Fournier’s Gangrene Diagnosis and Treatment: A Systematic Review

Fournier’s gangrene (FG) is a perineal and abdominal necrotizing infection. It is most commonly found in middle-aged men with comorbidities such as diabetes mellitus. Initial symptoms are often indistinct and can rapidly progress to overwhelming infections with a relatively high mortality rate. It is crucial to make a prompt diagnosis so that the patient receives appropriate treatment. Given the importance of the identification of FG, we explored what were the most common signs and symptoms associated with FG, as well as distinguished the gold standard treatment. This systematic review utilized articles identified exclusively through PubMed using key terms such as Fournier’s gangrene, signs, symptoms, and treatment. A total of 37 studies, including a total of 3,224 patients (3,093 males and 131 females), fit our inclusion parameters for relevance that included either the most identifiable presentation of FG or the most effective treatment. From our search, the most common clinical presentation was scrotal and labial pain, fever, abscesses, crepitus, erythema, and cellulitis. Diagnosis is made from clinical findings in conjunction with imaging. The gold standard for treatment was found to be a combination of surgical debridement, broad-spectrum antibiotics, and the administration of intravenous fluids. Further, patient survival was found to be directly related to the time from diagnosis to treatment when they underwent surgical debridement. The importance of early identification for improved outcomes or survival highlights the need for further studies or measures to enhance the identification of the signs and symptoms of FG.


Introduction And Background
In the United States, Fournier's gangrene (FG) is a rare and fatal form of necrotizing fasciitis, with an incidence rate of approximately 1.6 per 100,000 males [1]. Even with aggressive treatment, the current mortality rate for FG is approximately 40% [2], with literature estimates ranging from 20% to 80% [3]. FG is a rapidly spreading infection that spreads through the superficial and deep fascial layers in the perineal, genital, or perianal regions, causing multiple organ failure and septic shock. Jean Alfred Fournier, a French venereologist, was the first to discover it in 1883 [4,5]. FG is considered to be a polymicrobial infection caused by multiple organisms, including aerobic and anaerobic species such as Escherichia coli and Bacteroides fragilis. These microbes collaborate to release enzymes that cause tissue necrosis [6]. The bacterial organisms that cause this necrotic infection release collagenases, which cause rapid tissue destruction at a rate of one inch per hour [3], allowing the infection to quickly spread from the genital region to the anterior abdominal wall and vital organs [7].
Even those who survive, suffer from sexual and urological disabilities, with debridement often necessitating multiple reconstructive surgeries [3]. Furthermore, these surgeries frequently necessitate tissue grafting as a means of reconstruction. This is a problem in immunocompromised patients who are unable to accept skin grafts and suffer from poor wound healing [8]. Although FG can affect people of all ages and genders, it is most common in men between the ages of 30 and 60 [9]. Advanced age is a risk factor for FG [2]. FG can develop in patients with no medical history, as well as in those with comorbidities such as diabetes, alcoholism, atherosclerosis, peripheral arterial disease, malnutrition, prostate cancer, human immunodeficiency virus (HIV) infection, leukemia, and liver diseases [10]. Patients with multiple comorbidities are more likely to develop FG and have worse outcomes [2]. The importance of early detection and aggressive treatment in FG recovery cannot be overstated [11].
In this review, our goal was to collect data on the clinical signs and symptoms of FG in the emergency department because early detection is critical to survival. In addition, we examined the most common treatment protocols for initially infected tissue remediation and subsequent assistive rehabilitation procedure.

Review
Methodology 1 1 1 1 1 This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [12]. A review of the literature was done in the PubMed database for articles from 2016 to 2021 with the keywords "Fournier's gangrene" AND (symptom* OR sign OR present* OR identif* OR display OR treatment) on June 12, 2021. Non-English articles irrelevant to FG were not included. Studies investigating other types of necrotizing fasciitis were also excluded. Included studies addressed the signs, symptoms, patient presentation, and identification of FG by the hospital staff. Further, articles that reviewed treatments, prognoses, and outcomes of patients diagnosed with FG were included in this study, as shown in Figure 1 [12]. Studies published in the last five years examining FG were included. We included full-text case studies, systematic reviews, case reviews, literature reviews, retrospective reviews, and original studies. Duplicate studies and books were not included in the review. Screening of the literature was done as described in the PRISMA statement [12].
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-analyses; FG: Fournier's gangrene

Results
Our search yielded 223 articles based on the applied criteria and filters. After screening and assessment of the results based on inclusion criteria and study objectives, 37 articles were included for the presentation, symptoms, or treatment of FG [2,[5][6][7][10][11]. In these included articles, a total of 3,224 patients were evaluated, including 3,093 males and 131 females. The review indicated that the main symptoms were scrotal and labial pain, fever, abscesses, crepitus, erythema, and cellulitis. The gold standard for treatment was found to be emergent surgical debridement, broad-spectrum antibiotics, and the administration of intravenous (IV) fluids [2,[5][6][7][10][11].

