Discussion
The first patient had NF and muscle necrosis of the adductor compartment of his thigh from the outset, but failure of the primary care center to realize the masked signs of NF led to the infection moving up to involve his upper trunk and arm. The delay in definitive management resulted in spread of infection with eventual sepsis and death. Case 2 was an immunocompromised patient who presented late. The inability of her body to mount an effective immune response resulted in rapid progression of NF with sepsis and septic shock despite urgent surgical and medical intervention.
Diagnosis of NF is a challenge to a clinician because it is a rare entity and there may be no obvious pointers favoring its diagnosis [
8]. Expected manifestations like skin necrosis are not always obvious, and care should be taken to search for suggestive local (severe spontaneous pain that is disproportional to the degree of inflammation, indurated edema, bullae, cyanosis, skin pallor, absence of lymphangitis, skin hypoesthesia, crepitation, muscle weakness) and systemic signs of ongoing sepsis [
2,
6]. Furthermore the classic bronze or reddish discoloration of skin due to clostridial infections may not be commonly visualized due to the already tanned skin complexion of Asians, although Case 2 demonstrated typical skin manifestations with bullae formation. In Case 1 the possible missed sign was the out of proportion pain with a sense of weakness and heaviness which are nonspecific presenting features of gas-forming NF [
9]. These were mistaken for a milder form of infection, cellulitis, with absence of superficial skin manifestations.
Risk factors include compromised integrity of skin or mucous membranes, diabetes, arteriopathy, alcoholism, obesity, immunosuppression, malnutrition, renal failure, and age > 60 years. Non-steroidal anti-inflammatory drugs have been suggested as possible risk factors for NF [
2,
6]. Both our patients had predisposing factors. The patient in Case 1 suffered multiple injuries secondary to his occupation as a laborer, but none were recent. However,
Clostridium spores may remain dormant for many years before germination and resultant NF [
10]. NF in SLE is uncommon [
11] and Kamran
et al. state that only 13 cases were reported up to 2008 [
12]. A dampened immune system due to immunosuppressive (azathioprine with prednisolone in our patient) therapy, the disease process per se [
12] or skin fragility secondary to prednisolone [
13] could be additional predisposing factors for patients with SLE to get NF.
Although any part of the body may be involved, the lower limbs are the most commonly affected sites for infection (28%) [
14]. The absence of fibrous attachments in the limbs and trunk lead to widespread infection and tissue destruction. Infection can also spread to venous and lymphatic channels with resultant edema and thrombosis of blood vessels which cause ischemia and gangrene of subcutaneous fat and dermis [
2]. The involvement of the trunk carries a poorer prognosis compared with the extremities in isolation [
15]. The rapidity at which the infection spread up the lower limbs in both our patients and the involvement of the trunk and upper limb in Case 1 can thus be explained.
Polymicrobial NF infections are poorly demonstrated on blood cultures which are found positive only in 20 to 27% [
3,
7] of patients. Neither of our patients’ blood cultures became positive. However, Case 1 had MRSA present on deep tissue culture. But the presence of gas in MRI suggested presence of an additional gas-forming organism, possibly a clostridial species. Although NF is commonly classified into type I and II, some extend the classification further and identify Gram negative or clostridial induced as type III and fungal-induced NF as type IV [
4,
5,
16]. Type III due to clostridial species with muscle involvement is also considered clostridial myonecrosis. Clostridial sepsis can be secondary to trauma due to penetrating injuries, underlying intestinal pathology or even occur spontaneously. The patient in Case 1 most probably had type III NF as gas was present with muscle necrosis. In Case 2 neither blood nor deep tissue culture yielded growth, in keeping with culture patterns observed in polymicrobial NF or it may also be due to the immunocompromised state which may result in atypical organisms causing NF in SLE, for example
Pseudomonas aeruginosa, and
Serratia marcescens[
17,
18].
