Prognostic factors for intraoperative detection of necrotizing fasciitis in severe soft tissue infections.

BACKGROUND: Necrotizing fasciitis (NF) is a rare but lethal soft-tissue infection. There is still a paucity of information regarding the diagnostic tools and therapeutic strategies for the treatment of this devastating disease. This study aims to identify important perioperative parameters related to necrotizing fasciitis and to assess their relevance in terms of identifying NF. METHODS AND MATERIAL: We retrospectively analyzed patients who underwent surgical exploration for suspected necrotizing fasciitis at a tertiary referral center, to explore the clinical features and factors related to the presence of necrotizing fasciitis and mortality. RESULTS: Between 2010 and 2017, 88 patients underwent surgical exploration for suspected NF. The infection occurred in the lower extremities in 48 patients, in the thoracocervical region in 18 patients, and the perineum and abdomen in 22 patients. Histological evidence of NF was present in 59 of 88 patients. NF was associated with a longer hospital stay and ICU stay (p = 0.05 and 0.019 respectively) compared to patients without NF. ROC analysis showed that only macroscopic fascial appearance could discriminate patients with histological evidence of NF. Moreover, multivariate logistic regression revealed, that liver failure (p = 0.019), sepsis (p = 0.011), positive Gram stain (p = 0.032), and macroscopic fascial appearance (p <0.001) were independent prognostic parameters for histological evidence of NF. CONCLUSION: Intraoperative tissue evaluation by an experienced surgeon is the most important diagnostic tool in identifying necrotizing fasciitis. An intraoperative Gram stain is an independent prognostic tool and therefore its use can be recommended especially in case of clinical uncertainty.

Sarcopenia Is Associated With Increased Mortality in Patients With Necrotizing Soft Tissue Infections.

INTRODUCTION: Necrotizing soft tissue infections (NSTIs) are surgical emergencies associated with high morbidity and mortality. Identifying risk factors for poor outcome is a critical part of preoperative decision-making and counseling. Sarcopenia, the loss of lean muscle mass, has been associated with an increased risk of mortality and can be measured using cross-sectional imaging. Our aim was to determine the impact of sarcopenia on mortality in patients with NSTI. We hypothesized that sarcopenia would be associated with an increased risk of mortality in patients with NSTI. METHODS: This is a retrospective cohort study of NSTI patients admitted from 1995 to 2015 to two academic institutions. Operative and pathology reports were reviewed to confirm the diagnosis in all cases. Average bilateral psoas muscle cross-sectional area at L4, normalized for height (Total Psoas Index [TPI]), was calculated using computed tomography (CT). Sarcopenia was defined as TPI in the lowest sex-specific quartile. Primary outcome was in-hospital mortality. Multivariate logistic regression was performed to assess the association between sarcopenia and in-hospital mortality. RESULTS: There were 115 patients with preoperative imaging, 61% male and a median age of 57 y interquartile range (IQR 46.6-67.0). Overall in-hospital mortality was 12.1%. There was no significant difference in sex, body mass index (BMI), comorbidities and American Society of Anesthesiologists classification (Table 1). After multivariate analysis, sarcopenia was independently associated with increased in-hospital mortality (Odds ratio, 3.5; 95% Confidence Interval [CI], 1.05-11.8). CONCLUSIONS: Sarcopenia is associated with increased risk of in-hospital mortality in patients with NSTIs. Sarcopenia identifies patients with higher likelihood of poor outcomes, which can possibly help surgeons in counseling their patients and families.

Soft tissue masses of the epitrochlear region.

The epitrochlear lymph nodes (ELN) are rarely examined clinically and are difficult to identify radiologically in healthy patients. They are, therefore, generally under appreciated as a source of significant pathology. Despite this, enlargement of an ELN is almost always secondary to a pathological process, the differential for which is relatively narrow. The following pictorial review illustrates the spectrum of infectious, inflammatory and malignant conditions affecting the ELN, some of which are quite specific to this location. We also emphasise the importance of distinguishing enlarged ELNs from benign and malignant non-nodal soft tissue masses, which can have very similar clinical presentation and imaging appearances.

