, abdominal NF has been described as a result of consumption of raw or undercooked sea food. 15
Clinical Predisposing Factors
Epidemiological studies have identified some conditions predisposing to the development of NF. Such conditions, in fact, whenever present, are strongly associated with the disease. These clinical states are, generally, not sufficient to determine the development of NF in the absence of a primum movens, but when present, they contribute with a synergistic effect to the development of NF. 15
The most important of these condition is, with no doubt, diabetes mellitus. Its prevalence, in patients suffering from NF, has been demonstrated to range between 40% and 60% percent. 16 Other associated conditions are reported in Table 1. 17
Clinical Condition Predisposing to Necrotizing Fasciitis. 17
From the analysis of factors predisposing to NF, it can be clearly detected that diabetes mellitus not only represents an independent risk predictor but is also often associated to other risk factors, such as renal failure, heart failure, hypertension, or macroangiopathy. Therefore, the diabetic patient has a very high risk to develop the disease and is hence very prone to develop NF, even after mild traumas. 18 Among these, distrectual ischemia and metabolic immunopathy seem to play a major role in predisposing the patient to NF and in worsening its clinical course.14,19
Classification
NF can be classified into 3 different types according to the bacterial strains responsible for the infective process. 20
Type 1 NF, known as the polymicrobial form, is due to multiple bacteria: generally 2 or 3 in association even if the average of number of pathogens involved in the infection has been reported to be as high as 4.4. Usually the microbiological cultures are able to identify both aerobic and anaerobic microorganisms. This type of NF affects immunocompromised host or patients affected by chronic disease: the ideal victim is the patient suffering from diabetes mellitus, preferably uncontrolled. 21
Type 2 NF, otherwise called the monomicrobial form, affects usually younger healthy people, despite the possibility that it could occur at any age, and is generally located in the lower extremities. It involves β-hemolytic Streptococcus bacteria of group A (especially Streptococcus pyogenes). In particular, this bacterium produces types 1 and 3 Streptococcal M proteins, exotoxins A and B, and mitogenic factors. 22 These compounds cooperate in stimulating the immune system: this results is a cytokine “storm” with subsequent severe infection, and shock and multiple organ failure may intervene in most serious cases. 23 Tissue destruction can be further increased by other proteases and proteolytic enzymes produced by the same strain of Streptococcus species. 21 Type 2 NF, despite being monomicrobial and therefore generally due to the presence of a single bacterial strain, can be further worsened, in some cases, by concomitant infection by Staphylococcus aureus. This bacterium releases toxins able to determine leukocyte destruction and tissue necrosis. This condition typically leads to fulminant NF forms. This condition is very hard to handle, especially if the Staphylococcus strains are methicillin-resistant, whose occurrence nowadays ranges from 10% to 30% of all cases but is in sharp increase. These patients usually develop toxic shock syndrome and thus present a very unfavorable outcome. 24
Eventually, type 3 NF is a less common monomicrobial form generally due to Gram-negative bacterial strains, such as Clostridium species, Enterobacteriaceae (Escherichia coli, Pseudomonas species, Klebsiella species) and, more rarely, Vibrio vulnificus and Aeromonas hydrophila. 25 This form usually originates from external injuries or surgical wounds and sometimes, especially when related to rarer microorganisms, can lead to fatal sepsis more rapidly than in type 2 NF. These bacteria, especially Vibrio, produce several very powerful virulent factors. 26 This form of NF can be generally found in patients presenting a history of chronic illness: sometimes diabetes mellitus but more often alcohol-related cirrhosis, chronic renal failure, or gouty arthritis. 27 In particular, these disease are able to elicit alterations in neutrophil and macrophage function. The result is increased immunosuppression. In particular, in cirrhotic patients, due to shunting through the portal-systemic circulation, these microorganisms cannot be phagocyted by hypo-functioning Kuppfer cells and can so freely access the gastrointestinal tract. 28 Clostridium species infection is instead more frequent among drug addicts. 29
In Table 2 we report the distribution of different NF subtypes of a cohort of 54 consecutive patients, affected from NF, followed in our diabetic foot clinic in the last 4 years.