Imaging aids diagnosis. X-rays can show gas, although only in a minority (13%) of cases, and show increased soft tissue thickness. Ultrasound can help identify fascial edema and gas and fluid collection, having a sensitivity of 88.2% and a higher specificity of 93.3%, although user limitations may affect interpretation. Contrast-enhanced computed tomography can reveal soft tissue air and fluid and abscess collection, but its use may be limited by concomitant renal failure. MRI has been found to have a sensitivity of 100% and specificity of 86%. It can demonstrate gas bubbles as signal voids, and identify fascial fluid secondary to necrosis and inflammatory edema because it causes variation in signal intensity. When not enhanced the severity may be overestimated due to its inability to differentiate affected tissue from that of non-affected, and underestimated when gadolinium enhanced because tissue hypoperfusion may limit uptake [
19‐
22]. Overall, MRI is considered the investigation of choice, but none of the imaging modalities should delay definitive surgical intervention [
23]. Case 1 demonstrated typical imaging changes on MRI with presence of gas with fascial and adjacent muscle compartment involvement as NSTI has been known to cross and involve neighboring tissue planes [
1].
A Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score of 6 or above (parameters made of total white cell count, hemoglobin, sodium, glucose, serum creatinine, and C-reactive protein) introduced by Wong
et al. in their retrospective analysis [
24] was found to be useful in detecting NF early. Although our patients’ ESR was elevated and available it is not included in the scoring system and, unfortunately, C-reactive protein is not available in the free health-care system offered in our country, thus limiting initial assessment using the LRINEC scoring system, but clinical sense should take precedence when other parameters are unavailable and when the LRINEC score contradicts diagnosis of NF on clinical grounds [
25].
Treatment is mainly surgical with relevant early radical debridement of devitalized tissue. Being too judicious and attempting to conserve tissue may in fact be detrimental in the long run as it has been shown to worsen mortality [
26]. In addition, supportive measures should be implemented with broad spectrum antibiotic treatment to target the spectrum of causative microorganisms (
Streptococcus pyogenes,
Staphylococcus aureus including MRSA, and Gram-negative aerobes and anaerobes) until cultures are available [
2]. Other novel treatment options and adjuncts have been tried and suggested, for example intravenous immunoglobulin to counteract systemic toxicity produced by beta-hemolytic Streptococci [
27] and hyperbaric oxygen as an effective adjunct in reducing morbidity and mortality [
28], although it remains disputed [
29]. Vacuum-assisted closing as a postsurgical adjunct to expedite healing [
30] also has been tried.
NF without treatment has a mortality of 100% [
2] but with medical and mainly surgical intervention it now has an overall mortality of 16 to 20% [
15,
31]. Type I NF was found to have a mortality of 21% by Wong
et al.[
7] but mortality in type III NF due to clostridial species can range from 25 to 80% [
32]. Female gender, presence of malignant disease, and diabetes mellitus were found to be independent factors associated with increased mortality in the idiopathic variants [
33]. However time plays the most significant role as a delay of no greater than 24 hours can literally double the mortality rate [
27]. The primary focus in the first patient was shifted to the intestinal obstruction which was due to two possible mechanisms. One was that he developed paralytic ileus, an observed complication of an abdominal abscess [
34] which could occur with infection tracking up to involve the psoas. The second possibility is of an occult intestinal malignancy, which is known to have an association with type III NF due to
Clostridium species [
35,
36], which in turn could track through fascial and muscle planes to involve the lower limb and upper trunk. However, since lower limb features were predominant in the absence of any abdominal involvement at the outset and the transient intestinal obstruction resolved, the former is more likely. The urgency of time in managing NF is reinforced as there is little doubt that mortality was due to failure in identifying and curtailing the disease in time in Case 1 and delay in seeking management in Case 2.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
AK, MRN, JY, and TK diagnosed the clinical scenario. MRN and AK researched and drafted the document. All authors provided care for the patient. All authors read and approved the final manuscript.