Can The Systemic Immune-Inflammation Index (SII) and Charlson Comorbidity Index (CCI) be used to predict mortality in patients with necrotizing fasciitis?

PURPOSE: This study aimed to determine the impact of mortality and morbidity indices on the diagnosis and prognosis of patients suffering from necrotizing fasciitis. METHODS: A retrospective analysis was performed on 41 patients (26 females, 15 males) with necrotizing fasciitis (NF). The SII (Systemic Immune-Inflammation Index) was computed using the formula SII = (P × N)/L, where P, N, and L measure the counts of peripheral platelets, neutrophils, and lymphocytes, respectively. This study evaluated the clinicopathological characteristics and follow-up information to assess the comparative effectiveness of SII, CCI (Charlson Comorbidity Index), and LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) scores as mortality and morbidity indices for patients with NF. RESULTS: The optimal cut-off for SII was determined to be 455. The SII value in the group with mortality was significantly higher compared to the group without mortality (p < 0.05). The CCI value in the group with mortality was significantly higher than the group without mortality (p < 0.05). The SII and CCI values were found to be effective in distinguishing between patients who suffered mortality and those who did not. CONCLUSION: SII is a powerful tool for predicting mortality in patients with necrotizing fasciitis (NF). The SII index provides a novel, easily accessible, and inexpensive indicator for monitoring the progress and predicting the survival of patients with NF.

Yokenella regensburgei necrotizing fasciitis in an immunocompromised host.

We report a case of necrotizing skin infection caused by Yokenella regensburgei in an immunosuppressed patient with orthotopic liver transplantation. Initial bacterial culture identification was suggestive of Hafnia alvei. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) confirmed identification of Y. regensburgei. Necrotizing fasciitis is potentially fatal and requires aggressive management, including early diagnosis, appropriate antibiotic selection, and operative debridement.

Cyclic neutropenia with a novel gene mutation presenting with a necrotizing soft tissue infection and severe sepsis: case report.

BACKGROUND: Cyclic neutropenia is a rare disease. We report a 31-month-old girl with congenital cyclic neutropenia with a novel mutation in the ELANE gene who developed an acute necrotizing soft-tissue infection on her left axillary legion. CASE PRESENTATION: A 31-month-old girl was admitted to our pediatric emergency room because of a necrotizing soft tissue infection of the left axillary area. The infection progressed rapidly and resulted in septic shock. Despite a medical treatment and surgical debridement, the sepsis was not controlled, and severe inflammation developed. After applying of negative-pressure wound therapy, her clinical symptoms improved. Finally, she was diagnosed with cyclic neutropenia with a novel genetic mutation. One month after admission, she was discharged with a completely recovered wound and no need for skin grafting. CONCLUSION: Both adequate medical treatment and effective control of the source of infection are critically important to reduce morbidity in such complex cases of necrotizing fasciitis as appeared in an immunocompromised pediatric patient.

Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense.

Phylogenetically conserved serine protease cascades play an important role in invertebrate and vertebrate immunity. The mammalian coagulation system can be traced back some 400 million years and shares homology with ancestral serine proteinase cascades that are involved in, for example, Toll receptor signaling in insects and release of antimicrobial peptides during hemolymph clotting. In the present study, we show that the induction of coagulation by bacteria leads to immobilization and killing of Streptococcus pyogenes bacteria inside the clot. The entrapment is mediated via cross-linking of bacteria to fibrin fibers by the action of coagulation factor XIII (fXIII), an evolutionarily conserved transglutaminase. In a streptococcal skin infection model, fXIII(-/-) mice developed severe signs of pathologic inflammation at the local site of infection, and fXIII treatment of wild-type animals dampened bacterial dissemination during early infection. Bacterial killing and cross-linking to fibrin networks was also detected in tissue biopsies from patients with streptococcal necrotizing fasciitis, supporting the concept that coagulation is part of the early innate immune system.

Recruited macrophages control dissemination of group A Streptococcus from infected soft tissues.