Prevalence Observed for the Different Subtypes of Necrotizing Fasciitis in a Cohort of 54 Consecutive Cases Followed in Our Diabetic Foot Section in the Last 4 Years.
Pathophysiology
NF starts in hypodermis and superficial fascia while the more superficial sheets, where the trauma originated, usually are not involved in the initial stages of the development of NF. The interaction between bacterial virulence capacities and host reactions to the infection explain the subsequent evolution of NF. The enzymes produced by bacterial strains first of all destroy fascia and hypodermal layers, especially fat, thus determining necrosis. 30 In these layers, a high number of feeding vessels is contained; bacteria overrun these little vessels and occlude them by thrombotic phenomena. The derived ischemia is the main cause of the pain usually felt by patients. The same thrombosis can be detected also in lymphatic vessels determining lymphangitis and subsequent lymphadenopathy for nodal infection localization. The bacterial products determine eventually edema that enhances the ischemia of arterial vessels and involve nerve branches. Both mechanisms greatly increases pain like in meningococcal septicemia-related NF. In other cases, especially in diabetic patients affected from peripheral somatic neuropathy, the nerve involvement originates from hypoesthetic skin and subcutaneous areas, thus reducing or even eliminating pain. 31
In all NF cases fascial and hypodermal involvement is greater than cutaneous, so miming a not severe disease, and in less experienced centers, seriously delays the diagnosis. 31
Diagnosis
Necrotizing fasciitis is a rapidly progressive life-threatening infection. Therefore, an early diagnosis often is lifesaving. Furthermore, if NF affects the limbs, an accurate diagnosis can prevent an amputation. This is why it is important to stress that the diagnostic methods should confirm a diagnosis that in most cases can be done on the basis of clinical objectivity. 32
Clinical Presentation
The presence of NF is usually characterized by the presence of the classic triad of symptoms: local pain, swelling, and erythema. 15 Unfortunately, in daily clinical practice it is not so easy. The disease encompasses a wide range of severity and scarce evidence of clinical symptoms. 14
The difficulty in the diagnosis of NF at the first access of the patient in the emergency department is so strong that a high percentage of patients are misdiagnosed. 33 The incorrect diagnosis is usually posed in cases of patients with atypical symptoms, or if the inflammatory response is limited. This happens in immunecompromised patients, in neuropathic diabetic patients, or after the use of nonsteroidal anti-inflammatory drugs, most often self-administered by the patients. 33 These cases have been associated to a severe increase in mortality rates, which score the impressive figure of 50% of late diagnosed patients, and to a more proximal needed level of amputation in case of the lower limbs NF. 33
To help in correctly diagnosing NF, symptoms have been classified as early and late ones. 34 In the first category symptoms usually include erythema, local warmth, edema, and skin sclerosis. In this phase the patients generally complain pain just on the site of the wound, thus increasing the difficulty of diagnosis. In the later stages of NF the patients begin to present intense pain, not explainable, and much more diffuse than apparent tissue involvement, and also symptoms of general toxicity. We can find dehydration, confusion, dizziness, diarrhea, weakness, nausea, and vomiting. In the clinical examination of the patient in this phase appear the vital signs abnormalities: tachycardia, hypotension, fever, and tachypnea. 16
The cutaneous involvement, initially not well demarcated, may progress to blisters and bullae. These formations in earlier stages contain serous fluids while after that may become hemorrhagic. Further on it can be observed as necrosis of the skin. The limits of tissue involvement are usually not well circumscribed, and rarely present is lymphangitis because the process is located in the deep fascia rather than in the skin. 35 Due to enzymatic and toxin action, the tenderness at palpation goes beyond the cutaneous interest limit. To this pattern can be associated, in case of Clostridium perfringens or other anaerobic bacteria infection, gas formation, which can lead to crepitus in the overlying skin. 36
From a clinical point of view, the disease can be classified into 2 different presentations: a fulminant form and a subacute form. Both forms present the aforementioned distinction phases but the evolution to the later stages is much faster in the fulminant presentation. At first examination the patient is already critically ill and presents signs of septic shock and multiple organ failure. Since onset the pain seems to be disproportionate to the clinical findings. 37 Conversely, the subacute form has a slightly slower clinical course, up to a few days. At the beginning of its evolution the clinical characteristics are just the ones related to the condition leading to infection. Typically for lower limbs, which represent the more common site of subacute NF, the patient presents a skin infection, for example, folliculitis, abscess, or gangrene, or a complicated and dehiscent surgical wound. At this site the patient usually complains pain that can be strongly reduced in case of nerve infectious involvement, peripheral neuropathy, typical of diabetes, and eventually if the patient has used nonsteroidal anti-inflammatory drugs. The evolution is the one previously described in the subacute form, but signs and symptoms of multiple organ dysfunction and septic shock in this case appear more slowly, and to be fully expressed requires generally 2 or 3 days. 38
Bedside Tests
In case of equivocal diagnosis, some tests, easy applicable, have been identified that can increase the suspicion of NF.
