NF is likely to develop in immunocompromised patients with underlying medical conditions, such as alcohol abuse, malignancy, chronic cardiac and renal disease, intravenous drug usage, immunosuppressive therapy, and malnutrition [9]. Diabetes is a disorder that adversely affects the immune system, thus representing a common underlying disease in NF patients. In our series, the diabetic NF patients were significantly older than the nondiabetic patients at the onset of NF. Moreover, diabetic patients were significantly more likely than nondiabetic patients to exhibit a high blood level of glucose upon admission. Insulin therapy for glycaemic control at a target blood glucose level of 140 to 200 mg/dl has been suggested in critically ill patients [20]. Therefore, the high incidence of hyperglycaemia observed upon admission among diabetic NF patients warrants initiating monitor of blood glucose level and glycaemic control immediately after hospitalisation.
Traditionally, type 1 (polymicrobial) NF was the most common type of infection, emphasizing the synergetic effects of multiple pathogens [2, 3]. Analysis of the causative agents of NF revealed that significantly more diabetic patients exhibited polymicrobial infections than did nondiabetic patients, possibly reflecting the susceptibility of diabetic patients to multiple pathogens [21]. However, single organism infection accounted for the majority of NF (74 %) in this study, which is in line with the recent studies demonstrating a trend of increasing monomicrobial NF [8, 14, 22]. Among the monomicrobial NF cases, we observed significantly more K. pneumoniae-related infections in the DM group than in the non-DM group. We previously described K. pneumoniae as a common pathogen of monomicrobial NF in Taiwan, particularly in patients with underlying host immunocompromising conditions [8]. The present study further emphasized the importance of recognizing monomicrobial NF caused by K. pneumoniae as a common entity of NF in diabetic patients. Therefore, initial empirical antimicrobial agents for NF should be considered depending on the presence of underlying diabetes.
In our series, a non-significant difference in case fatality rate between diabetic and nondiabetic patients was observed. This is in line with the finding of previous studies that DM combined with other comorbidities was associated with an increased risk of death, but DM alone was not a risk factor for mortality [4, 17]. Also consistent with many previous studies, NF was most commonly involved in the lower limbs in this study [6, 8, 9]. Moreover, we found that significantly more diabetic patients than nondiabetic patients experienced limb loss during the treatment course. Diabetic patients are well known to be afflicted with foot problems caused by neuropathy and microvascular disease, which render limb preservation more difficult in the presence of a superimposed NF infection. Amputation typically requires less time than radical debridement of the necrotic soft tissue, and requires few, if any, reconstructive procedures [4]. Although major limb amputation deprives the amputee of motional dexterity and should be avoided whenever possible, NF is one of the few exceptions for which this extreme procedure should be considered to save lives [23].
Multiple patient- and treatment-related risk factors for NF-associated mortality have been described [24–27]. However, the identified risk factors among various studies exhibited some discrepancies. For example, some studies linked poor outcomes to delays in surgical management [6, 28], whereas other studies, similar to this one, found delayed surgical management did not significantly impact mortality [19, 27]. The discrepancies among different studies reflect the diversity of the populations included and the variables studied. In this study, we focused on factors that can be easily identified at the initial presentation of NF patients.
In all NF cases in this series, mortality was associated with a high level of serum potassium on admission. Electrolyte imbalance is a common clinical presentation of NF [6, 29], and Ogilvie et al. also showed an increased risk of mortality in NF patients with elevated potassium levels [30]. The elevated serum potassium level on admission may reflect acute renal impairment. Unfortunately, serum creatinine level was not collected in our database so the association between hyperkalemia and renal impairment could not be confirmed. Nonetheless, our finding still highlights the importance of the supportive care with fluid and electrolyte management in NF patients. Further subgroup analysis revealed that a positive blood culture upon admission was associated with mortality in diabetic NF patients. Bacteraemia frequently causes sepsis, which is the typical cause of death in NF patients. As virulent organisms and toxins are released into the bloodstream from severely infected soft tissue, a systemic toxic reaction is initiated, resulting in hypotension, disseminated intravascular coagulation, and eventually multiorgan failure.
The presence of SIRS upon admission was also identified as a mortality- associated factor in nondiabetic NF patients. Moreover, a completely independent functional status and the presence of pus at the infection site upon admission were associated with a more favourable chance of survival in the non-DM group. The functional status reflects the general physical condition of a person, thus an independent functional status can reasonably serves as a predictor of better outcome. However, the association between the presence of pus upon admission and a favourable outcome is intriguing. Similarly, a previous study identified the presence of hemorrhagic bullae on admission as an independent negative predictor of mortality in NF patients [22]. Diagnosis of NF at an early stage is often difficult and depends on a high index of suspicion because early cutaneous findings, including edema, erythema, and local anaesthesia, are typically nonspecific [6, 29]. Therefore, we speculated that obvious cutaneous manifestations, such as pus or bullae formation, at the infection sites may prompt surgical consultation, necessitating early diagnosis and immediate surgical intervention, which are crucial for the survival of NF patients.
The limitations of this study are attributable to the retrospective study design and possible inaccuracy of the information retrieved from the medical records or the possible misinterpretation of this information. However, we attempted to address these problems by setting clear definition for variables prior to data collection. We also excluded variables without sufficient data from further statistical analysis, such as arterial blood gas and serum albumin level. Moreover, not all of the factors related to NF prognosis, such as nutrition, surgical dexterity, and postoperative wound care, could be considered. To enhance our understanding of NF, a prospective registry for all NF patients confirmed according to surgery will be a valuable tool [9]. It may include standard recording of underlying diseases, presenting symptoms and signs, clinical photography, thorough laboratory data of blood samples, imaging and bacteriological studies, and treatment course.