A dose response model for Staphylococcus aureus.

Dose-response models (DRMs) are used to predict the probability of microbial infection when a person is exposed to a given number of pathogens. In this study, we propose a new DRM for Staphylococcus aureus (SA), which causes skin and soft-tissue infections. The current approach to SA dose-response is only partially mechanistic and assumes that individual bacteria do not interact with each other. Our proposed two-compartment (2C) model assumes that bacteria that have not adjusted to the host environment decay. After adjusting to the host, they exhibit logistic/cooperative growth, eventually causing disease. The transition between the adjusted and un-adjusted states is a stochastic process, which the 2C DRM explicitly models to predict response probabilities. By fitting the 2C model to SA pathogenesis data, we show that cooperation between individual SA bacteria is sufficient (and, within the scope of the 2C model, necessary) to characterize the dose-response. This is a departure from the classical single-hit theory of dose-response, where complete independence is assumed between individual pathogens. From a quantitative microbial risk assessment standpoint, the mechanistic basis of the 2C DRM enables transparent modeling of dose-response of antibiotic-resistant SA that has not been possible before. It also enables the modeling of scenarios having multiple/non-instantaneous exposures, with minimal assumptions.

The Skin-Sparing Debridement Technique in Necrotizing Soft-Tissue Infections: A Systematic Review.

BACKGROUND: Skin-sparing debridement (SSd) was introduced as an alternative to en bloc debridement (EBd) to decrease morbidity caused by scars in patients surviving Necrotizing soft-tissue infections (NSTI). An overview of potential advantages and disadvantages is needed. The aim of this review was to assess (1) whether SSd is noninferior to EBd regarding general outcomes, that is, mortality, length of stay (LOS), complications, and (2) if SSd does indeed result in decreased skin defects. METHODS: A systematic literature search was performed according to the PRISMA guidelines. All human studies describing patients treated with SSd were included, when at least of evidence level consecutive case series. Studies describing up to 20 patients were pooled to improve readability and prevent overemphasis of findings from single small studies. RESULTS: Ten studies, one cohort study and nine case series, all classified as poor based on Chambers criteria for case series, were included. Compared to patients treated with EBd, patients treated with SSd had no increased mortality rate, LOS or complication rate. SSd-treated patients had a high rate (75%) of total delayed primary closure (DPC) in the pooled case series. CONCLUSION: The current available evidence is of insufficient quality to conclude whether SSd is noninferior to EBd for all assessed outcomes. There are suggestions that SSd may result in a decreased need for skin transplants, which could potentially improve the (health related) quality of life in survivors. Experienced surgical teams could cautiously implement SSd under close monitoring, ideally with uniform outcome registry.

Hyperbaric oxygen treatment is associated with a decrease in cytokine levels in patients with necrotizing soft-tissue infection.