Group A Streptococcus (GAS) causes diverse infections in humans, ranging from mild to life-threatening invasive diseases, such as necrotizing fasciitis (NF), a rapidly progressing deep tissue infection. Despite prompt treatments, NF remains a significant cause of morbidity and mortality, even in previously healthy individuals. The early recruitment of leukocytes is crucial to the outcome of NF; however, although the role of polymorphonuclear neutrophils (PMNs) in host defense against NF is well established, the role of recruited macrophages remains poorly defined. Using a cutaneous murine model mimicking human NF, we found that mice deficient in TNF-α were highly susceptible to s.c. infections with GAS, and a paucity of macrophages, but not PMNs, was demonstrated. To test whether the effects of TNF-α on the outcome of infection are mediated by macrophages/monocytes, we systemically depleted C57BL/6 mice of monocytes by pharmacological and genetic approaches. Systemic monocyte depletion substantially increased bacterial dissemination from soft tissues without affecting the number of recruited PMNs or altering the bacterial loads in soft tissues. Enhanced GAS dissemination could be reverted by either i.v. injection of monocytes or s.c. administration of peritoneal macrophages. These experiments demonstrated that recruited macrophages play a key role in defense against the extracellular pathogen GAS by limiting its spread from soft tissues.

A case of necrotising fasciitis caused by Serratia marsescens: extreme age as functional immunosuppression?

We report the case of a 97-year-old woman who had a prolonged hospital admission for the treatment of right-sided heart failure. During her stay she experienced a rapid deterioration, characterised by shortness of breath, cardiovascular compromise and a hot, red, swollen calf. Post-mortem examination demonstrated that this was caused by necrotising fasciitis due to Serratia marcescens as a single pathogen. This is only the second reported case of this condition in the absence of diabetes or immunosuppression, and clinical deterioration was much more rapid. The case underlines the importance of circumspection and regular review in the diagnosis of the elderly patient. It reminds us that these patients should be viewed as functionally immunosuppressed, and that some or all of the haematological markers of infection can be absent even in severe disease.

Decreased necrotizing fasciitis capacity caused by a single nucleotide mutation that alters a multiple gene virulence axis.

Single-nucleotide changes are the most common cause of natural genetic variation among members of the same species, but there is remarkably little information bearing on how they alter bacterial virulence. We recently discovered a single-nucleotide mutation in the group A Streptococcus genome that is epidemiologically associated with decreased human necrotizing fasciitis ("flesh-eating disease"). Working from this clinical observation, we find that wild-type mtsR function is required for group A Streptococcus to cause necrotizing fasciitis in mice and nonhuman primates. Expression microarray analysis revealed that mtsR inactivation results in overexpression of PrsA, a chaperonin involved in posttranslational maturation of SpeB, an extracellular cysteine protease. Isogenic mutant strains that overexpress prsA or lack speB had decreased secreted protease activity in vivo and recapitulated the necrotizing fasciitis-negative phenotype of the DeltamtsR mutant strain in mice and monkeys. mtsR inactivation results in increased PrsA expression, which in turn causes decreased SpeB secreted protease activity and reduced necrotizing fasciitis capacity. Thus, a naturally occurring single-nucleotide mutation dramatically alters virulence by dysregulating a multiple gene virulence axis. Our discovery has broad implications for the confluence of population genomics and molecular pathogenesis research.

Superantigens in dermatology.

Superantigens (SAgs) are virulent polypeptides that are produced by a variety of infectious organisms. They are capable of causing nonspecific T cell activation by circumventing normal antigen processing in the human host. The genetic makeup of the host plays a role in conferring susceptibility or protection against SAgs. They are linked to a variety of conditions, ranging from toxic shock syndrome to recurrent toxin-mediated perineal erythema. The early recognition of signs and symptoms of SAg-mediated illnesses is important to ensure prompt medical treatment.

Neutrophil-derived hyperresistinemia in severe acute streptococcal infections.

The concept of neutrophil activation and degranulation as important contributors to disease pathology in invasive group A streptococcal infections has recently been emphasized. This study focuses on two of the most severe streptococcal manifestations, toxic shock syndrome and necrotizing fasciitis, and the newly described proinflammatory molecule resistin, known to derive from adipocytes and monocytes. We demonstrate for the first time that these conditions are characterized by hyperresistinemia in circulation as well as at the local site of infection. Importantly, analyses of patient tissue biopsies and whole blood revealed that neutrophils represent a novel and dominant source of resistin in bacterial septic shock. This was confirmed by the identification of resistin within neutrophil azurophilic granules. In vitro assays using primary neutrophils showed that resistin release was readily triggered by streptococcal cell wall components and by the streptococcal M1 protein, but not by the potent streptococcal superantigens. This is the first report demonstrating that resistin is released from neutrophils in response to microbial stimuli, which adds resistin to the neutrophil granule proteins that are likely to contribute to the pathologic inflammatory responses associated with severe streptococcal infections.