The first is the so-called “finger test.” The exam procedure, performed under local anesthesia, consists in a 2 cm incision that has to reach the deep fascia. After that there is a gentle probing of the index finger throughout the fascia. The test is considered positive in case of lack of bleeding, lack of tissue resistance to blunt finger, and the presence of pus material, which is much thinner than normal pus 39 : the so-called “dishwater pus.” This is due to the lysis of neutrophils caused by the lecithinases and other bacterial toxins. 40
Another useful test, always to be reserved for questionable diagnosis, is the “frozen biopsy.” This consists of an incisional biopsy down to the fascial level. Immediately after the withdrawal the sample gets frozen. Then the frozen biopsy is analyzed for Gram stain and culture examination. 35
Laboratory Tests
In the earlier stages of disease, usually laboratory analysis are not able to add any value to clinical findings. We might expect for leucocytosis, increased level of blood urea nitrogen, or serum creatinine and creatine kinase. But, unfortunately, these parameters are often abnormal in consideration of preexisting chronic disease or patients’ comorbidities. Also, inflammatory index, such as white blood cell count, erythrocyte sedimentation rate, or C-reactive protein often are not increased for the concomitant immunosuppressive state presented by the patient. The typical immunosuppressed condition of a patient affected from NF is diabetes mellitus, especially when not compensated. 41
In the final stages of the disease, during the development of multiple organ failure, chemical analysis can become more useful and detect severe liver and kidney disorders, elevated serum creatine kinase level, and coagulopathy. These conditions signal the fast evolution to septic state. 21
Imaging Tests
Radiological studies have to be considered just as further confirmation for doubtful cases; for the high incidence of false-negative radiological images these methods cannot be used to exclude NF. Any eventual delay in obtaining radiological images should not delay surgical procedures, 42 though plain radiography is able to identify gas formation in soft tissue, a characteristic strongly suggestive of Clostridium perfringens infection. 43 It is not to be considered however in daily use due to its low sensitivity and specificity levels. 44
More effective imaging methods, such as computed tomography (CT) and magnetic resonance imaging (MRI) might be more helpful for physicians, despite their high costs making them less easily applicable. 45 These exams can identify the extent of tissue involvement and presence of air in skin layers. 46 MRI, however, can be too sensitive because it is not capable of differentiating NF from cellulitis and usually overestimates deep tissue engagement. 23
Eventually a method potentially very useful although not widely used is ultrasonography. Its aim is to identify subcutaneous gas that should appear as hyperechoic foci in the site of infection associated to reverberation artefact and dirty shadows. 47 The potential of this method is secondary to the experience of the operator, and this greatly hinders its use in emergency departments in order to perform a diagnosis of NF. 47
Diagnostic Scores
As in many medical conditions, also for the management of NF some scoring systems have been proposed. As usual the aim of these systems is to allow earlier diagnosis and to help stratify patients’ severity and thus appropriate treatment. 48
The most important of score proposed for the management of NF is the LRINEC Score (Laboratory Risk Indicator for Necrotizing Fasciitis) proposed by Wong et al. 41 The system, as reported in Table 3, consists of a sum of scores assigned to C-reactive protein, white blood cells count, total hemoglobin, serum creatinine, sodium, and glucose level. 40 The possible maximum score is 13, and a score higher than 6 has been demonstrated to be strongly suggestive for NF, with a 92% positive predictive value and a 96% negative predictive value. 49
LRINEC Scoring System as Proposed by Wong and Colleagues. 41
Abbreviation: LRINEC, Laboratory Risk Indicator for Necrotizing Fasciitis.