BACKGROUND: The pathophysiological understanding of the inflammatory response in necrotizing soft-tissue infection (NSTI) and its impact on clinical progression and outcomes are not resolved. Hyperbaric oxygen (HBO2 ) treatment serves as an adjunctive treatment; however, its immunomodulatory effects in the treatment of NSTI remains unknown. Accordingly, we evaluated fluctuations in inflammatory markers during courses of HBO2 treatment and assessed the overall inflammatory response during the first 3 days after admission. METHODS: In 242 patients with NSTI, we measured plasma TNF-α, IL-1ß, IL-6, IL-10, and granulocyte colony-stimulating factor (G-CSF) upon admission and daily for three days, and before/after HBO2 in the 209 patients recieving HBO2 . We assessed the severity of disease by Simplified Acute Physiology Score (SAPS) II, SOFA score, and blood lactate. RESULTS: In paired analyses, HBO2 treatment was associated with a decrease in IL-6 in patients with Group A-Streptococcus NSTI (first HBO2 treatment, median difference -29.5 pg/ml; second HBO2 treatment, median difference -7.6 pg/ml), and overall a decrease in G-CSF (first HBO2 treatment, median difference -22.5 pg/ml; 2- HBO2 treatment, median difference -20.4 pg/ml). Patients presenting with shock had significantly higher baseline cytokines values compared to non-shock patients (TNF-α: 51.9 vs. 23.6, IL-1ß: 1.39 vs 0.61, IL-6: 542.9 vs. 57.5, IL-10: 21.7 vs. 3.3 and G-CSF: 246.3 vs. 11.8 pg/ml; all p < 0.001). Longitudinal analyses demonstrated higher concentrations in septic shock patients and those receiving renal-replacement therapy. All cytokines were significantly correlated to SAPS II, SOFA score, and blood lactate. In adjusted analysis, high baseline G-CSF was associated with 30-day mortality (OR 2.83, 95% CI: 1.01-8.00, p = 0.047). CONCLUSION: In patients with NSTI, HBO2 treatment may induce immunomodulatory effects by decreasing plasma G-CSF and IL-6. High levels of inflammatory markers were associated with disease severity, whereas high baseline G-CSF was associated with increased 30-day mortality.

Analyzing Outcomes Among Older Adults With Necrotizing Soft-Tissue Infections in the United States.

BACKGROUND: Necrotizing soft-tissue infections (NSTIs) encompass a group of severe, life-threatening diseases with high morbidity and mortality. Evidence suggests advanced age is associated with worse outcomes. To date, no large data sets exist describing outcomes in older individuals, and risk factor identification is lacking. METHODS: Retrospective data were obtained from the 2015 Medicare 100% sample. Included in the analysis were those aged ≥65 y with a primary diagnosis of an NSTI (gas gangrene, necrotizing fasciitis, cutaneous gangrene, or Fournier's gangrene). Risk factors for in-hospital mortality and discharge disposition were examined. Continuous variables were assessed using central tendency, t-tests, and Wilcoxon rank-sum tests. Categorical variables were assessed using the chi-squared and Fisher's exact tests. Statistical significance was defined as P < 0.05. RESULTS: 1427 patient records were reviewed. 59% of patients were male, and the overall mean age was 75.4±8.6 y. 1385 (97.0%) patients required emergency surgery for their NSTI diagnosis. The overall mortality was 5.3%. Several underlying comorbidities were associated with higher rates of mortality including cancer (OR: 3.50, P = 0.0009), liver disease (OR: 2.97, P = 0.03), and kidney disease (OR: 2.15, P = 0.01). While associated with high in-hospital mortality, these diagnoses were not associated with a difference in the rate of discharge to home compared with skilled nursing or rehab. Overall, patients discharged to skilled nursing facilities or rehab had higher rates of underlying comorbidities than patients who were discharged home (3 or more comorbid illness 84.3% versus 68.6%, P < 0.0001); however, no individual comorbid illness was associated with discharge location. CONCLUSIONS: In our Medicare data set, we identified several medical comorbidities that are associated with increased rates of in-hospital mortality. Patients with underlying cancers had the highest odds of increased mortality. The effect on outcomes of the potentially immunosuppressive cancer treatments in these patients is unknown. These data suggest that patients with underlying illnesses, especially cancer, kidney disease, or liver disease have higher mortalities and are more likely to be discharged to skilled nursing facilities or rehab. It is unclear why these illnesses were associated with these worse outcomes while others including diabetes and heart disease were not. These data suggest that these particular comorbid illnesses may have special prognostic implications, although further analysis is necessary to identify the causative factors.

Getting it Right the First Time: Frozen Sections for Diagnosing Necrotizing Soft Tissue Infections.

