Evidence summary
The severity of NSTI was recognized as early as 500 BC by Hippocrates, who described numerous deaths from whole-body erysipelas incurred by a trivial injury.9 The incidence of NSTI varies considerably across the world from as low as 0.3 per 100 000 in Norway to 15.5 per 100 000 in Thailand.1 2 This can be partly explained by the difference in risk factors for NSTI across the globe which include heterogeneous groups such as large penetrating wounds, exposure of wounds to seawater, skin breaches from insect bites and childbirth and immunocompromised states.10
The clinical course typically observed in the USA is of a minor skin breech, allowing bacteria to gain entry resulting in a monomicrobial or polymicrobial infection.1 Ischemic tissues, such as in peripheral vascular disease, have a predilection for anaerobes, which drives the development of gas gangrene. Once bacteria burden increases and there is the release of exotoxins, various pathological effects can be noted. The aggregation of platelets and leukocytes damage endothelial integrity producing local edema. As swelling increases, ecchymoses and bullae appear, along with the progressive invasion of the infection into the deeper tissue layers. Thrombosis of larger vessels can occur, producing ischemic necrosis of all tissue layers.
The mortality following NSTI can be high, at 29%,4 11 which in the setting streptococcal infection with toxic shock syndrome or septic shock, increases to 38% and 45%, respectively.11 12 Optimal survival is dependent on early recognition and aggressive surgical debridement. The initial debridement is often extensive and generally patients require multiple OR trips for serial debridement. Large open wound can be managed by topical negative pressure dressings until subsequent plastic surgical reconstruction.
The timing of the initial surgery appears to be important, although this has not been studied comprehensively and there is no consensus on specific time goals beyond ‘as soon as possible’. This issue is partly confounded by a lack of standard timing definitions—does the clock start on suspicion of diagnosis, admission to hospital or onset of symptoms? Different studies apply different definitions.
A retrospective study of 65 patients from a single US center demonstrated that survivors (71%) of NSTI has shorter times (hours) to debridement compared with non-survivors (25 vs 90; P<0.001).4 More recently, the experience from New Zealand was reported in a 20-patient series, which reported an 8.3% survival rate following median time to debridement of 20 hours.5 The most recent assessment of time to debridement assessed 87 patients with NSTI, dichotomized into early (<6 hours) or late (≥6 hours) debridement. Although the early cohort (n=40) had a lower mortality of 7.5% compared with the late cohort (n=47) of 17%, it did not achieve statistical significance.6 The issue of timing remains poorly understood and there are many confounding factors such as time to antimicrobial therapy and fluid resuscitation; however, safe practice involves rapid access to surgery.
Despite these established management principles for NSTI, diagnosis remains difficult, both in terms of occult presentations and mimics.1 Fever can be absent due to the administration of antipyretic or infection with Clostridium sordellii, which is a rare necrotizing infection characterized by a persisting apyrexia. Severe pain from an NSTI may be erroneously ascribed to musculoskeletal strains or venous thrombosis, especially when the infection spontaneously originates from within deep compartments. Crucially, where the pain is out of proportion to the clinical findings, an astute clinician will consider NSTIs in their differential diagnosis.
Furthermore, several conditions can mimic the initial presentation of NSTI, clouding the diagnostic pathway. Severe candidiasis of the groin, cutaneous necrosis in calciphylaxis, stasis dermatitis and cellulitis can appear similar to NSTI. Important discriminators can be elucidated from the patient history such as comorbid conditions and concomitant medication use.
Efforts have been made to enhance diagnostic confidence with the use of laboratory indices; however, no single value has been found to reliable.13 The LRINEC score was developed to overcome these shortcomings by incorporating several weighted values.7 These investigators used data from 89 patients with a confirmed NSTI and 225 patients with non-NSTI cutaneous sepsis to develop a regression model of factors predictive of NSTI. Ultimately, they included WCC, hemoglobin, sodium, glucose creatinine and CRP level. Patients with a score higher than six are at high risk of NSTI, with the original authors presenting a positive predictive value (PPV) of 92.0%, negative predictive value (NPV) of 96.0% and area under the curve (AUC) of 0.976.
This score has been evaluated in several settings which has yielded a spread of predictive values ranging from a PPV of 57%–92% and an NPV of 86%–92%.14-16 This variation is likely reflective of the differing rates of NSTI in the studied cohorts which generally used a convenience sample of non-necrotizing infections. This scoring is not infallible and appears to work best where the clinical features are ambiguous and there is time to obtain laboratory investigations. A recent re-examination of this score suggested that the historical description of ‘pain out-of-proportion’ along with a CRP greater than 150 mg/L was comparable to the LRINEC score.17
Imaging is another diagnostic modality to consider. Plain films have been demonstrated to be of low sensitivity and specificity and should not be used in the diagnosis of NSTI but may be useful in certain patient groups such as intravenous drug users to identify foreign bodies. Cross-sectional imaging appears to have some promise. CT seems to be the most clinically available, with images that are rapidly acquired and interpretable by surgeons. The first reported series of 67 patients with NSTI who underwent CT scanning as part of their management concluded that CT was 100% sensitive and 81% specific.18 Those investigators concluded that CT could reliably exclude NSTI. The features specifically assessed were soft tissue asymmetry, muscle necrosis, gas and fluid collections.
The findings of this study were confirmed and extended by a group which examined a series of 305 patients undergoing CT imaging for NSTI assessment.8 Using these data, the authors synthesized a weighted scoring system based on the presence of fascial air, muscle/fascial edema, fluid tracking, lymphadenopathy and subcutaneous edema. A value greater than six or greater had a sensitivity of 86.3%, a specificity of 91.5% with an AUC of 0.928.
Although the presented evidence is compelling, most studies are collected retrospectively and the few studies with a control group generally rely on patients with non-NSTI, which can introduce significant heterogeneity. To address this issue, a large prospective observational study is currently underway in Northern Europe called the Immune Failure in Critical Therapy study.19 This project aims to recruit 400–500 patients collecting data on several diagnostic, treatment and outcome variables.