An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections.

The role of host genetic factors in conferring predisposition or protection in infectious diseases has become evident. Infection with group A streptococci causes a wide spectrum of disease ranging from pharyngitis to streptococcal toxic shock syndrome. The release of inflammatory cytokines triggered by streptococcal superantigens has a pivotal role in invasive streptococcal disease. However, individuals infected with the same strain can develop very different manifestations. We report here that the immunogenetics of the host influence the outcome of invasive streptococcal infection, and demonstrate the underlying mechanism for these genetic associations. Specific human leukocyte antigen class II haplotypes conferred strong protection from severe systemic disease, whereas others increased the risk of severe disease. Patients with the DRB1*1501/DQB1*0602 haplotype mounted significantly reduced responses and were less likely to develop severe systemic disease (P < 0.0001). We propose that human leukocyte antigen class II allelic variation contributes to differences in severity of invasive streptococcal infections through their ability to regulate cytokine responses triggered by streptococcal superantigens.

The characteristics of oro-cervical necrotizing fasciitis-Comparison with severe cellulitis of oro-cervical region and necrotizing fasciitis of other body regions.

BACKGROUND: Necrotizing fasciitis (NF) is an acute and life-threatening soft-tissue infection however rarely seen in oro-cervical region. Therefore, the details of oro-cervical NF (OCNF) are not well known. The purpose of this study was to investigate the characteristics of OCNF by comparing it with severe cellulitis of oro-cervical region (OCSC) or NF of other body regions (e.g., limb, perineum, and trunk) (BNF), respectively. MATERIALS AND METHODS: At first, various risk factors for OCNF in oro-cervical severe infection (OCSI; composed of OCNF and OCSC), including neutrophil-to-lymphocyte ratio (NLR) and Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score, were investigated by univariate and multivariate analyses. Next, the differences between OCNF and BNF, including inflammatory markers and mortality, were investigated. RESULTS: In the present study, 14 out of 231 OCSI patients had OCNF. Multivariate analyses of OCSI patients showed that NLR ≥15.3 and LRINEC score ≥6 points were significantly related to OCNF. During the same period, 17 patients had BNF. The OCNF group had significantly higher inflammatory markers than the BNF group when diagnosis, but significantly lower clinical stages at the time and mortality as outcomes. CONCLUSION: We found that compared to BNF, OCNF can be detected at lower clinical stage by using indexes, such as NLR and LRINEC score, besides clinical findings, which may help contributing to patient's relief.

A Rare Presentation of Escherichia coli Necrotizing Fasciitis in Renal Transplantation.

Necrotizing fasciitis is a devastating, rapidly pro-gressive soft tissue infection. We present an unusual case of Escherichia coli necrotizing fasciitis following renal transplant. The patient was a 50-year-old woman previously on long-term hemodialysis who presented with left thigh erythema adjacent to the site of a central venous catheter 5 days after renal transplant. The classical features of necrotizing fasciitis were initially absent, and, despite aggressive resuscitation and debridement, she did not survive. Monomicrobial E. coli necrotizing fasciitis is rare, especially in this cohort of patients. Immunosuppression is a known risk factor for infection, and patients may present atypically. Shock and erythema may be the only clues to infection. Necrotizing fasciitis must be considered in acutely unwell renal transplant recipients so that immediate and life-saving surgical debridement can be delivered.

Complement Activation Is Associated With Mortality in Patients With Necrotizing Soft-Tissue Infections-A Prospective Observational Study.

