Article 1
Risk Factors and Predictors of Mortality in Streptococcal Necrotizing Soft-tissue Infections: A Multicenter Prospective Study. Bruun T, Rath E, Madsen MB, Oppegaard O, Nekludov M, Arnell P, Karlsson Y, Babbar A, Bergey F, Itzek A, Hyldegaard O, Norrby-Teglund A, Skrede S. Clin Infect Dis. 2021 Jan 27;72(2):293-300.
Necrotizing soft tissue infections (NSTI) are highly lethal and life-altering conditions commonly caused by polymicrobial infections. However, recent surveillance studies have noticed an emergence of invasive streptococcal infections, noticeably group A Streptococcus pyogenes (GAS), responsible for the onset of NSTI. In addition, an illness commonly encountered in individuals with pre-existing comorbidities, streptococcal NSTI, has been widely recognized to occur in healthy individuals of all ages without underlying comorbidities. However, despite these findings, there remains a paucity of data elaborating on the risk factors and predictors of mortality in streptococcal NSTI.
The INFECT study by Bruun and colleagues describes a multicenter, prospective observational cohort study aimed to further the understanding of the risk factors for the development of streptococcal NSTI and associated predictors of mortality. The study enrolled 409 adults admitted with NSTI to 5 clinical centers in Scandinavia. The exposure group of 152 individuals comprised of those cultured positive for GAS or Streptococcus dysgalactiae (SD) in blood or tissue samples obtained before or within 48 hours of diagnosis. To identify predisposing factors for NSTI, the comparison group consisted of serology or culture-positive non-necrotizing cellulitis cases with GAS or SD. Lastly, patients with streptococcal NSTI were compared to patients with polymicrobial, nonstreptococcal NSTI. The study found that more than a third of GAS cases had no underlying comorbidity. Over a half (57%) of streptococcal NSTI cases were without any precipitating event defined as surgery, trauma, wound, chronic skin disease, or intravenous
drug use. When compared to polymicrobial cases of NSTI, the rate of septic shock was more prominent in GAS 65% (82/126) versus 46% (77/166) (P = .001). The presence of bacteremia was more prevalent for GAS 56% (70/126) compared to polymicrobial cases 23% (38/166) (P < .005).
The INFECT study is the largest prospective cohort study for streptococcal NSTI to be conducted. The study provides a comprehensive profile of the unique clinical features, risk factors, and predictors of mortality for streptococcal NSTI. The data demonstrates the need for adequately powered prospective clinical trials focused solely on streptococcal NSTI management and intervention.
Article 2
Utility of modified Laboratory Risk Indicator for Necrotizing Fasciitis (MLRINEC) score in distinguishing necrotizing from non-necrotizing soft tissue infections. Wu PH, Wu KH, Hsiao CT, Wu SR, Chang CP. World J Emerg Surg. 2021 May 26;16(1):26.
Necrotizing soft tissue infections (NTSI) is a time-sensitive condition characterized by rapid tissue destruction with associated high morbidity and mortality; a delay in diagnosis and subsequent treatment is associated with worse outcomes. The clinical features of NSTI often overlap with nonnecrotizing soft tissue infections (non-NSTI), which may lead to a diagnostic dilemma early in the disease course, delaying timely and appropriate interventions. The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) risk stratification model, initially developed by Wong et al., is an adjunct to clinical assessment to facilitate early diagnosis and expedited management of NSTI. However, recent studies have questioned the performance and reliability of the LRINEC score in distinguishing early NSTI from non-NSTI. Therefore, the investigators of this study sought to evaluate the discriminating ability of a modified version of the LIRENIC score (MLRINEC) for NSTI from other skin and soft tissue infections.
The MLRINEC score developed by Wu and colleagues is based on the original LRINEC score with several modifications: 1.) the addition of serum lactate 2.) inclusion of liver disease 3.) redefining the cut-off values for CRP, total white blood cell count, and hemoglobin levels.
The article describes a retrospective cohort study of hospitalized patients with NSTI conducted in two tertiary hospitals in southern Taiwan between January 2015 and January 2020. A total of 101 cases were defined by surgical diagnosis of NSTI compared to propensity score-matched controls in a 1:2 ratio with non-necrotizing soft tissue infections. The study found all six original LRINEC score variables and serum lactate were significantly different between the NSTI and non-NSTI groups (all P < 0.05). The cut-off value for MLRINEC score was 12 points with a corresponding sensitivity of 91.8% and a specificity of 88.4%, and the area under ROC (AUC) was 0.893 (95% CI, 0.723 to 0.948; p < 0.01.