BACKGROUND: The aim of this study was to investigate which histopathologic findings are most indicative for necrotizing soft tissue infections (NSTIs) in ambivalent cases. METHODS: Patients undergoing surgical exploration for suspected NSTIs with obtainment of incisional biopsies for histopathological assessment were included from January 2013 until August 2019. The frozen sections and formalin-fixed paraffin-embedded (FFPE) samples were retrospectively re-assessed. The primary outcome was the discharge diagnosis. RESULTS: Twenty-seven (69%) biopsies of the 39 included samples were from patients with NSTIs. Microscopic bullae (p = 0.043), severe fascial inflammation (p < 0.001) and fascial necrosis (p < 0.001) were significantly more often present in the NSTI group compared to the non-NSTI group. Muscle edema (n = 5), severe muscle inflammation (n = 5), muscle necrosis (n = 8), thrombosis (n = 10) and vasculitis (n = 5) were most frequently only seen in the NSTI group. In thirteen tissues samples, there were some discrepancies between the severity of findings in the frozen section and the FFPE samples. None of these discrepancies resulted in a different diagnosis or treatment strategy. CONCLUSION: Microscopic bullae, severe fascial or muscle inflammation, fascial or muscle necrosis, muscle edema, thrombosis and vasculitis upon histopathological evaluation all indicate a high probability of a NSTI. At our institution, diagnosing NSTIs is aided by using intra-operative frozen section as part of triple diagnostics in ambivalent cases. Based on the relation between histopathologic findings and final presence of NSTI, we recommend frozen section for diagnosing NSTIs in ambivalent cases.

Mycobacterium marinum: nodular hand lesions after a fishing expedition.

Mycobacterium marinum is a slow-growing, acid-fast bacillus in the category of non-tuberculous mycobacteria which most commonly cause skin and soft tissue infections in patients, particularly those with aquatic exposure. Classically, M. marinum skin and soft tissue infections clinically manifest with formation of nodular or sporotrichoid extremity lesions, or deeper space infections such as tenosynovitis and osteomyelitis. Disseminated disease may occur in immunocompromised hosts. M. marinum is a slow-growing organism that is challenging to culture, as it typically requires 5-14 days (yet may take up to several weeks) with low temperatures of approximately 30°C to yield growth. In terms of treatment, further data are needed to elucidate the optimal regimen and duration for M. marinum infections. Combination therapy with clarithromycin and ethambutol is recommended for treatment of skin and soft tissue infections, with addition of rifampicin for deeper space infections. Surgery may be needed in addition to medical management.

Association of Negative Pressure Wound Therapy and Dermatotraction for Management of Necrotizing Soft Tissue Infections: A Case Series.

INTRODUCTION: Soft tissue infections (STIs), which include infections of the skin, subcutaneous tissue, fascia, and muscle, encompass a wide variety of heterogeneous pathologies. Treatment of STIs is based on surgical debridement of the affected area. One such treatment, negative pressure wound therapy (NPWT), has improved the management of STIs. OBJECTIVE: The purpose of this study is to assess the safety and utility of NPWT in conjunction with dermatotraction in the early stage management of necrotizing STIs. MATERIALS AND METHODS: The authors report a retrospective series of 3 cases in which NPWT and dermatotraction (NPWT-D) were used in an attempt to manage necrotizing STI. The NPWT-D device combination was employed to approximate the edges of the wounds. The NPWT device was changed every 2 or 3 days, and dermatotraction tension was adjusted concurrently. RESULTS: The NPWT-D device changes ranged from 3 to 4 times for 2 of the 3 patients, as 1 patient passed away secondary to STIs and therefore did not receive complete treatment. The total treatment ranged from 8 to 10 days in the remaining 2 patients. In both cases, complete wound closure was achieved while avoiding skin grafts. After 5 days of therapy in the incomplete treatment case, the wound area was reduced by about half. CONCLUSIONS: Based on the experiences herein, NPWT-D may be a safe and useful alternative surgical treatment for the management of necrotizing STIs. In the present cases, NPWT-D improved and shortened the wound healing process, and it achieved a tertiary wound closure, thereby avoiding the need for skin grafts.