Associated risk factors
Several modifiable and nonmodifiable risk factors have been linked to FG [2]. Modifiable risk factors are variables that can be changed or adjusted by the patient, either through pharmacotherapy or lifestyle changes. Chronic diseases such as diabetes, substance abuse, and others fall into this category. On the other hand, nonmodifiable risk factors, such as a patient's age, cannot be changed. In a study of 55 patients with FG, 52.7 % of the patients had pre-existing comorbidities such as diabetes, IV drug use, liver failure, and immune impairment [2,43]. Although the exact mechanism involved in diabetes leading to FG is unknown, it has been suggested that the use of sodium-glucose co-transporter-2 inhibitors may be to blame [44].
Furthermore, due to protein glycosylation and diabetic neuropathy, people with diabetes are more likely to develop lesions. The increased risk of infection in IV drug users is thought to be due to the opportunity for microbial organisms to breach intact skin during needle insertion. Pathogens that would normally be unable to penetrate the skin can be rapidly introduced into deeper tissue via needles, causing various pathogenic processes.
Furthermore, patients with compromised immune systems are less likely to be able to clear bacterial microbes once they have been introduced. Immunosuppressive medications, underlying disease processes such as cancer and HIV, and old age can contribute to an immunocompromised state. Immunosuppressive drugs are used to treat various illnesses, including cancer and autoimmune diseases. They are also administered before organ transplantation.

Evaluation of Fournier's gangrene
Physical findings: FG has an insidious onset, with 40% of patients presenting with no symptoms, which makes early detection crucial [5]. Pain in the genital or perianal regions, with little to no visible cutaneous damage, is one of the early symptoms [45]. More noticeable features of infection emerge as FG progresses through the deep facial planes. The skin tones of erythematosus patients become dusky and darker. Subcutaneous crepitus with a putrid odor (due to anaerobic microbial activity) may appear toward the end of the infection. Eventually, the infection manifests as gangrene, which has more obvious physical signs [46]. Due to a separate blood supply from the penis and scrotum, the testicles are often spared [47]. In a study, scrotal swelling was the most common symptom in 79% of cases, followed by tachycardia (61%), purulent "dishwater" exudate from the perineal region (60%), crepitus (54%), and fever (41%) [48].
Clinical scoring systems: In a clinical setting, scoring methods are used to determine the likelihood of mortality and to direct physicians to the best treatment options. The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) and the Fournier's Gangrene Severity Index (FGSI) are two scoring tests that are used. Biomarkers such as serum glucose, C-reactive protein, sodium, potassium, creatinine, heart rate, and body temperature are used in these tests. The LRINEC scale ranges from 0 to 13, with a score of 6 or higher indicating necrotizing soft tissue infections (NSTIs). The FGSI can be used in an emergency to determine the likelihood of survival or death by rating nine clinical parameters on a scale of 0 to 4. In patients with FG, a score of greater than or less than 10.5 indicates a 96% chance of death or survival, respectively [46].
Imaging: To visualize the presence of air and the spread of infection, various imaging techniques can be used. Because 90% of FG patients have subcutaneous emphysema, standard radiography is a quick and valuable tool [5]. Another tool that can be used to make a quick diagnosis is ultrasonography (US). The presence of subcutaneous gas in the perineum and the scrotal area appears as a "dirty" acoustic shadowing on US imaging [48]. The most specific imaging modality for determining the extent of infection is computed tomography (CT), which allows surgical teams to plan debridement accordingly [49]. When other imaging modalities are insufficient to determine the extent of infection, magnetic resonance imaging (MRI) is used [48]. Although MRI can aid in the diagnosis, its utility is limited due to the rapid progression of FG and should not be used to postpone surgical interventions [48].

Urgent Surgical Debridement
It is worth noting that successfully managing FG is extremely difficult. This is due to late diagnosis caused by nonspecific symptoms and the rapid progression of necrosis. Hemodynamic stabilization, parenteral broad-spectrum antibiotics, and urgent surgical debridement, in which all necrotic tissue is removed until viable tissue is identified, are the main principles of therapy in FG treatment [50]. According to the findings of a clinical review, it is critical to remove necrotic tissue as soon as possible to prevent infection progression [5]. On the other hand, surgical debridement frequently affects large areas and results in significant deficits. In a retrospective study of 72 patients with FG, a delay in surgical debridement was associated with a significant increase in mortality [51]. Consequently, time and extensive debridement play a large role in a better FG prognosis.

