If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Department of Zoology, Science College, King Saud University, Riyadh 11451, Saudi ArabiaPharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
To provide better management of Fournier’s gangrene, mortality-associated comorbidities and common etiologies were identified.
Methods
A systematic search was conducted using 12 databases, followed by meticulous screening to select relevant articles. Meta-analysis and meta-regression (for possible cofounders) were both done for all possible outcomes.
Results
Out of 1186 reports screened, 38 studies were finally included in the systematic review and meta-analysis. A higher risk of mortality was detected in patients with diabetes, heart disease, renal failure, and kidney disease, with risk ratios (RR) and 95% confidence intervals (95% CI) of 0.72 (0.59–0.89), 0.39 (0.24–0.62), 0.41 (0.27–0.63), and 0.34 (95% CI 0.16–0.73), respectively. However, there was no association between mortality rates and comorbid hypertension, lung disease, liver disease, or malignant disease (p > 0.05). The highest mortality rates were due to sepsis (76%) and multiple organ failure (66%), followed by respiratory (19.4%), renal (18%), cardiovascular (15.7%), and hepatic (5%) mortality.
Conclusions
Modifications to the Fournier’s Gangrene Severity Index (FGSI) are recommended, in order to include comorbidities as an important prognostic tool for FG mortality. Close monitoring of the patients, with special interest given to the main causes of mortality, is an essential element of the management process.
). In addition, many predisposing and etiopathogenic conditions such as immunodeficiency, diabetes, and alcoholism can participate in creating a favorable micro-environment that promotes the spread of the infection (
FG usually arises from an initial infection nidus in the genitourinary tract, which can extend rapidly, and sometimes in a fulminant fashion, causing multiple organ dysfunction, septic shock, and death (
). The most commonly isolated microorganisms are those normally found in the perineum and genital organs, including Escherichia coli, Klebsiella pneumonia, Bacteroides fragilis, and Staphylococcus aureus (
). Furthermore, laboratory investigations can be used to assess the risk of developing FG using the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score (
The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections.
). However, this score has shown a limited sensitivity when used in an emergency setting. Moreover, the Fournier’s Gangrene Severity Index (FGSI) has been developed to stratify the risks in FG patients and to predict mortality (
). Surgical debridement represents a potential therapeutic option for FG management: Carvalho et al. reported that aggressive debridement resulted in a remarkable reduction in FG mortality of up to 16% (
). Furthermore, inactivation of the common pathogens isolated from FG patients, such as S. aureus, has been noticed following the application of in vitro photodynamic inactivation associated with methylene blue (
Comorbidities play an important role in determining the survival of FG patients. Tenório et al. indicated that diabetes, but not hypertension, was significantly associated with non-survivors when compared to survivors (
). This review was performed in order to establish better management protocols for FG treatment. The association between comorbid risk factors and mortality was investigated. Moreover, the most common etiologies responsible for FG mortality were also assessed.
Methods
Search strategy and study selection
The study process was conducted following the accepted methodology recommendations of the PRISMA checklist for systematic reviews and meta-analyses, where registration of the protocol is not mandated (Supplementary material Table S1) (
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
). A systematic electronic database search was conducted to identify suitable studies. Twelve databases were searched from inception until July 10, 2018: Google Scholar, POPLINE, WHO Health Library (GHL), System for Information on Grey Literature in Europe (SIGLE), Scopus, Web of Science (ISI), PubMed, Virtual Health Library (VHL), ClinicalTrials.gov, metaRegister of Controlled Trials (mRCT), The WHO International Clinical Trials Registry Platform (ICTRP), and the Cumulative Index to Nursing and Allied Health Literature (CINHAL). The following search term was used: (Fournier’s gangrene OR Fournier’s putrefaction OR Gangrene of the perineum) AND (mortality OR survival OR death OR deaths). A manual search of references from included articles and a search of the references in articles that had cited our papers in PubMed and Google Scholar were performed to avoid missing any relevant publication, which could lead to a bias in the selection of papers (
All relevant original publications reporting comorbid risk factors for mortality and etiologies of mortality among FG patients were included. There were no restrictions on study design, country, language, or publication date. Papers were excluded if they met one of the following exclusion criteria: (1) in vitro or animal study; (2) data duplication, data overlapping, or unreliably extracted or incomplete data; (3) abstract only article, review, thesis, book, conference paper, or article without available full text (conference, editorial, author response, letter, and comments), along with any previous systematic review, meta-analysis, or literature review on the topic of interest. Title and abstract screening were performed by at least three independent reviewers to select relevant papers. Eligible articles were further screened for inclusion in the systematic review and meta-analysis. Any disagreement was resolved by discussion and by consulting the senior member when necessary.