Aim: We assessed whether different complement factors and complement activation products were associated with poor outcome in patients with necrotizing soft-tissue infection (NSTI). Methods: We conducted a prospective, observational study in an intensive care unit where treatment of NSTI is centralized at a national level. In 135 NSTI patients and 65 control patients, admission levels of MASP-1, MASP-2, MASP-3, C4, C3, complement activation products C4c, C3bc, and terminal complement complex (TCC) were assessed. Results: The 90-day mortality was 23%. In a Cox regression model adjusted for sex, and SAPS II, a higher than median MASP-1 (HR 0.378, CI 95% [0.164-0.872], p = 0.0226) and C4 (HR 0.162, 95% CI [0.060-0.438], p = 0.0003), C4c/C4 ratio (HR 2.290 95% CI [1.078-4.867], p = 0.0312), C3bc (HR 2.664 95% CI [1.195-5.938], p = 0.0166), and C3bc/C3 ratio (HR 4.041 95% CI [1.673-9.758], p = 0.0019) were associated with 90-day mortality, while MASP-2, C4c, C3, and TCC were not. C4 had the highest ROC-AUC (0.748, [95% CI 0.649-0.847]), which was comparable to the AUC for SOFA score (0.753, [95% CI 0.649-0.857]), and SAPS II (0.862 [95% CI 0.795-0.929]). Conclusion: In adjusted analyses, high admission levels of the C4c/C4 ratio, C3bc, and the C3bc/C3 ratio were significantly associated with a higher risk of death after 90 days while high admission levels of MASP-1 and C4 were associated with lower risk. In this cohort, these variables are better predictors of mortality in NSTI than C-reactive protein and Procalcitonin. C4's ability to predict mortality was comparable to the well-established scoring systems SAPS score II and SOFA on day 1.

Periocular necrotizing soft tissue infection in Greater Copenhagen.

PURPOSE: Necrotizing soft tissue infection, also known as necrotizing fasciitis (NF), is a fast-spreading life-threatening infection that most commonly affects the lower limbs, groin, or abdomen. Periocular necrotizing fasciitis (PNF) is rare. Limited data exist on PNF immune cell subset; hence, this study aims to determine the representation of immune cell subsets in patients diagnosed with PNF using immunohistochemical stainings. METHODS: All patients diagnosed with PNF at Copenhagen University Hospital from 2008 to 2018 were included. Their electronic medical records and pathology reports were assessed, and available tissue specimens were reviewed and stained with monoclonal antibodies for CD1a+ Langerhans' cells, CD3+ T lymphocytes, CD15+ granulocytes, CD44+ lymphohematopoietic cells, CD68+ histiocytes, CD79α+ B lymphocytes, and FXIIIa+ dendritic macrophages and Langerhans' cells. The number of positive cells was counted, and an average score was calculated. The location of immune cells and bacteria was assessed. RESULTS: The specimens were characterized by acute inflammation and necrosis of the fascia, while striated muscle involvement was less frequent. Haemolytic group A streptococci and Staphylococcus aureus were identified and mainly located in the deep dermis and subcutis in close relation to the fascia. Only few areas harboured both bacteria and inflammatory cells. Granulocytes, histiocytes and CD44+ lymphohematopoietic cells were demonstrated to be abundant in all patients, while B and T lymphocytes, dendritic macrophages and Langerhans' cells were less frequent. CONCLUSION: The immune cell subsets found in this study of PNF were consistent with those identified in the literature on NF in other anatomical locations. This study concludes that immune cells are abundant and exhibit a typical pattern in PNF.

Bacterial phenotype variants in group B streptococcal toxic shock syndrome.

We conducted genetic and functional analyses of isolates from a patient with group B streptococcal (GBS) necrotizing fasciitis and toxic shock syndrome. Tissue cultures simultaneously showed colonies with high hemolysis (HH) and low hemolysis (LH). Conversely, the HH and LH variants exhibited low capsule (LC) and high capsule (HC) expression, respectively. Molecular analysis demonstrated that the 2 GBS variants were of the same clonal origin. Genetic analysis found a 3-bp deletion in the covR gene of the HH/LC variant. Functionally, this isolate was associated with an increased growth rate in vitro and with higher interleukin-8 induction. However, in whole blood, opsonophagocytic and intracellular killing assays, the LH/HC phenotype demonstrated higher resistance to host phagocytic killing. In a murine model, LH/HC resulted in higher levels of bacteremia and increased host mortality rate. These findings demonstrate differences in GBS isolates of the same clonal origin but varying phenotypes.

DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps.

The innate immune response plays a crucial role in satisfactory host resolution of bacterial infection. In response to chemotactic signals, neutrophils are early responding cells that migrate in large numbers to sites of infection. The recent discovery of secreted neutrophil extracellular traps (NETs) composed of DNA and histones opened a novel dimension in our understanding of the microbial killing capacity of these specialized leukocytes. M1 serotype strains of the pathogen Group A Streptococcus (GAS) are associated with invasive infections including necrotizing fasciitis (NF) and express a potent DNase (Sda1). Here we apply a molecular genetic approach of allelic replacement mutagenesis, single gene complementation, and heterologous expression to demonstrate that DNase Sda1 is both necessary and sufficient to promote GAS neutrophil resistance and virulence in a murine model of NF. Live fluorescent microscopic cell imaging and histopathological analysis are used to establish for the first time a direct linkage between NET degradation and bacterial pathogenicity. Inhibition of GAS DNase activity with G-actin enhanced neutrophil clearance of the pathogen in vitro and reduced virulence in vivo. The results demonstrate a significant role for NETs in neutrophil-mediated innate immunity, and at the same time identify a novel therapeutic target against invasive GAS infection.