Obviously clinical judgement remains the milestone of NF diagnosis. Thus, scoring systems, despite sometimes being very helpful, does not preclude therapeutic interventions made necessary by the clinic evolution of the patient.
Hystopathological Examination
In selected cases, to confirm a suspect diagnosis of NF it can be useful, as mentioned above, to carry out a frozen section biopsy. To confirm the presence of NF, the histopathological examination should show coagulation necrosis of superficial fascia and which moves up to subcutaneous fat and, occasionally, deep fascia. While the bacterial infiltration is not always a required issue, in the analyzed section there should be present the signs of an inflammatory response: inflammatory cells, thrombosis of blood vessels, and necrosis of subcutaneous glands. 50
Differential Diagnosis
NF is often difficult to diagnose in the early stages because its clinical manifestation comprises many unspecific signs, for example, tenderness, pain, swelling, erythema, that are present in all soft tissue infections, and also in those that are less severe than NF, such as erysipelas and cellulitis. 51 The difference between the pathologies lies in the depth of the involved structures. In fact, while in other soft tissue infections the pathological process is restricted to dermis and epidermis, NF involves fascia and muscle. Also cellulitis can rarely engage the fascia but just its most shallow part. 1
Wide epidemiological studies have identified many factors that, if present, may increase the likelihood of diagnosis of NF than other soft tissue infections: the most important are tachycardia, hypotension, tachypnea, presence of bullae, edema, and sensory motor deficit. 46
The differentiation between the different pathological conditions is very important because they require different therapeutic approaches and the timing of therapies largely vary. 52
Guidelines Conclusion
The guidelines published by Infectious Disease Society of America recognizes 5 milestones to diagnose the involvement of deep tissue layers that can differentiate NF from cellulitis or other soft tissue infections:
Failure to respond to initial antibiotic therapy
Hard, wooden feel of subcutaneous tissue extending beyond the area of apparent skin involvement
Systemic toxicity, often associated with altered mental status
Bullous lesions
Skin necrosis or ecchymoses 53
Regarding diagnostic methods, actually the combination of surgical exploration, microbiological analysis, and histopathological analysis can be considered the gold standard to confirm a clinically posed diagnosis of NF. 42
Therapy
Antibiotic Treatment
The pathological process of development of NF includes the development of local ischemia and thus of hypoxia. These conditions compromise the achievement of an adequate blood supply and therefore antibiotics delivery to the infection site is also strongly compromised. For these reasons antibiotic therapy alone, even if perfectly focused on pathological bacterial strains responsible for NF, is not effective for the management of the condition. Despite this, antibiotic therapy represents a cornerstone for NF care, besides an early surgical therapy. 54
The first step, when there is suspicion of NF, is the introduction of broad-spectrum antibiotic drugs. The choice of the most appropriate antibiotic molecule depends, first of all, on the classification of NF. 54
For type 1 NF, the polymicrobial form, we need coverage for Gram-positive rods and anaerobic bacteria. For the former it should be usually chosen ampicillin-sulbactam while for the latter the best options are represented by metronidazole, clindamycin, or carbapenems. For patients referring a recent history of hospitalization or antibiotic therapy, we should also select a broad-spectrum Gram-negative coverage. In such cases ampicillin-sulbactam, piperacillin-tazobactam, third- or fourth-generation cephalosporins or carbapenems are usually used. 55
For type 2 NF, we need to cover Streptococcus species, usually Pyogenes and Staphylococcus aureus are generally associated. In case of methicillin-sensitive Staphylococcus aureus first- or second-generation cephalosporins can be used. If there is suspicion of the presence of methicillin-resistant Staphylococcus aureus, the chosen antibiotic molecule should be vancomycin, or daptomycin and linezolid if the bacterium is eventually vancomycin-resistant. 56 Some recent studies have analyzed the role of clindamycin as an alternative to penicillin antibiotic in the management of streptococcal infections. Clindamycin inhibits bacterial protein synthesis and is not subjected to inoculum effect of a lot of slow-growing microorganisms that present reduced expression of penicillin-binding proteins. 21 Recent studies have supposed a superiority of clindamycin to penicillin in overwhelming streptococcal infections 56 ; it is however important to note that the increasing prevalence of clindamycin-resistant Streptococcus pyogenes strains may seriously hamper the treatment of severe streptococcal infections. 57
