A previously well 20 - year - old female presents to the ED with fevers. Questioning reveals a history of sore throat over the previous week, and ongoing right lateral thigh pain following a blow from a hockey stick during a weekend match. Pharyngeal examination reveals mild erythema only and examination of the right thigh reveals bruising, redness and soft tissue swelling but with no obvious skin breach. No other obvious focus of infection is apparent on systems review. She is treated with paracetamol and NSAIDs and discharged home.
Twelve hours later she represents with worsening thigh pain and exquisite tenderness, fever and hypotension. Plain XR of the thigh reveals no fracture, CXR and urinalysis are unremarkable and beta HCG testing is negative. She becomes increasingly shocked, receiving > 4L of intravenous fluid and intravenous opiates for pain.
What is your differential diagnosis?
A sensible list of differentials would have to include necrotising fasciitis. However, other possibilities mentioned may include:
- Retropharyngeal abscess
- Severe cellulitis
- Soft tissue abscess
- Idiosyncratic drug reaction to NSAIDs (eg. angioedema)
- Sepsis of another source
- Autoimmune myofasciitis (eg. lupus)
- Gangrene from ischaemic muscle
- Diabetic myoencrosis
- Necrotising pyoderma gangrenosum
- Viral illness with mylagia and rhabdomyolysis
The combination of pharyngitis, NSAID use and minor injury with severe pain is pathognomonic for necrotising fasciitis. If the exam candidate does not come up with it themselves, they get a prompt in the next question:
The ID physician thinks this is necrotising fasciitis.
Which historical features make this diagnosis more likely?
- Rapidly develping symptoms
- Reasonably young patients
- Previously healthy
- History of minor trauma, eg. scratch, bruise
- Initial injury is frequently trivial and blunt rather than penetrating
- Intense pain and tenderness over the involved skin and underlying muscle
- Pain is out of proportion to physical findings
- Risk factors may be apparent: diabetes, alcoholism, obesity, steroid use.
- Usually, the use of NSAIDs is reported (Aronoff et al, 2003)
What features on examination might you expect to find?
- At the earliest stages, necrotising facsiitis is indistinguishable from severe cellulitis.
- Severe pain on palpation is an early feature
- The affected tissue is oedematous and has a "wooden, hardened feel"
- Erythema is present early.
- Skin "blebs", i.e. bullae with clear fluid develop as skin ischaemia progresses, and these become haemorrhagic in a late presentation
- Crepitus on palpation is another late sign
- Decreased sensation of the overlying skin develops late in the course, and the skin may appear clearly gangrenous
Which blood tests would you like to order, and which findings would you expect?
- Acute renal failure
- Coagulopathy; DIC
- Raised inflammatory markers (WCC, CRP)
- Metabolic (lactic) acidosis
- Rapid antigen detection test for Group A Strep: this is mainly for pharyngitis (Gerber et al, 2004), but has been used to achieve a rapid diagnosis of lifethreatening GAS soft tissue infection (Ault et al, 1996)
Are there any specific tests to confirm your diagnosis?
- "Streptozyme" tests; which, according to a 2009 book chapter by Gould and Reeves are "generally not helpful except as paired acute and convalescent titres", which means the patient will be long dead if you wait for these to become diagnostic of necrotising fasciitis. Oh well, here is a list of them anyway, directly from Question 2 from the second paper of 2016
- Anti-streptolysin (ASO)
- Anti-hyaluronidase (AHase)
- Anti-streptokinase (ASKase)
- Anti-nicotinamide-adenine dinucleotidase (anti-NAD)
- Anti-DNAse B antibodies
- CT findings:
- Deep fascial thickening
- Contrast enhancement
- Fluid and gas in the soft tissue planes in and around the superficial fascia
- Ultrasound findings:
- Thickening and distortion of the deep fascia
- Fluid collections along the deep fascia
- MRI findings
- Deep fascial thickening
- Deep fascial fluid collections
- Hyperintense T2W signal within the muscles
The ID physician also suspects there is is toxic shock because of the "classical features". What are these classical features?