An unexpected host in a soft-tissue lesion of thigh.

Rhinosporidiosis is an enigmatic entity and poses a major health problem in the developing countries of South-East Asia. A soft friable polypoid nasal mass is the most common presentation, while sparse literature is available on extranasal involvement. We describe the case of a 35-year-old female patient who presented with a slow-growing soft-tissue swelling with ulceration over the thigh. On clinical and radiological examination, a provisional diagnosis of soft-tissue neoplasm was made. After resection, histopathological sections showed a closely packed cyst with innumerable endospores. The present case report documents the rare occurrence of an incidentally detected cutaneous rhinosporidiosis causing diagnostic difficulty.

The INFECT-Project: An International and Multidisciplinary Project on Necrotizing Soft Tissue Infections.

This book describes clinical and microbiologic aspects, pathogenesis, and diagnostics, related to the severe and rapidly spreading necrotizing soft tissue infections. The work has its foundation in a recently completed European Union funded FP7-project called INFECT, which during the period 2013-2018 focused on utilizing a systems medicine approach to increase our understanding of these heterogenous and complex life-threatening infections. In this chapter, the aim and scope as well as key achievements of the INFECT-project are described.

Necrotizing Soft Tissue Infections: Case Reports from the Patients Prospective.

All who have contributed in writing this chapter have been patients and parents that have experienced an horrific life event. The horrific disease named necrotising fasciitis has affected our lives for ever. All four stories have explained how easily an everyday infection can develop incredibly quickly into a life-threatening experience. Three stories are expressed from the worn hearts of being a mother, fighting for their child every step of the way. Knowing our children and how they react through pain and illness is felt in each word, sentence, paragraph and even between the lines. Dedicating our unmarkable love and devotion for the child we carried for 9 months. To see them suffer in illness is heart wrenching, but to experience this disease necrotising fasciitis is something else. We must live through every day watching them grow with their scars of debridement, and to support them through further operations, let alone mental scars. Parents show a strength of support like no other and we hope that their lives can be enhanced through the battle they have individually won let alone their family. Robert's story from a patient's perspective is quite different and you will read his courage throughout. We continue to raise awareness through education.

Necrotizing Soft Tissue Infections: Case Reports, from the Clinician's Perspectives.

Necrotizing soft tissue infections (NSTI) are rapidly spreading and life-threatening infections of skin and soft tissue. Essentially there are two types of NSTI, based on the invasive microorganisms. The speed of development and associated clinical features differ markedly depending on the bacterial etiology. Early recognition, extensive surgical debridement, and appropriate antimicrobials are pivotal for successful management. In this chapter, we present three cases from the INFECT-study population. This study was an international, multicenter, prospective cohort study of adult patients with NSTI. We describe the clinical presentations, pre-, peri-, and postoperative clinical findings, microbiology, and treatment in cases of monobacillary Streptococcus pyogenes necrotizing soft tissue infections NSTI, polymicrobial infection, and an unusual presentation of pelvic monobacillary S. pyogenes infection in an immunocompromised patient.

Necrotizing Soft-Tissue Infections: Clinical Features and Diagnostic Aspects.

The term necrotizing soft-tissue infection (NSTI) encompasses a heterogenous group of patients with necrotizing infections, involving any body part. NSTI is diagnosed by surgical exploration, where necrosis of the subcutaneous tissue and/or muscle tissue, undermining of the skin, thrombosis of the superficial veins, and deliquescent tissue can be seen. Patients can present with vague symptoms, and approximately half of patients experience severe pain. The clinical presentation and microbiological etiology vary according to affected body site, with NSTI located to the extremities being dominated by monomicrobial group A streptococcal infections, and NSTI located to the anogenital area dominated by polymicrobial infections. No set of diagnostic criteria exists, and suspicion of the diagnosis should come from careful clinical examination and signs of local or systemic severity. Laboratory blood values show no distinct pattern but resemble those of sepsis. Imaging can aid the diagnostic process but must not delay surgical intervention.