Eventually type 3 NF should be treated with clindamycin and penicillin together, to cover Clostridium species. Instead, if Vibrio infection is probable, tetracyclines and third-generation cephalosporins should be promptly started. It has been actually demonstrated how the early use of these antibiotics in Vibrio-related infections significantly increased the survival rate of patients. 55
The initial antibiotic therapy dose should be adapted on the basis of clinical characteristics of the local and systemic states, for example, reduced in case of chronic renal failure. As soon as the microbiological culture is available, the antibiotic should be focused on the bacterial species detected. The therapy must be continued until the process is fully controlled, for at least 48 hours after clinical and hemodynamic stabilization and, if possible, up to 5 days after local signs have been resolved. 58 The mean reported antibiotic duration ranges from about 4 to 6 weeks. 58
Surgical Treatment
An extensive emergency surgical debridement represents the mainstay for the treatment of NF. Surgical intervention, including debridement, necrosectomy, and fasciotomy must be put in place as soon as the disease has been diagnosed, and in any case within 12 hours after admission of the patient. 59 An early surgical procedure represents the first barrier to the spread of infection throughout the fascial plane. 60
Only rarely is a single surgical procedure sufficient to solve the disease: more frequently the debridement has to been repeated during the next 24 hours, the so-called “second look,” and sometimes again later. Patients with NF may require up to 40 consecutive sessions of surgery. 61
The extent of debridement depends both on the severity of the condition and on the segment with tissue necrosis. The debridement procedure should be extended to where healthy tissue is found, to healthy bleeding margins, beyond the infected region. A careful search and maintenance of salvageable soft tissue is mandatory. Even leaving only a minimal amount of actively infected or necrotic tissue might allow an insidious resumption of the disease. 62 After the section of the fascia usually a release of pus and hemorrhagic fluids follows. As mentioned above, the purulent material is usually less thick than usual for the presence of proteolytic bacterial enzymes. After pus release, an incision should be made to keep the wound open and allow drainage and removal of further necrotic fragments. 60
This procedure can be life-saving, and both the clinical evolution and the mortality risk are strictly associated to the timing and extent of the first surgical debridement. Delaying the first surgical debridement beyond 24 hours from the onset of symptoms increases the mortality rate by about 9 times. 16 Regarding the extension of procedure, a very restricted primary surgical debridement has been associated with a 7.5 times greater risk of death. 63
Special considerations are necessary for NF of the limbs. In these cases the amount of tissue that should be removed is quite difficult to define due to different involvement of skin and subcutaneous layers. Also, apparently healthy soft tissues present often extensive vascular microthrombosis and thus the risk of full-thickness necrosis is quite high. 64 Clinicians should accurately evaluate the adequate extension of the debridement keeping in mind that lower limb NF frequently need major amputations. Despite amputation not reducing mortality rates, it has been demonstrated to be effective in reducing the rate of re-intervention in NF patients. Amputation is considered a safer procedure than the extensive conservative debridement, and usually determines less severe blood losses. 65 Therefore, in fragile patients, with hypotension or shock, major amputation can be considered a valid option. The indications for limb amputation are today well defined: the most important is an extensive necrosis of soft tissue that involves underlying muscle and presents a rapidly progressive infection. 66 Other conditions in which the amputation is a considerable alternative are the following: presence of concurrent medical disease that determines increased mortality rate risks, the presence of toxic or cardiogenic shock, and eventually the presence of vascular impairment, a condition closely associated to the disease, especially in diabetic patients. 65
Systemic Management
Patients with NF usually suffer from hemodynamic instability. It is of paramount importance that, as much as possible, this condition be stabilized before surgical intervention. Stabilizing the patient, if feasible in an intensive care unit, could actually increase the survival rate of patients. 16
From the first day of a patient’s admission nutritional support is required to replace lost proteins and fluid through large wounds or due to toxic shock. Metabolic needs are quite similar to those presented in case of major trauma or burns, so twice the basic caloric intake. In diabetic patients, insulin should be promptly adapted to allow achievement of good glycemic profile without increase hypoglycemia risk. And, eventually, therapy with oral hypoglycemic agents must be shifted to insulin, which should be administered intravenously up to the end of the surgical procedure, and then converted to a multiple injections scheme. 16