According to the CDC, there are four stereotypical criteria for toxic shock syndrome, all of which must be met:
- High fever (> 38.9°)
- Hypotension and shock
- Rash consistent with diffuse macular erythroderma
- Desquamation, particularly of the palms and soles
There are also non-diagnostic associated features:
- Rapid onset: ~ 2 days
- Multisystem organ involvement
- Streptococcus may grow in the blood (but blood cultures otherwise negative)
- Staphylococcus aureus is only rarely (5%) recovered from blood cultures in toxic shock, in contrast to Group A Streptococci which are typically easily cultured from the blood.
What is the pathophysiology of toxic shock syndrome?
Some staphylococci and some Group A streptococci produce a characteristic protein (the Toxic Shock Syndrome Toxin, or TSST-1, 2 and 3).
- TSST activates T-cells directly, acting as a "superantigen"
- Massive inflammatory cytokine release is the result
- Endothelial dysfunction and vasodilatory shock ensues, which is out of proportion to the severity of the initiating infection
What specific management strategies will you offer this patient?
- Source control is the most important thing
- Immediate debridement of the necrotic tissue if it is a streptococcal necrotising fasciitis.
- In fact, a delay in surgery of over 24 hours seems to increase the relative risk of mortality by 9.4 (i.e. the mortality is ten times greater if you wait another day).
- β-lactam antibiotics
- Clindamycin as an adjunct (prevents the synthesis of TSST)
- Intravenous immunoglobulin (to bind circulating TSST)
- IVIG also decreases in the production of proinflammatory cytokines and causes a downregulation of adhesion molecules and chemokines.
- Hyperbaric oxygen could be considered
What is the rationale for the use of clindamycin?
- Clindamycin is a bacteriostatic agent which inhibts bacterial protein synthesis
- The addition of clindamycin is well supported - particularly with Group A streptococci, where it inhibits the bacterial synthesis of endotoxin.
- A nice retrospective audit of necrotising fasciitis patients from Victoria (Australia) had revealed that patients who were treated with clindamycin, though on average sicker, were much more likely to survive (their mortality improved from 39% to 15%).
- Clindamycin also penetrates well into devitalised tissues and offers some anaerobic cover
What is the rationale and evidence for the use of immunoglobulin?
- IV immunoglobulin is a valid strategy in streptococcal toxic shock syndrome; though the investigators of the linked study didn't reach statistical significance in their primary endpoit (mortality), they did note a significant decrease in organ failure scores in the IVIG group.
- Encouraged by such evidence, people have also used polyspecific immunolgobulin to manage necrotising fasciitis, or to moderate its systemic effects, to be more precise. In actual fact, the abovelinked study features patients whose surgical management was conservative, and of whom the majority did have toxic shock syndrome anyway.
- The already-mentioned retrospective audit from Victoria had also suggested that people with severe soft tissue infections benefit from IVIg irrespective of whether they ahve toxic shock syndrome or not. The addition of polyspecific immunoglobulin to clindamycin reduced mortality from 15% to 7%, even though these patients were on average sicker, with more organ dysfunction.
The Oh's Manual chapter on severe soft tissue infections (Ch. 71, p. 736) brings up some interesting points about the use of IV immunoglobulin in toxic shock:
- All the evidence in support of this therapy comes from the same group of researchers
- The mortality benefit was a trend, and was non-significant
- The dose of IVIG varies;
- Some give a single dose of 2g/kg
- Others give 1g/kg and then 0.5g/kg for two more days
- The effect of the polyspecific IVIG might vary from bottle to bottle, as the immunoglobulin infusion is a pooled product, representing a mixture of immunoglobulins from the population. Populations might vary in their expression of anti-TSST antibodies. One might call this the "Soylent Green Effect" (flavour varies from person to person).