Data extraction
The data extraction form was developed by two authors, using a Microsoft Excel file. Three reviewers independently extracted data from the included studies using the Excel sheet. Data were rechecked by at least three independent reviewers and a fourth reviewer when necessary to ensure the accuracy of the extracted data. All disagreements and discrepancies were resolved by discussion and consultation with a senior member when necessary. Papers published by the same research group and studying the same factors were checked for potential duplicate data based on the year of patient recruitment and the hospital where the patients were recruited, and by confirmation from the study authors.
Quality assessment
Three independent reviewers evaluated the risk of bias in included studies. The methodological quality assessment was done using the National Institutes of Health (NIH) quality assessment tool (
). The quality of each study was obtained through a scoring system including 14 questions, with the following interpretation: a score of 13–14 was defined as good quality and a score of 9–12 as fair; studies scoring below 9 were considered of poor quality for cohort studies (
). Any discrepancy between the reviewers was resolved by consensus.
Statistical analysis
Meta-analysis was performed using Comprehensive Meta-analysis software version 3 when there was more than one study. The comorbidity data were pooled from each study and the risk ratio (RR) and 95% confidence interval (CI) were used to determine risk factors for mortality. To determine the most frequent cause of death, we pooled each specified cause of mortality divided by the number of mortalities in each study to calculate the event rate (ER) and the corresponding 95% CI. Model selection (random or fixed) was chosen based upon the Mantel–Haenszel method (
). The Q statistic and I2 test were used to determine heterogeneity between the pooled studies. The random-effects model was adopted when there was no evidence of heterogeneity; otherwise, the fixed-effects model was used (
). The statistical significance of publication bias was considered at a p-value < 0.1 (two-tailed test). Furthermore, meta-regression analyses were performed to verify the dependency of the outcome measure on publication year, sample size, and male prevalence.
Results
Study selection and characteristics
The literature search yielded 1186 reports after removing duplicates using endnote software. Out of these, 272 papers were eligible for full-text screening against the inclusion and exclusion criteria and 28 studies were subsequently included. An additional 10 studies were added from the manual search trials. Finally, 38 studies were included for systematic review and meta-analysis, with a total sample size of 1990, ranging from 9 to 110 patients per study (Figure 1, Supplementary material Table S2). There were 31 retrospective cohort studies, three prospective cohort studies, three case series studies, and one cross-sectional study. In terms of risk of bias, all studies obtained a ‘fair’ criterion.
Figure 1PRISMA flow diagram showing the process of the review.
Significantly higher mortality rates were detected in patients with diabetes (RR 0.72, 95% CI 0.59–0.89; p < 0.01), heart disease (RR 0.39, 95% CI 0.24–0.62; p < 0.01), renal failure (RR 0.41, 95% CI 0.27–0.63; p < 0.01), and kidney disease (RR 0.34, 95% CI 0.16–0.73; p = 0.006) (Table 1, Figure 2, Figure 3, Figure 4, Figure 5). However, there was no association between mortality rates and comorbid hypertension (RR 0.92, 95% CI 0.69–1.24; p = 0.59), lung disease (RR 0.60, 95% CI 0.29–1.22; p = 0.16), liver disease (RR 0.51, 95% CI 0.25–1.03; p = 0.06), or malignant disease (RR 0.54, 95% CI 0.25–1.16; p = 0.12) (Supplementary material Figures S1–S4). No publication bias was found in diabetes outcome (p = 0.25) (Supplementary material Figures S5 and S6). Furthermore, meta-regression was performed and the results showed no effect of sample size (p = 0.69). In contrast, publication year was a significant moderator of the diabetes results (p = 0.006) (Supplementary material Figures S7 and S8).
Table 1Meta-analysis of comorbid risk factors and Fournier’s gangrene mortality.
Figure 2Forest plot showing the association between survival status and diabetes, represented by the pooled risk ratio (RR) and 95% confidence interval (CI).
Figure 3Forest plot showing the association between survival status and heart disease, represented by the pooled risk ratio (RR) and 95% confidence interval (CI).
Figure 4Forest plot showing the association between survival status and renal failure, represented by the pooled risk ratio (RR) and 95% confidence interval (CI).
Figure 5Forest plot showing the association between survival status and kidney disease, represented by the pooled risk ratio (RR) and 95% confidence interval (CI).
There were 249 deaths in 28 reports. The most frequent cause of death was sepsis, revealing a prevalence of 76% (95% CI 63–86%), followed by multiple organ failure 66% (95% CI 37–87%), with significant heterogeneity (p = 0.01 and p = 0.002, respectively) (Table 2). This was followed by respiratory, renal, cardiovascular, and hepatic mortality assuming a prevalence of 19.4% (95% CI 12–29%), 18% (95% CI 10–30%), 15.7% (95% CI 9–25%), and 5% (95% CI 1–17%), respectively (Figure 2). Publication bias was assessed and the results showed evidence of publication bias in sepsis (p = 0.001). However, after adjustment of the sepsis results using the trim and fill method, the pooled ER decreased to 55% (95% CI 38–71%) (Supplementary material Figures S9 and S10). Furthermore, meta-regression showed no effect of publication year or sample size on sepsis results (p = 0.15 and p = 0.55, respectively) (Supplementary material Figures S11 and S12).