Innovative Approaches
The use of negative pressure wound therapy (NPWT) for fastening the closure of NF surgical wounds is nowadays increasing. 67 NPWT have been demonstrated to exert effective cleaning and removing the exudate, thus helping the production of granulation tissue after the acute therapy. 68
In some cases of type 2 NF, to reduce the action of streptococcal toxins, intravenous immunoglobulins have been used. 69 Reports of the beneficial effect of this therapy in severe streptococcal infections are nowadays available, but this option has yet to be confirmed with randomized studies. 70
Recently the use of hyperbaric oxygen therapy has been proposed, but its usefulness as adjunctive treatment has not yet been definitively proven. 42
Prognosis
The mortality rate, approximately 100% in the absence of treatment, has been reduced in recent years due to the introduction of efficient therapies. The mean reported rate is about 22%. 15
Recent studies have tried to identify predictors of mortality in NF patients. The development of toxic shock syndrome, as expected, worsens the prognosis in these patients. 2 Elderly patients are not only more prone to be affected by NF but also are associated with worse prognosis. 35 The presence of chronic renal failure has also been associated with an increase in mortality rate. 71 Also, the evolution of a clinical condition could allow the focus on possible predictors of mortality: the appearance of hypotension, systemic acidosis, low hematocrit or albumin levels, and the development of bacteremia have all been associated with an increase of mortality rate. 25 Eventually, while the use of clindamycin, among antibiotics, could promote a better survival, 65 the use of nonsteroidal anti-inflammatory drugs to treat patients’ pain have been associated with a significantly increased mortality for related delay in the diagnosis of the condition. 72
Discussion
NF represents a severe life-threatening condition associated with a very high mortality rate.
The diagnosis of NF is based on the clinical findings and on dramatic systemic signs developing within hours from onset. Diagnostic imaging and further evaluation can be very useful in equivocal cases but their timing should not delay surgical procedure.
NF of limbs, in particular of lower limbs, is one of the most important indication to urgent lower limb amputation. Therefore, its accurate management is not only a life-saving therapy but also a limb-saving procedure, thus preventing a major amputation. The cornerstone of this management consists in early radical surgical debridement: just surgically removing all necrotic tissue and infection foci prevents the further spread of the infection process. Antibiotic therapy, since the beginning of the treatment, represents a basic measure to help control infection. New therapies, such as NPWT, can help secondary intent healing of surgical wounds left open at surgical moment to ensure drainage and to prevent compartmental syndrome development.
Our experience speaks of a higher prevalence of NF in DF, compared to that found in the literature, possibly due to a selection bias and to the reference level of our diabetic foot clinic. In Figures 1 to 4, we report relevant clinical cases recently followed in our clinic. Despite these high rates, we observed how, when promptly and aggressively treated, NF has a relative good prognosis and is not associated with an excess of limb loss and death. An early diagnosis and prompt surgical treatment are the cornerstone of the therapy of NF in diabetic foot.
NF due to Clostridium difficilis. (A) and (B) show the condition of the foot at first patient admission: the NF had spread from a plantar neuropathic ulcer complicated with osteomyelitis; (C) The findings 48 hours after first surgical debridement with amputation of the fourth ray and opening of the lateral compartment of the leg; (D) The picture after the second surgical look; (E) The application of NPWT; (F) the condition after 7 days of NPWT, at patient discharge.
NF due to streptococcal infection. (A) The clinical findings at onset of the condition; (B) and (C) the operatory room scenario, with the involvement of the deep compartments of the midfoot and the spreading of infection proximally.
NF due to Pseudomonas aeruginosa. (A) The clinical findings at onset of the condition; (B) The first postoperative day clinical condition.
Polymicrobial NF complicating a first-toe amputation for gangrene done in another hospital 2 weeks before. Because of nonhealing the patient was referred to our hospital for a second opinion. (A) and (B) The clinical findings at first admission; (C), (D), and (E) The clinical condition 5 days after surgical debridement and fasciotomy of the leg.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.