Treatment of Necrotizing Soft Tissue Infections: Antibiotics.

Necrotizing soft tissue infections (NSTIs) are severe, life-threatening infections, and early therapeutic intervention is essential. Prompt administration of potent antimicrobial agents is pivotal, but inadequate empirical therapy is unfortunately common. Optimization of the antibiotic treatment strategy in NSTIs requires consideration of local epidemiology of causative pathogens and antimicrobial resistance patterns, knowledge on common pathogenetic mechanisms in NSTIs, and adaptations to pharmacokinetic and pharmacodynamic physiological changes in critically ill patients. In the present article we address all these issues, as well as review and compare contemporary guidelines for antimicrobial treatment of NSTIs from around the world.

Treatment of Necrotizing Soft Tissue Infections: IVIG.

Immunoglobulins are key effector molecules in the humoral immune response. Intravenous polyspecific immunoglobulin (IVIG) is a preparation of polyclonal serum immunoglobulins, typically IgG, from thousands of donors. It has been used as adjunctive therapy in critically ill patients with severe infections, i.e. sepsis, septic shock, and necrotizing soft tissue infections. IVIG has been used for patients with severe invasive group A streptococcal infection since the early nineties and off-label use of IVIG for necrotizing soft tissue infections is common. It is also used for a variety of autoimmune, inflammatory, and immunodeficiency diseases. A meta-analysis of the clinical studies available for IVIG use in group A streptococcal toxic shock syndrome indicates a survival benefit. A blinded, placebo-controlled clinical trial (INSTINCT) assessed the effect of IVIG in 100 intensive care unit patients with necrotizing soft tissue infections, including all bacterial etiologies. The study did not demonstrate any effect on self-reported physical functioning at 6 months. In this chapter, we review the mechanisms of action of IVIG and the clinical studies that are available for necrotizing soft tissue infections as well as severe group A streptococcal infections.

Pathogenic Mechanisms of Streptococcal Necrotizing Soft Tissue Infections.

Necrotizing skin and soft tissue infections (NSTIs) are severe life-threatening and rapidly progressing infections. Beta-hemolytic streptococci, particularly S. pyogenes (group A streptococci (GAS)) but also S. dysgalactiae subsp. equisimilis (SDSE, most group G and C streptococcus), are the main causative agents of monomicrobial NSTIs and certain types, such as emm1 and emm3, are over-represented in NSTI cases. An arsenal of bacterial virulence factors contribute to disease pathogenesis, which is a complex and multifactorial process. In this chapter, we summarize data that have provided mechanistic and immuno-pathologic insight into host-pathogens interactions that contribute to tissue pathology in streptococcal NSTIs. The role of streptococcal surface associated and secreted factors contributing to the hyper-inflammatory state and immune evasion, bacterial load in the tissue and persistence strategies, including intracellular survival and biofilm formation, as well as strategies to mimic NSTIs in vitro are discussed.

Systems Biology and Biomarkers in Necrotizing Soft Tissue Infections.

In necrotizing soft tissue infection (NSTI) there is a need to identify biomarker sets that can be used for diagnosis and disease management. The INFECT study was designed to obtain such insights through the integration of patient data and results from different clinically relevant experimental models by use of systems biology approaches. This chapter describes the current state of biomarkers in NSTI and how biomarkers are categorized. We introduce the fundamentals of top-down systems biology approaches including analysis tools and we review the use of current methods and systems biology approaches to biomarker discover. Further, we discuss how different "omics" signatures (gene expression, protein, and metabolites) from NSTI patient samples can be used to identify key host and pathogen factors involved in the onset and development of infection, as well as exploring associations to disease outcomes.