). Many conditions are linked to its occurrence, including diabetes, alcoholism, acquired immunodeficiency, trauma, genitourinary infections, and immunosuppression (
Evaluation of the utility of the Fournier’s gangrene severity index in the management of Fournier’s gangrene in North India: a multicentre retrospective study.
This study showed that mortality from FG is associated with diabetes, heart disease, renal failure, and kidney disease. It is well known that many systemic diseases, such as diabetes and cardiovascular diseases, can affect the microvasculature of many tissues and organs (
). Furthermore, hyperglycemia can affect white blood cell adherence, chemotaxis, and bactericidal potential. It is also associated with reduced cellular immunity (
UK Renal Registry 17th Annual Report: Chapter 12 Epidemiology of Reported Infections amongst Patients Receiving Dialysis for Established Renal Failure in England in 2012 to 2013: a Joint Report from Public Health England and the UK Renal Registry.
Prognostic aspects, survival rate, and predisposing risk factors in patients with Fournier’s gangrene and necrotizing soft tissue infections: evaluation of clinical outcome of 55 patients.
). More specifically, chronic cardiac insufficiency, congestive heart failure, and coronary heart disease have been reported as significant mortality indicators in FG patients (
Prognostic aspects, survival rate, and predisposing risk factors in patients with Fournier’s gangrene and necrotizing soft tissue infections: evaluation of clinical outcome of 55 patients.
Prognostic aspects, survival rate, and predisposing risk factors in patients with Fournier’s gangrene and necrotizing soft tissue infections: evaluation of clinical outcome of 55 patients.
Furthermore, in the present study, the most frequent cause of death was sepsis, followed by multiple organ failure. This may be due to the nature of the disease, since different species of aerobic and anaerobic organisms can contribute to the infection in FG. They can act either directly and disseminate to the circulatory system or indirectly through their toxins, resulting in systemic toxicity and in organ hypoperfusion, which is associated with multiple organ failure (
). However, FG cases with methicillin-resistant S. aureus (MRSA) and other multidrug-resistant organisms are increasing and can be a source of higher death rates (
). In the face of these obstacles, it has been suggested that therapeutic plasma exchange can improve organ function and reduce mortality by decreasing circulating inflammatory mediators in the blood (
), and surgical debridement remains the key element in the management of FG.
Conclusions
This study suggests that comorbidities can be used as a determinant prognostic tool to predict FG mortality. We recommend modifications to the FGSI criteria, to include comorbidities as a potential element affecting survival rates.
Limitations
Significant heterogeneity was found. This can be explained by the differences in the populations included. Furthermore, the retrospective nature of the included studies is another limitation that makes selection bias unavoidable.
Funding
This research was funded by the Deanship of Scientific Research at Princess Nourah Bint Abdulrahman Universitythrough the Fast-track Research Funding Program.
Ethical approval
Not required.
Conflict of interest
The authors declare that they have no conflict of interest.
Authors’ contributions
AEE was responsible for the idea and study design under the supervision of SG and MMA. All authors determined the inclusion and exclusion criteria. AEE analyzed the data and interpreted it under the supervision of SG and MMA. All authors wrote the manuscript and approved the final version.
Acknowledgements
This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-track Research Funding Program.
Appendix A. Supplementary data
The following is Supplementary data to this article:
Quality assessment tool for observational cohort and cross-sectional studies.
National Heart, Lung, and Blood Institute,
2014 (Avaliable from: www.nhlbinihgov/health-pro/guidelines/indevelop/cardiovascular-risk-reduction/tools/cohort. [Accessed 5 November 2015])
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
Prognostic aspects, survival rate, and predisposing risk factors in patients with Fournier’s gangrene and necrotizing soft tissue infections: evaluation of clinical outcome of 55 patients.
UK Renal Registry 17th Annual Report: Chapter 12 Epidemiology of Reported Infections amongst Patients Receiving Dialysis for Established Renal Failure in England in 2012 to 2013: a Joint Report from Public Health England and the UK Renal Registry.
Evaluation of the utility of the Fournier’s gangrene severity index in the management of Fournier’s gangrene in North India: a multicentre retrospective study.
The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections.
30503-X&id=gr1.jpg){kind=link}
30503-X&id=gr2.jpg){kind=link}
30503-X&id=gr3.jpg){kind=link}
30503-X&id=gr4.jpg){kind=link}
30503-X&id=gr5.jpg){kind=link}