The study demonstrated the performance of a modified prediction model, the MLRINEC score, on distinguishing NSTI from other skin and soft tissue infections with overall high sensitivity and specificity. However, the study lacks external validity; therefore, further confirmatory studies are needed to establish the validity of the MLRINEC model.
Article 3
A Novel Immune Modulator for Patients With Necrotizing Soft Tissue Infections (NSTI): Results of a Multicenter, Phase 3 Randomized Controlled Trial of Reltecimod (AB 103). Bulger EM, May AK, Robinson BRH, Evans DC, Henry S, Green JM, Toschlog E, Sperry JL, Fagenholz P, Martin ND, Dankner WM, Maislin G, Wilfret D, Bernard AC. Ann Surg. 2020 Sep 1;272(3):469-478.
The treatment of necrotizing soft tissue infections has not advanced beyond surgical debridement and antibiotics in decades. With improved surgical care, mortality for NSTIs has decreased but there remains opportunity for new therapies. This impactful, new study from Dr. Eileen Bulger and colleagues reports the findings of a phase 3 multicenter, prospective randomized, placebo-controlled trial of a synthetic peptide, reltecimod, shown in previous work to modulate the immune response in bacterial infection. Reltecimod works by blocking bacterial antigen binding to CD28 and endotoxin activation of T lymphocytes thus inhibiting the Th1 cytokine induction that is proposed to mediate early organ dysfunction in NSTI.
The ACCUTE study enrolled patients > 12-years-old with NSTI across 93 centers in the US and Europe over a 4-year period. The study required attending surgeon diagnosis of NSTI and plans for operative debridement. Over 7000 patients were screened and 290 were ultimately enrolled, randomized (1:1) and received the intervention. The control group of 148 individuals received placebo and the experimental group of 142 patients received Reltecimod within 6 hours of diagnosis of NSTI. The primary outcome of this trial was improvement in the validated endpoint NICCE (necrotizing infection clinical composite endpoint) which incorporates 28-day mortality, number of debridement's, and resolution of organ dysfunction amongst others. The results of this ambitious study demonstrated no difference in mortality between the control and experimental groups with an overall mortality of 15% in the study population consistent with previous reports. There was no improvement in NICCE organ dysfunction in the modified, intent to treat analysis, however there was a significant improvement in NICCE for patient receiving Reltecimod in the per protocol analysis. Resolution or improvement in organ dysfunction was improved with Reltecimod administration.
The ACCUTE study is the largest, randomized controlled trial of necrotizing soft tissue infections and one of the first to report clinical use of the immune modulator Reltecimod for organ dysfunction in severe NSTI. Based in part on the results of the ACCUTE study, Reltecimod is pending Food and Drug Administration approval for use in NSTI.
Article 4
Necrotizing Soft Tissue Infection: Time is Crucial, and the Admitting Service Matters. Kongkaewpaisan N, Hwabejire J, Lee JM, Narueponjirakul N, Meier K, Mendoza A, Saillant N, Rosenthal M, King D, Fagenholz P, Velmahos G, Kaafarani HMA. Surg Infect (Larchmt). 2020 Dec;21(10):828-833.
Necrotizing soft tissue infections can present a diagnostic quandary as the presenting signs and symptoms can be subtle and overlap with non-surgical diagnoses such as cellulitis that do not require surgical intervention. Misdiagnosis or delays in diagnosis of NSTI can result in poor patient outcomes. This study by Kongkaewpaisan and colleagues investigated the impact of the admitting hospital service on delays to definitive treatment and mortality in NSTI. This was a retrospective cohort study of patients with NSTI at a single institution over a 12-year period. The authors identified 91 NSTI patients in the study population and grouped NSTI patients into 2 cohorts: those admitted to the Acute Care Surgery (ACS) service (n=71) and those admitted to a non-ACS service (n=21). The two groups were demographically similar apart from non-ACS service admitted patients being less likely to have erythema and more likely to have HIV. The median time to operative debridement of the entire cohort was 4.6 hours with the non-ACS patients having a significantly longer time to debridement of 24.8 hours. Overall mortality in the study population was 9.9% with 94% of the non-ACS NSTI cohort classified as having a delay in treatment resulting in a 20% mortality rate. The ACS cohort had a mortality of 7%, though this was not statistically significant due to low numbers of death overall. Admission to non-ACS service resulted in a significant delay in surgical treatment on multivariate analysis. This study reinforces previous literature showing time to definitive surgical debridement is paramount in the treatment of NSTI. Admission to a non-ACS service resulted in significantly delayed surgical intervention contributing to a trend towards increased mortality. Atypical presentation of NSTI with lack of erythema increased the risk of admission to non-ACS service. A high index of suspicion must be maintained for NSTI and prompt evaluation by surgeons experienced with necrotizing soft tissue infections is crucial to improving outcomes.