Group A Streptococcal DNase Sda1 Impairs Plasmacytoid Dendritic Cells' Type 1 Interferon Response.

Group A Streptococcus causes severe invasive infections, including necrotizing fasciitis. The expression of an array of virulence factors targeting specific host immune functions impedes successful bacterial clearance. The virulence factor streptococcal DNase Sda1 was previously shown to interfere with the entrapment of bacteria through neutrophil extracellular traps and TLR9 signaling. In this study, we showed that plasmacytoid dendritic cells are recruited to the infected tissue during group A streptococcal necrotizing fasciitis. We found that the streptococcal DNase Sda1 impairs plasmacytoid dendritic cell recruitment by reducing IFN-1 levels at the site of infection. We found that streptococcal DNase Sda1 interferes with stabilization of the DNA by the host molecule HMGB1 protein, which may account for decreased IFN-1 levels at the site of infection.

Increased surface toll-like receptor 2 expression in superantigen shock.

OBJECTIVE: Examination of the interaction between gram-positive bacterial superantigens and toll-like receptor 2 (TLR2) in health and critical illness. DESIGN: Laboratory ex vivo model and prospective clinical, cohort study. SETTING: Two research laboratories in university hospitals and two intensive care units. SUBJECTS/PATIENTS: Laboratory study was performed in transfected HeLa cells and primary human monocytes from healthy volunteers. Clinical study used cells from 20 healthy controls and 45 critically ill patients with circulatory shock. INTERVENTIONS: HeLa cells and purified monocytes were exposed to purified superantigens or isogenic bacterial supernatants and readout obtained by cytokine enzyme-linked immunosorbent assay, flow cytometry, and quantitative real-time polymerase chain reaction. Peripheral blood mononuclear cells from patients with circulatory shock were compared with controls using flow cytometry and measurement of cytokines after ligand exposure. MEASUREMENTS AND MAIN RESULTS: Superantigens were unable to signal through ligation by TLR2. However, TLR2 was up-regulated on the surface of primary human monocytes, without detectable TLR2 messenger RNA neosynthesis, by a range of superantigens and superantigen-containing Streptococcus pyogenes supernatants, although not by isogenic superantigen-negative strains. Superantigen mutant constructs with disrupted major histocompatibility complex class II-binding sites did not support TLR2 up-regulation. TLR2 up-regulation was associated with an increase in the proinflammatory response to TLR2 ligands only at high ligand concentrations. TLR2 was up-regulated in a small subset of patients with severe S. pyogenes sepsis but not in patients with any other category of septic or circulatory shock; responses to TLR2 ligands were reduced in all categories of critically ill patient, however. CONCLUSIONS: Superantigens up-regulate monocyte surface TLR2 expression through major histocompatibility complex class II signaling. Enhanced surface TLR2 expression may be a specific feature of patients with S. pyogenes-induced shock. Importantly, intensity of TLR2 signaling is not necessarily coupled to TLR2 expression when ligand concentrations are low or after onset of critical illness.

Atypical Presentation of Escherichia coli Monomicrobial Necrotizing Fasciitis in a Renal Transplant Patient: A Case Report.

Skin and soft tissue infections (SSTIs) are one of most frequent infectious causes for referral to the emergency department and one of the most frequent infectious causes of hospital admissions. Escherichia coli, the most commonly occurring gram-negative pathogen involved in these infections, contributes to about 7% of all SSTIs cases where gram-positive organisms reign dominant. Patients are more susceptible to these gram-negative SSTIs if they are neutropenic, have hematologic malignancies, have undergone solid organ or hematopoietic transplantation, or have cirrhotic liver disease. Due to their immunocompromised state, the prognosis is very poor and not well understood. We report a case of an atypical presentation of an E coli monomicrobial necrotizing fasciitis in a renal transplant patient. Our findings support improved mortality with rapid aggressive interventions, such as amputation, in immunocompromised patients.