Hyperbaric Oxygen Therapy
Hyperbaric oxygen therapy (HBOT) can be a viable adjunct for a better prognosis in FG treatment [5]. This is based on the pathogenesis of FG; the hypoxia caused by arterial vessel thrombosis leads to ischemia and necrosis, creating a favorable environment for anaerobic bacteria to grow. Therefore, if an environment with optimal oxygen is created, bacterial proliferation slows down. In addition to early surgical debridement, the use of this treatment modality is indicated in patients who are unresponsive to conventional therapies such as sterile honey and maggots. However, it is essential to note that some studies have reported an increased mortality rate in patients receiving HBOT [52]. This can be attributed to the fact that patients with more severe presentations were administered HBOT. Thus, there is a risk of bias. It may be challenging to correlate the two (increased morbidity and HBO therapy) because of the rarity of the disease, its intrinsic complexity, and the limited availability of HBOT chambers.

Negative Pressure Wound Therapy or Vacuum-Assisted Closure
After surgical debridement of all the necrotic tissue, vacuum-assisted closure (VAC) can be used to promote wound healing physiologically [23] while reducing the need for reconstructive surgery with skin grafting in the future [14]. There is also evidence to suggest that it can speed up tissue healing [24]. VAC is based on the negative pressure vacuuming that leads to the increase in blood supply and inflammatory cell migration to the affected area. This leads to granulation tissue formation, as well as the clearance of bacterial contamination, toxins, exudates, and debris [23]. VAC therapy involves applying a sterile open-cell foam sponge to the wound and adding transparent adhesive drapes and a noncollapsible tube, which is connected to a portable pump that provides negative pressure to this air-tight environment of the wound [24]. Because of the clinical benefits of VAC compared to traditional wound dressing, it is now being used more frequently than traditional wound dressing, which requires multiple changes, and, in some cases, requires subsequent surgeries to clear the necrosis. Knowledge of the predisposing and risk factors on the initial presentation can allow performing diverting procedures such as hemodialysis before it is too late.

Discussion
FG, a rapidly progressing, high-mortality condition, is frequently misdiagnosed because of the nonspecific nature of the symptoms. Therefore, it is crucial to identify the pathological process as soon as possible to ensure the best possible recovery. A clinical diagnosis is made using a combination of physical findings, standardized scoring, and imaging, as well as the patient's risk factors.
Diabetes mellitus is the most common risk factor for FG, which typically manifests in men over the age of 55. Although FG has traditionally been portrayed as a disease primarily affecting men, identification of FG in female patients has improved [2,42].
FG begins with symptoms such as fever and perineum edema and is occasionally accompanied by disproportionate pain in relation to how the tissue appears. Crepitus, purulent discharge, and necrosis become distinct diagnostic features of necrotizing fasciitis as the infection spreads. Scoring with LRINEC and FGSI can be a useful tool in determining survivability in FG patients.
The presence of various biomarkers is scored by assigning a numerical value, with values above a standardized threshold indicating a higher risk of death [42]. Subcutaneous crepitus, a distinguishing feature of anaerobic microbial infections, can be detected using imaging techniques such as radiographs, US, CT, and MRI. Imaging can also help the surgical team determine the extent of the spread [48].
Once the diagnosis has been confirmed, immediate surgical intervention is required. The foundation of all FG treatments is a combination of surgical debridement to remove necrotic tissue and broad-spectrum antibiotic administration [5]. The rate at which a patient receives surgical treatment has a direct correlation with survival. Supplemental HBOT treatment can help stop bacterial growth, but it has also been shown to have a negative impact on disease prognosis if surgical intervention is delayed. After the surgery, recovery from a major procedure presents new challenges and may necessitate multiple wound dressings, skin grafts, and plastic surgery. Negative pressure wound therapy and VAC are two postsurgical treatments that improve wound healing by encouraging new blood vessel growth and immune cell migration [14]. All the studies included in this review are presented in Table 1.

Limitations of the study
While identification is improving in female patients, they may continue to be under and misdiagnosed as a majority of studies used in this review focus on signs and symptoms in males. Further, while early diagnosis and prompt surgical intervention are more likely to lead to a better outcome, FG continues to have high morbidity and mortality rates, and favorable outcomes are not guaranteed.

Conclusions
Necrotizing fasciitis, such as FG, is a life-threatening infection and necessitates immediate medical attention. Given the rapid progression of this infection, it is critical for physicians to rapidly identify vulnerable populations at high risk of developing this infection and recognize the clinical presentation to correctly diagnose the patients at an early stage. This systematic review found that the most common clinical presentations were perineal pain, erythema, cellulitis, fever, abscesses, and crepitus. Patients may present with many or only a few symptoms depending on the stage of infection. Our search found a range of treatment options, including HBOT and less conventional therapies such as sterile honey and maggots. The most effective treatment protocol for patient survival was the administration of broad-spectrum antibiotics along with emergency surgical debridement. With clinical training and early recognition, mortality can be reduced in patients with FG. Because the presentation of FG can sometimes be nonspecific and vague, it is important for future research to look for more definitive characteristics that can differentiate FG from similarly presenting conditions.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.